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Mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor: new endoplasmic reticulum stress response proteins Hao Liu, Xiaolei Tang, Lei Gong
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Received date: 7 June 2014 Revised date: 9 December 2014 Accepted date: 7 January 2015 Cite this article as: Hao Liu, Xiaolei Tang, Lei Gong, Mesencephalic astrocytederived neurotrophic factor and cerebral dopamine neurotrophic factor: new endoplasmic reticulum stress response proteins, European Journal of Pharmacology, http://dx.doi.org/10.1016/j.ejphar.2015.01.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor: new endoplasmic reticulum stress response proteins Hao Liua, Xiaolei Tangb, Lei Gonga*
a
Yuhuangding Hospital, Yantai, Shandong Province, PR China
b
Taishan Medical College, Taian, Shandong Province, PR China
*Corresponding author. Tel.: E-mail
+86 535 6691999
address: [email protected] (L. Gong).
Full post address: Biochip laboratory of Yuhuangding Hospital, Yantai, Shandong Province, PR China Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are a novel evolutionary conserved neurotrophic factor (NTF) family. There are two distinct domains in MANF and CDNF 3-dimentional structure, N-terminal saposin-like domain and C-terminal SAP-domain, which suggest their unique mode of action. Although identified for their neurotrophic activity, recent studies have shown MANF and CDNF can protect cells during endoplasmic reticulum (ER) stress. This review summarizes the unique structure and related potential protective role for cells during ER stress of MANF and CDNF. Key words: MANF, CDNF, ER stress, NTF
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1. Introduction Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) form a novel evolutionary conserved neurotrophic factor (NTF) family in the vertebrates. MANF together with CDNF can efficiently protect and repaire midbrain dopaminergic neurons in animal models of Parkinson’s disease (PD) and protect cardiac myocytes in myocardial infarction and cortical neurons against ischemic stroke (Airavaara et al., 2009; Apostolou et al., 2008; Glembotski et al., 2012; Hellman et al., 2011; Lindholm et al., 2008; Lindholm et al., 2007; Voutilainen et al., 2009). While in the invertebrates, including Drosophila and Caenorhabditis, there is a single protein homologous to vertebrate MANF and CDNF (Lindholm and Saarma, 2010). Recently, MANF has been found to regulate the development of dopaminergic neurons in Drosophila and zebra fishes . In Drosophila, DmMANF, homologous to mammalian MANF and CDNF, is expressed in glia and essential for maintenance of dopamine positive neurites and dopamine levels. The abolishment of DmMANF leads to the degeneration and nonapoptotic cell death of axonal bundles in the embryonic central nervous system (Palgi et al., 2009), increased expression of several genes involved in endoplasmic reticulum (ER) stress and increased eIF2Į phosphorylation (Palgi et al., 2012). As well as in larval zebra fish, knockdown of MANF expression results in no apparent abnormal phenotype and the dopaminergic neuron development is impaired (Chen et al., 2012). In rat brain, MANF is developmentally regulated and may play a role in the maturation of the central nervous system (CNS) (Wang et al., 2014). Surprisingly, recent data show that MANF deficiency in mice leads to a progressive loss of ȕ cells resulting in diabetes mellitus. And MANF can specifically promotes ȕ cell proliferation and survival, constituting a therapeutic candidate for ȕ cell protection and
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regeneration (Lindahl et al., 2014). However, the cytoprotective mechanisms of MANF and CDNF are not known. MANF and CDNF show no amino acid sequence homology with any other known NTFs, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Different from the cellular localization of "normal" growth factors, major part of MANF and CDNF proteins is located in the luminal side of the ER and only a small fraction is secreted (Apostolou et al., 2008; Sun et al., 2011). So the mechanism of MANF and CDNF function by analogy study of other previously reported NTFs is difficult. Current hypothesis concerning the mechanism are based on domains that they share with other proteins. The N-terminal domain is a saposin-like lipid-binding domain (Parkash et al., 2009), and the C-terminal domain is SAP-domain first found in NMR analysis (Hellman et al., 2011). This review will focus on the unique 3-dimentional structure and related unique action mode of MANF and CDNF, which will help to understand their protective role and secretory regulation during ER stress. 2. Expression and 3-dimentional structure Both MANF and CDNF sequence is highly conserved across species. Human MANF amino acid sequence shows 98% identity with mouse, 82% identity with Xenopus, 72% identity with zebra fish and 50% identity with Caenorhabditis MANF proteins, respectively (Lindholm et al., 2008). Human CDNF shows 59% amino acid identity with human MANF, 49% identity with Drosophila, and 46% identity with Caenorhabditis MANF proteins (Lindholm et al., 2007). A wide expression of MANF and CDNF can be found in mouse and human brain and nonneuronal tissues (Lindholm et al., 2008; Lindholm et al., 2007) (Table 1). In the adult mouse and human tissues, high levels of MANF mRNA and protein are detected in the liver, salivary gland and testis as compared with low
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levels of MANF in the brain, lung and skeletal muscle (Lindholm et al., 2008). For CDNF, relatively high levels of CDNF mRNA and protein are observed in the heart, skeletal muscle and testis (Lindholm et al., 2008; Lindholm et al., 2007) (Table 1). In the brain, the expression of MANF and CDNF are found in all embryonic and postnatal stages, and in all adult brain regions, including the striatum and midbrain (Lindholm et al., 2007; Wang et al., 2014). Human MANF and CDNF have similar crystal structure that is dominated by Į-helices as shown in Figure 1 (Lindstrom et al., 2013). Their characteristic feature is eight structurally conserved cysteine residues forming four intramolecular disufide bridges which determine the unique protein fold (Lindholm et al., 2007; Mizobuchi et al., 2007; Petrova et al., 2003). The unique 3-dimentional structure of MANF and CDNF composes of two domains, an N-terminal saposin-like domain (Parkash et al., 2009) and a C-terminal SAP-domain (Lindholm and Saarma, 2010). The two domains are not tightly packed to each other, but instead tumble as independent structural modules separated by the short flexible linker between them (Lindstrom et al., 2013). The two domains not only involve in diverse biological functions, but also differentially regulate intracellular trafficking and secretion of the two proteins. And the high sequence and structural similarity between MANF and CDNF must reflect their common function. 3. The N-terminal saposin-like domain The N-terminal domain (N-MANF and N-CDNF) has a typical ‘closed’ globular saposin-like architecture with five Į-helices (Į1–Į5) and helices Į1, Į2, Į4 and Į5 form an up-and-down four-helix bundle topology distorted by the insertion of Į3. This domain is structurally homologous to saposin-like proteins (SAPLIPs), a lipid and membrane binding protein superfamily (Parkash et al., 2009). SAPLIPs are a great family composed of a variety of small
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cysteine-rich proteins and most of which appear to involve the interaction with lipids and membranes (Munford et al., 1995). The four human saposins (A-D) are produced in late endosomes or lysosomes by proteolysis of prosaposin and they all are lysosomal glycoproteins involved in degrading glycosphingolipids and promote their hydrolytic processing by exohydrolases (Bruhn, 2005; Sandhoff, 2013). The other two SAPLIPs, membrane-lytic NK-lysin (Brandenburg et al., 2010) and granulysin (Zitvogel and Kroemer, 2010), have a ring of positively charged residues around the protein which may direct their interaction toward the negatively charged lipid head groups in the membrane. They act as defense proteins against bacterial cells and disrupt the target cell membranes (Krensky and Clayberger, 2009; Linde et al., 2005; Qiu et al., 2012). The saposin-like domain of MANF and CDNF has conserved positively charged residues on the surface that may contribute to the membrane interactions. In this respect, the MANF and CDNF seem to be more similar to NK-lysin and granulysin than to other SAPLIPs (Parkash et al., 2009). There are many studies about the N-terminal domain of MANF and CDNF. In Drosophila, Lindstrom et al have found that positive charge on the surface of the N-terminal domain of DmMANF is not essential for fly viability (Lindstrom et al., 2013). The replacement of selected positively charged lysines and arginines with neutral alanines can disrupt the putative lipid interaction but can not abolish the functionality of DmMANF. But the N-terminal can also affect the secretion and intracellular trafficking of proteins. Deletion of several Į-helices of mouse MANF decreases its intracellular stability and secretion (Oh-Hashi et al., 2012). In our previous studies, we have found that disrupting the first helix (Į1) of CDNF by inserting a proline significantly reduce its constitutive and regulated secretion. And the Į1 mutant is retained in the
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ER (Sun et al., 2011) but can not traffic to Golgi apparatus or secrete out of the cells. But why the N-terminal can affect protein secretion and cellular trafficking will need more studies. And the putative receptors for MANF and CDNF have not yet been identified. Whether extracellular MANF and CDNF may exert its function by binding to cell-surface membrane lipids through its N-terminal is also unknown. 4. The C-terminal SAP-domain The structure of C-terminal is composed of three helices, where the first helix (Į6) is loosely formed and the two consecutive helices (Į7 and Į8) are found in parallel orientation forming a helix-loop-helix arrangement. Deletion of C-terminal helices (Į6, Į7 and Į8) of mouse MANF will induce rapid protein transport and secret out the cells (Oh-Hashi et al., 2012). In our previous studies, inserting a proline into Į7 of CDNF to destabilize the helix can significantly reduce its regulated secretion but has no effect on its constitutive secretion. By NMR spectroscopy, the C-terminal domain (C-MANF and C-CDNF) shares the highest structural homology with the SAP domain of Ku70 protein (Hellman et al., 2011; Hellman et al., 2010) . Ku70 together with Ku80 forms a heterodimeric Ku protein, which is essential for nonhomologous DNA double-strand break repair (Qiu et al., 2012). Importantly, Ku70 exerts cytoplasmic antiapoptotic function by binding the proapoptotic protein Bax via its C-terminal SAP domain which can keep Bax in the inactive conformation. In the apoptotic cells, Ku70 dissociates from Bax, thereby Bax is activatied and trigger the mitochondrial cell death pathway (Amsel et al., 2008; Gama et al., 2009; Sawada et al., 2003). Strikingly, the C-terminal domain of MANF and C-terminal domain of Ku70 (C-Ku70) share a similar epitope, located at the beginning of the helix-7. Cellular studies have demonstrated that MANF protected neurons from apoptosis as
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efficiently as Ku70 (Hellman et al., 2011). When cultured newborn mouse sympathetic superior cervical ganglion (SCG) neurons were microinjected directly into the cytoplasm with the expression plasmids or recombinant proteins of MANF or C-MANF, MANF, and more efficiently, C-MANF are able to protect the neurons intracellularly against the Bax-dependent apoptosis (Hellman et al., 2011). The C-terminal domain also contains a CXXC motif (127CKGC130 and 132CRAC135 in HsMANF and HsCDNF, respectively) forming a disulphide bridge. The C-X-X-C motif is common in thiol/disulfide oxidoreductases, also called protein disulfide isomerases (PDIs). During ER stress, ER-targeted PDIs are often induced and catalyze the formation of intramolecular protein disulfide bonds to restore protein folding and, in so doing, exert protective functions (Higa and Chevet, 2012; Ni and Lee, 2007). MANF and CDNF may facilitate the formation of cysteine bridges and protein folding in the ER, thus reducing the ER stress caused by unfolded or incorrectly folded proteins (Lindholm and Saarma, 2010). At the C-terminus, both HsMANF and HsCDNF contain putative ER retention signal sequences (RTDL and KTEL, respectively) which resemble the canonical KDEL ER retention signal. The C-terminal RTDL sequence is critical for MANF localization and removal of RTDL increases MANF secretion (Oh-Hashi et al., 2012). Furthermore, another new study has shown that the RTDL sequence of MANF is necessary and sufficient for cell surface binding (Henderson et al., 2013). Many ER-resident proteins, like GRP78 (glucose-regulated protein 78 kDa), have a C-terminal KDEL motif that facilitates high affinity binding to the KDEL receptor (Capitani and Sallese, 2009). These ER-resident proteins are retrieved from the Golgi apparatus back to the ER by KDEL receptor and are efficiently retained in the ER but not secreted. The RTDL and KTEL sequence also can bind with KDEL receptor but the affinity is weakly than KDEL. It is possible
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that differences in affinity for the KDEL receptor are important for protein secretion. Interestingly, MANF and CDNF may have important functions in the ER, as discussed below. 5. MANF/CDNF and ER stress Previous studies have suggested both a secretion-based neuroprotective role and an ER stress-induced cytoprotective role of MANF and CDNF. Differently from the cellular localization of "normal" growth factors, MANF and CDNF are not typical secretory growth factors, because major part of these proteins is located in the luminal side of the ER and only a small fraction is secreted (Apostolou et al., 2008; Sun et al., 2011). The CXXC motif and the putative ER retention signal sequences in the C-terminal indicate that they may be involved in ER stress (Apostolou et al., 2008; Lindholm et al., 2007; Mizobuchi et al., 2007; Petrova et al., 2003). During ER stress, the accumulation of misfolded proteins in the ER is the ultimate cause of the unfolded protein response (UPR) and ER stress (Marciniak and Ron, 2006). The CXXC motif in the C-terminal domain form a fourth disulphide bridge that may have reductase or disulphide isomerase activity, which might help remove misfolded proteins from the ER by degradation and/or enhancing protein folding. The KDEL-like sequence at C-terminus also indicates that MANF and CDNF may be partially present in the ER lumen. Moreover, there is a type 2 ER stress response element (ERSRE II) in the MANF promoter (Mizobuchi et al., 2007; Tadimalla et al., 2008) hence the MANF expression can be regulated by ER stress. Many studies have shown that MANF is upregulated in ER stress and can protect several cell populations from ER stress-induced cell death in vivo or in vitro (Airavaara et al., 2009; Apostolou et al., 2008; Glembotski et al., 2012; Voutilainen et al., 2009). Such as, MANF protein is upregulated in Hela cells by various ER stress inducing agents and knockdown of endogenous
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MANF aggravates ER stress-induced cell death (Apostolou et al., 2008). But in U2OS cells, overexpression of MANF renders cells more resistant to cell death under glucose-free condition and in response to tunicamycin treatment (Apostolou et al., 2008). Cerebral ischemia or myocardial ischemia also can induce MANF expression and secretion, and extracellular MANF may protect neurons and cardiac myocytes from apoptosis in an autocrin/paracrine manner (Shen et al., 2012; Yang et al., 2014; Yu et al., 2010). But in cultured newborn mouse SCG neurons, MANF protect the neurons intracellularly but not extracellularly. Overexpressing MANF or microinjecting directly into the cytoplasm with recombinant MANF proteins can protect the neurons intracellularly against the Bax-dependent apoptosis (Hellman et al., 2011). But when MANF protein is added in the culture medium, which neither binds, enters, nor protects the cultured SCG neurons. So whether MANF can act in autocrine/paracrine manner will need more studies. Recently, Lindahl et al have generated MANF knockout mice (Manf Ø/Ø) (Lindahl et al., 2014). Surprisingly, Manf Ø/Ø mice develop insulin-deficient diabetes due to progressive postnatal reduction of ȕ cell mass caused by decreased ȕ cell proliferation and increased apoptosis. And pancreatic islets of Manf Ø/Ø mice display activation of UPR genes and proteins, including spliced Xbp1 and Chop mRNA, and genes in the PERK and ATF6 pathways, implicating unresolved ER stress as a primary cause of ȕ cell failure. Therefore, besides a neurotrophic factor, MANF is also an important cellular survival factor that is involved in ER stress, especially in tissues with high secretory function (Palgi et al., 2012). However, little is known about the role of CDNF during ER stress. Any ER stress response element in CDNF promoter have not been reported. In HEK293 cells, CDNF expression and secretion are not significantly affected by tunicamycin indicating that CDNF functions in the ER
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in a constitutive manner (Apostolou et al., 2008). But a new study has shown that overexpression of CDNF in astrocytes can alleviate ER stress-induced astrocyte damage and suppress proinflammatory cytokine secretion (Cheng et al., 2013). So CDNF maybe play an important role in astrocyte inflammation and functioning by resisting ER stress. Currently, studies on CDNF are dominantly in PD disease. For example, in a rat 6-hydroxydopamine (6-OHDA) model of PD, single injections of CDNF protein is able to restore function and increase survival of midbrain dopamine neurons (Lindholm et al., 2007; Voutilainen et al., 2009). In the same model, also a 2-week continuous infusion of CDNF can attenuate the degeneration of the nigrostriatal dopaminergic system (Voutilainen et al., 2011). CDNF has also a significant neuroprotective and neurorestorative effect in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD (Airavaara et al., 2012). In PD, ER stress is well known activated and modulation of the UPR in neurodegeneration is a promising target for future therapeutic treatments (Halliday and Mallucci, 2014). But whether protective and restorative effect of CDNF on PD is related with ER stress still need more studies in detail. 6. How can ER stress regulate MANF secretion? As an ER stress-inducible genes, MANF plays important roles in ER stress response. But what is responsible for the rapid secretion of MANF in response to ER stress? Now there are mainly two explains, KDEL receptor and GRP78. Glembotski has suggested a hypothetical KDEL receptor competition model for MANF secretion in response to ER stress (Glembotski, 2011). It is possible that under basal unstressed conditions, MANF expression is low and the C-terminal RTDL sequence can be recognized by the KDEL receptor to retain MANF intracellularly. However, upon ER stress, levels of ER stress response gene products that have both C-terminal KDEL
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(e.g.GRP78) and RTDL (e.g. MANF) proteins increase, while KDEL receptor levels do not change (Llewellyn et al., 1997). Compared with the canonical KDEL sequence, there is only 40-80% percent binding capability of the RTDL sequence with KDEL receptor (Raykhel et al., 2007). KDEL proteins with a high affinity for the KDEL receptor can compete better for binding to the KDEL receptor than RTDL proteins. Thus, KDEL proteins are efficiently retained in the ER but in the case of MANF, inefficient retention in the ER during ER stress leads to an increase in its secretion. But in another study, KDEL receptor at the cell surface increase after thapsigargin-induced ER stress and the C-terminal RTDL sequence of MANF is necessary and sufficient for MANF trafficking, cell surface binding and response to ER stress in neuronal cell types (Henderson et al., 2013). Furthermore, this group also find the C-terminal of MANF, alanine-serine-alanine-arginine-threonine-aspartic acid-leucine (ASARTDL), is sensitive to ER calcium homeostasis (Henderson et al., 2014). Proteins with ASARTDL terminal has lower affinity for the KDEL receptor and is more likely to be released after Ca2+ depletion. All of these findings suggest that interaction between C-terminal sequence and KDEL receptor is important for regulating MANF secretion. In addition to KDEL receptor, MANF can also be retained in the SR/ER via its calcium-dependent interaction with the SR/ER-resident protein, GRP78, in cultured ventricular myocytes and HeLa cells, both of which secrete proteins via the constitutive pathway (Glembotski et al., 2012). In this study, MANF can form complex with GRP78 and this complex formation is not dependent upon the C-terminal RTDL of MANF but sensitive to changes in calcium concentrations. SR/ER calcium depletion triggered MANF secretion by decreasing its retention. Under conditions of normal SR/ER calcium, MANF is retained by calcium-dependent binding to GRP78. When
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SR/ER calcium is decreased, MANF retention by GRP78 is decreased. So The KDEL receptor and GRP78 comprise two separate MANF retention mechanisms. All of these results indicate that calcium may play important role in MANF retention, whether in the affinity of C-terminal sequence with KDEL receptor or in the complex of MANF formed with GRP78, but the exact mechanism still need further studies. 7. Conclusions In summary, MANF and CDNF are exceptional proteins with very different N- and C-terminal domains. The unique structure suggests their unique function. Especially MANF, as an ER stress-inducible genes, plays important roles during ER stress in cells. All of these findings provide insight into the mechanism of MANF and CDNF in protection of progressive diseases associated with ER dysfunction, such as PD and diabetes, which makes them a highly potential therapeutic agent.
Conflict of interest All authors have no conflict of interests.
Acknowledgements The present work was
supported by Shandong Province Natural Science
Foundation (No. ZR2012HL24) and A Project of Yantai City Science and Technology Development Program (No. 2013WS224).
Fig. 1. Amino acid sequence alignment and crystal structure of MANF and CDNF (Lindstrom et
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al., 2013). A) Amino acid sequence alignment of HsMANF and HsCDNF. Numbering corresponds to HsMANF amino acid residues. Signal sequence (ss), N-terminal domain and C-terminal domain are coloured in orange, blue and green, respectively. The eight conserved cysteines are indicated with asterisks. C-terminal CXXC (purple) and RTDL/KTEL (red) motifs are rectangled. B) Crystal structure of HsMANF. CXXC and RTDL motifs are indicated.
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Cell Struct Funct 32, 41-50. Munford, R.S., Sheppard, P.O., O'Hara, P.J., 1995. Saposin-like proteins (SAPLIP) carry out diverse functions on a common backbone structure. J Lipid Res 36, 1653-1663. Ni, M., Lee, A.S., 2007. ER chaperones in mammalian development and human diseases. FEBS Lett 581, 3641-3651. Oh-Hashi, K., Tanaka, K., Koga, H., Hirata, Y., Kiuchi, K., 2012. Intracellular trafficking and secretion of mouse mesencephalic astrocyte-derived neurotrophic factor. Mol Cell Biochem 363, 35-41. Palgi, M., Greco, D., Lindstrom, R., Auvinen, P., Heino, T.I., 2012. Gene expression analysis of Drosophilaa Manf mutants reveals perturbations in membrane traffic and major metabolic changes. BMC genomics 13, 134. Palgi, M., Lindstrom, R., Peranen, J., Piepponen, T.P., Saarma, M., Heino, T.I., 2009. Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons. Proceedings of the National Academy of Sciences of the United States of America 106, 2429-2434. Parkash, V., Lindholm, P., Peranen, J., Kalkkinen, N., Oksanen, E., Saarma, M., Leppanen, V.M., Goldman, A., 2009. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein engineering, design & selection : PEDS 22, 233-241. Petrova, P., Raibekas, A., Pevsner, J., Vigo, N., Anafi, M., Moore, M.K., Peaire, A.E., Shridhar, V., Smith, D.I., Kelly, J., Durocher, Y., Commissiong, J.W., 2003. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci 20, 173-188. Qiu, Y., Hu, A.B., Wei, H., Liao, H., Li, S., Chen, C.Y., Zhong, W., Huang, D., Cai, J., Jiang, L., Zeng, G., Chen, Z.W., 2012. An atomic-force basis for the bacteriolytic effects of granulysin. Colloids and surfaces. B, Biointerfaces 100, 163-168. Raykhel, I., Alanen, H., Salo, K., Jurvansuu, J., Nguyen, V.D., Latva-Ranta, M., Ruddock, L., 2007. A molecular specificity code for the three mammalian KDEL receptors. The Journal of cell biology 179, 1193-1204. Sandhoff, K., 2013. Metabolic and cellular bases of sphingolipidoses. Biochem Soc Trans 41, 1562-1568. Sawada, M., Hayes, P., Matsuyama, S., 2003. Cytoprotective membrane-permeable peptides designed from the Bax-binding domain of Ku70. Nature cell biology 5, 352-357. Shen, Y., Sun, A., Wang, Y., Cha, D., Wang, H., Wang, F., Feng, L., Fang, S., Shen, Y., 2012. Upregulation of mesencephalic astrocyte-derived neurotrophic factor in glial cells is associated with ischemia-induced glial activation. Journal of neuroinflammation 9, 254. Sun, Z.P., Gong, L., Huang, S.H., Geng, Z., Cheng, L., Chen, Z.Y., 2011. Intracellular trafficking and secretion of cerebral dopamine neurotrophic factor in neurosecretory cells. J Neurochem 117, 121-132. Tadimalla, A., Belmont, P.J., Thuerauf, D.J., Glassy, M.S., Martindale, J.J., Gude, N., Sussman, M.A., Glembotski, C.C., 2008. Mesencephalic astrocyte-derived neurotrophic factor is an ischemia-inducible secreted endoplasmic reticulum stress response protein in the heart. Circ Res 103, 1249-1258. Voutilainen, M.H., Back, S., Peranen, J., Lindholm, P., Raasmaja, A., Mannisto, P.T., Saarma, M., Tuominen, R.K., 2011. Chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Experimental neurology 228, 99-108. Voutilainen, M.H., Back, S., Porsti, E., Toppinen, L., Lindgren, L., Lindholm, P., Peranen, J., Saarma, M., Tuominen, R.K., 2009. Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's disease. The Journal of neuroscience : the official journal of the Society for
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Neuroscience 29, 9651-9659. Wang, H., Ke, Z., Alimov, A., Xu, M., Frank, J.A., Fang, S., Luo, J., 2014. Spatiotemporal expression of MANF in the developing rat brain. PloS one 9, e90433. Yang, W., Shen, Y., Chen, Y., Chen, L., Wang, L., Wang, H., Xu, S., Fang, S., Fu, Y., Yu, Y., Shen, Y., 2014. Mesencephalic astrocyte-derived neurotrophic factor prevents neuron loss via inhibiting ischemia-induced apoptosis. Journal of the neurological sciences 344, 129-138. Yu, Y.Q., Liu, L.C., Wang, F.C., Liang, Y., Cha, D.Q., Zhang, J.J., Shen, Y.J., Wang, H.P., Fang, S., Shen, Y.X., 2010. Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 30, 79-91. Zitvogel, L., Kroemer, G., 2010. The multifaceted granulysin. Blood 116, 3379-3380.
Table 1 Widespread distribution of MANF and CDNF in adult mouse tissues
Brain
Heart
Kidney
Liver
Lung
Skeletal muscle
Salivary gland
Testis
mRNA
L
M
M
H
L
L
H
H
protein
L
L
L
H
L
L
H
H
mRNA
M
H
M
M
M
H
M
H
protein
L
H
L
M
M
H
M
H
MANF
CDNF
H: high level; M: middle level; L: low level
16
Figure
Table
Mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor: new endoplasmic reticulum stress response proteins Hao Liu, Xiaolei Tang, Lei Gong
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PII: DOI: Reference:
S0014-2999(15)00038-2 http://dx.doi.org/10.1016/j.ejphar.2015.01.016 EJP69712
To appear in:
European Journal of Pharmacology
Received date: 7 June 2014 Revised date: 9 December 2014 Accepted date: 7 January 2015 Cite this article as: Hao Liu, Xiaolei Tang, Lei Gong, Mesencephalic astrocytederived neurotrophic factor and cerebral dopamine neurotrophic factor: new endoplasmic reticulum stress response proteins, European Journal of Pharmacology, http://dx.doi.org/10.1016/j.ejphar.2015.01.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor: new endoplasmic reticulum stress response proteins Hao Liua, Xiaolei Tangb, Lei Gonga*
a
Yuhuangding Hospital, Yantai, Shandong Province, PR China
b
Taishan Medical College, Taian, Shandong Province, PR China
*Corresponding author. Tel.: E-mail
+86 535 6691999
address: [email protected] (L. Gong).
Full post address: Biochip laboratory of Yuhuangding Hospital, Yantai, Shandong Province, PR China Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are a novel evolutionary conserved neurotrophic factor (NTF) family. There are two distinct domains in MANF and CDNF 3-dimentional structure, N-terminal saposin-like domain and C-terminal SAP-domain, which suggest their unique mode of action. Although identified for their neurotrophic activity, recent studies have shown MANF and CDNF can protect cells during endoplasmic reticulum (ER) stress. This review summarizes the unique structure and related potential protective role for cells during ER stress of MANF and CDNF. Key words: MANF, CDNF, ER stress, NTF
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1. Introduction Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) form a novel evolutionary conserved neurotrophic factor (NTF) family in the vertebrates. MANF together with CDNF can efficiently protect and repaire midbrain dopaminergic neurons in animal models of Parkinson’s disease (PD) and protect cardiac myocytes in myocardial infarction and cortical neurons against ischemic stroke (Airavaara et al., 2009; Apostolou et al., 2008; Glembotski et al., 2012; Hellman et al., 2011; Lindholm et al., 2008; Lindholm et al., 2007; Voutilainen et al., 2009). While in the invertebrates, including Drosophila and Caenorhabditis, there is a single protein homologous to vertebrate MANF and CDNF (Lindholm and Saarma, 2010). Recently, MANF has been found to regulate the development of dopaminergic neurons in Drosophila and zebra fishes . In Drosophila, DmMANF, homologous to mammalian MANF and CDNF, is expressed in glia and essential for maintenance of dopamine positive neurites and dopamine levels. The abolishment of DmMANF leads to the degeneration and nonapoptotic cell death of axonal bundles in the embryonic central nervous system (Palgi et al., 2009), increased expression of several genes involved in endoplasmic reticulum (ER) stress and increased eIF2Į phosphorylation (Palgi et al., 2012). As well as in larval zebra fish, knockdown of MANF expression results in no apparent abnormal phenotype and the dopaminergic neuron development is impaired (Chen et al., 2012). In rat brain, MANF is developmentally regulated and may play a role in the maturation of the central nervous system (CNS) (Wang et al., 2014). Surprisingly, recent data show that MANF deficiency in mice leads to a progressive loss of ȕ cells resulting in diabetes mellitus. And MANF can specifically promotes ȕ cell proliferation and survival, constituting a therapeutic candidate for ȕ cell protection and
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regeneration (Lindahl et al., 2014). However, the cytoprotective mechanisms of MANF and CDNF are not known. MANF and CDNF show no amino acid sequence homology with any other known NTFs, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Different from the cellular localization of "normal" growth factors, major part of MANF and CDNF proteins is located in the luminal side of the ER and only a small fraction is secreted (Apostolou et al., 2008; Sun et al., 2011). So the mechanism of MANF and CDNF function by analogy study of other previously reported NTFs is difficult. Current hypothesis concerning the mechanism are based on domains that they share with other proteins. The N-terminal domain is a saposin-like lipid-binding domain (Parkash et al., 2009), and the C-terminal domain is SAP-domain first found in NMR analysis (Hellman et al., 2011). This review will focus on the unique 3-dimentional structure and related unique action mode of MANF and CDNF, which will help to understand their protective role and secretory regulation during ER stress. 2. Expression and 3-dimentional structure Both MANF and CDNF sequence is highly conserved across species. Human MANF amino acid sequence shows 98% identity with mouse, 82% identity with Xenopus, 72% identity with zebra fish and 50% identity with Caenorhabditis MANF proteins, respectively (Lindholm et al., 2008). Human CDNF shows 59% amino acid identity with human MANF, 49% identity with Drosophila, and 46% identity with Caenorhabditis MANF proteins (Lindholm et al., 2007). A wide expression of MANF and CDNF can be found in mouse and human brain and nonneuronal tissues (Lindholm et al., 2008; Lindholm et al., 2007) (Table 1). In the adult mouse and human tissues, high levels of MANF mRNA and protein are detected in the liver, salivary gland and testis as compared with low
3
levels of MANF in the brain, lung and skeletal muscle (Lindholm et al., 2008). For CDNF, relatively high levels of CDNF mRNA and protein are observed in the heart, skeletal muscle and testis (Lindholm et al., 2008; Lindholm et al., 2007) (Table 1). In the brain, the expression of MANF and CDNF are found in all embryonic and postnatal stages, and in all adult brain regions, including the striatum and midbrain (Lindholm et al., 2007; Wang et al., 2014). Human MANF and CDNF have similar crystal structure that is dominated by Į-helices as shown in Figure 1 (Lindstrom et al., 2013). Their characteristic feature is eight structurally conserved cysteine residues forming four intramolecular disufide bridges which determine the unique protein fold (Lindholm et al., 2007; Mizobuchi et al., 2007; Petrova et al., 2003). The unique 3-dimentional structure of MANF and CDNF composes of two domains, an N-terminal saposin-like domain (Parkash et al., 2009) and a C-terminal SAP-domain (Lindholm and Saarma, 2010). The two domains are not tightly packed to each other, but instead tumble as independent structural modules separated by the short flexible linker between them (Lindstrom et al., 2013). The two domains not only involve in diverse biological functions, but also differentially regulate intracellular trafficking and secretion of the two proteins. And the high sequence and structural similarity between MANF and CDNF must reflect their common function. 3. The N-terminal saposin-like domain The N-terminal domain (N-MANF and N-CDNF) has a typical ‘closed’ globular saposin-like architecture with five Į-helices (Į1–Į5) and helices Į1, Į2, Į4 and Į5 form an up-and-down four-helix bundle topology distorted by the insertion of Į3. This domain is structurally homologous to saposin-like proteins (SAPLIPs), a lipid and membrane binding protein superfamily (Parkash et al., 2009). SAPLIPs are a great family composed of a variety of small
4
cysteine-rich proteins and most of which appear to involve the interaction with lipids and membranes (Munford et al., 1995). The four human saposins (A-D) are produced in late endosomes or lysosomes by proteolysis of prosaposin and they all are lysosomal glycoproteins involved in degrading glycosphingolipids and promote their hydrolytic processing by exohydrolases (Bruhn, 2005; Sandhoff, 2013). The other two SAPLIPs, membrane-lytic NK-lysin (Brandenburg et al., 2010) and granulysin (Zitvogel and Kroemer, 2010), have a ring of positively charged residues around the protein which may direct their interaction toward the negatively charged lipid head groups in the membrane. They act as defense proteins against bacterial cells and disrupt the target cell membranes (Krensky and Clayberger, 2009; Linde et al., 2005; Qiu et al., 2012). The saposin-like domain of MANF and CDNF has conserved positively charged residues on the surface that may contribute to the membrane interactions. In this respect, the MANF and CDNF seem to be more similar to NK-lysin and granulysin than to other SAPLIPs (Parkash et al., 2009). There are many studies about the N-terminal domain of MANF and CDNF. In Drosophila, Lindstrom et al have found that positive charge on the surface of the N-terminal domain of DmMANF is not essential for fly viability (Lindstrom et al., 2013). The replacement of selected positively charged lysines and arginines with neutral alanines can disrupt the putative lipid interaction but can not abolish the functionality of DmMANF. But the N-terminal can also affect the secretion and intracellular trafficking of proteins. Deletion of several Į-helices of mouse MANF decreases its intracellular stability and secretion (Oh-Hashi et al., 2012). In our previous studies, we have found that disrupting the first helix (Į1) of CDNF by inserting a proline significantly reduce its constitutive and regulated secretion. And the Į1 mutant is retained in the
5
ER (Sun et al., 2011) but can not traffic to Golgi apparatus or secrete out of the cells. But why the N-terminal can affect protein secretion and cellular trafficking will need more studies. And the putative receptors for MANF and CDNF have not yet been identified. Whether extracellular MANF and CDNF may exert its function by binding to cell-surface membrane lipids through its N-terminal is also unknown. 4. The C-terminal SAP-domain The structure of C-terminal is composed of three helices, where the first helix (Į6) is loosely formed and the two consecutive helices (Į7 and Į8) are found in parallel orientation forming a helix-loop-helix arrangement. Deletion of C-terminal helices (Į6, Į7 and Į8) of mouse MANF will induce rapid protein transport and secret out the cells (Oh-Hashi et al., 2012). In our previous studies, inserting a proline into Į7 of CDNF to destabilize the helix can significantly reduce its regulated secretion but has no effect on its constitutive secretion. By NMR spectroscopy, the C-terminal domain (C-MANF and C-CDNF) shares the highest structural homology with the SAP domain of Ku70 protein (Hellman et al., 2011; Hellman et al., 2010) . Ku70 together with Ku80 forms a heterodimeric Ku protein, which is essential for nonhomologous DNA double-strand break repair (Qiu et al., 2012). Importantly, Ku70 exerts cytoplasmic antiapoptotic function by binding the proapoptotic protein Bax via its C-terminal SAP domain which can keep Bax in the inactive conformation. In the apoptotic cells, Ku70 dissociates from Bax, thereby Bax is activatied and trigger the mitochondrial cell death pathway (Amsel et al., 2008; Gama et al., 2009; Sawada et al., 2003). Strikingly, the C-terminal domain of MANF and C-terminal domain of Ku70 (C-Ku70) share a similar epitope, located at the beginning of the helix-7. Cellular studies have demonstrated that MANF protected neurons from apoptosis as
6
efficiently as Ku70 (Hellman et al., 2011). When cultured newborn mouse sympathetic superior cervical ganglion (SCG) neurons were microinjected directly into the cytoplasm with the expression plasmids or recombinant proteins of MANF or C-MANF, MANF, and more efficiently, C-MANF are able to protect the neurons intracellularly against the Bax-dependent apoptosis (Hellman et al., 2011). The C-terminal domain also contains a CXXC motif (127CKGC130 and 132CRAC135 in HsMANF and HsCDNF, respectively) forming a disulphide bridge. The C-X-X-C motif is common in thiol/disulfide oxidoreductases, also called protein disulfide isomerases (PDIs). During ER stress, ER-targeted PDIs are often induced and catalyze the formation of intramolecular protein disulfide bonds to restore protein folding and, in so doing, exert protective functions (Higa and Chevet, 2012; Ni and Lee, 2007). MANF and CDNF may facilitate the formation of cysteine bridges and protein folding in the ER, thus reducing the ER stress caused by unfolded or incorrectly folded proteins (Lindholm and Saarma, 2010). At the C-terminus, both HsMANF and HsCDNF contain putative ER retention signal sequences (RTDL and KTEL, respectively) which resemble the canonical KDEL ER retention signal. The C-terminal RTDL sequence is critical for MANF localization and removal of RTDL increases MANF secretion (Oh-Hashi et al., 2012). Furthermore, another new study has shown that the RTDL sequence of MANF is necessary and sufficient for cell surface binding (Henderson et al., 2013). Many ER-resident proteins, like GRP78 (glucose-regulated protein 78 kDa), have a C-terminal KDEL motif that facilitates high affinity binding to the KDEL receptor (Capitani and Sallese, 2009). These ER-resident proteins are retrieved from the Golgi apparatus back to the ER by KDEL receptor and are efficiently retained in the ER but not secreted. The RTDL and KTEL sequence also can bind with KDEL receptor but the affinity is weakly than KDEL. It is possible
7
that differences in affinity for the KDEL receptor are important for protein secretion. Interestingly, MANF and CDNF may have important functions in the ER, as discussed below. 5. MANF/CDNF and ER stress Previous studies have suggested both a secretion-based neuroprotective role and an ER stress-induced cytoprotective role of MANF and CDNF. Differently from the cellular localization of "normal" growth factors, MANF and CDNF are not typical secretory growth factors, because major part of these proteins is located in the luminal side of the ER and only a small fraction is secreted (Apostolou et al., 2008; Sun et al., 2011). The CXXC motif and the putative ER retention signal sequences in the C-terminal indicate that they may be involved in ER stress (Apostolou et al., 2008; Lindholm et al., 2007; Mizobuchi et al., 2007; Petrova et al., 2003). During ER stress, the accumulation of misfolded proteins in the ER is the ultimate cause of the unfolded protein response (UPR) and ER stress (Marciniak and Ron, 2006). The CXXC motif in the C-terminal domain form a fourth disulphide bridge that may have reductase or disulphide isomerase activity, which might help remove misfolded proteins from the ER by degradation and/or enhancing protein folding. The KDEL-like sequence at C-terminus also indicates that MANF and CDNF may be partially present in the ER lumen. Moreover, there is a type 2 ER stress response element (ERSRE II) in the MANF promoter (Mizobuchi et al., 2007; Tadimalla et al., 2008) hence the MANF expression can be regulated by ER stress. Many studies have shown that MANF is upregulated in ER stress and can protect several cell populations from ER stress-induced cell death in vivo or in vitro (Airavaara et al., 2009; Apostolou et al., 2008; Glembotski et al., 2012; Voutilainen et al., 2009). Such as, MANF protein is upregulated in Hela cells by various ER stress inducing agents and knockdown of endogenous
8
MANF aggravates ER stress-induced cell death (Apostolou et al., 2008). But in U2OS cells, overexpression of MANF renders cells more resistant to cell death under glucose-free condition and in response to tunicamycin treatment (Apostolou et al., 2008). Cerebral ischemia or myocardial ischemia also can induce MANF expression and secretion, and extracellular MANF may protect neurons and cardiac myocytes from apoptosis in an autocrin/paracrine manner (Shen et al., 2012; Yang et al., 2014; Yu et al., 2010). But in cultured newborn mouse SCG neurons, MANF protect the neurons intracellularly but not extracellularly. Overexpressing MANF or microinjecting directly into the cytoplasm with recombinant MANF proteins can protect the neurons intracellularly against the Bax-dependent apoptosis (Hellman et al., 2011). But when MANF protein is added in the culture medium, which neither binds, enters, nor protects the cultured SCG neurons. So whether MANF can act in autocrine/paracrine manner will need more studies. Recently, Lindahl et al have generated MANF knockout mice (Manf Ø/Ø) (Lindahl et al., 2014). Surprisingly, Manf Ø/Ø mice develop insulin-deficient diabetes due to progressive postnatal reduction of ȕ cell mass caused by decreased ȕ cell proliferation and increased apoptosis. And pancreatic islets of Manf Ø/Ø mice display activation of UPR genes and proteins, including spliced Xbp1 and Chop mRNA, and genes in the PERK and ATF6 pathways, implicating unresolved ER stress as a primary cause of ȕ cell failure. Therefore, besides a neurotrophic factor, MANF is also an important cellular survival factor that is involved in ER stress, especially in tissues with high secretory function (Palgi et al., 2012). However, little is known about the role of CDNF during ER stress. Any ER stress response element in CDNF promoter have not been reported. In HEK293 cells, CDNF expression and secretion are not significantly affected by tunicamycin indicating that CDNF functions in the ER
9
in a constitutive manner (Apostolou et al., 2008). But a new study has shown that overexpression of CDNF in astrocytes can alleviate ER stress-induced astrocyte damage and suppress proinflammatory cytokine secretion (Cheng et al., 2013). So CDNF maybe play an important role in astrocyte inflammation and functioning by resisting ER stress. Currently, studies on CDNF are dominantly in PD disease. For example, in a rat 6-hydroxydopamine (6-OHDA) model of PD, single injections of CDNF protein is able to restore function and increase survival of midbrain dopamine neurons (Lindholm et al., 2007; Voutilainen et al., 2009). In the same model, also a 2-week continuous infusion of CDNF can attenuate the degeneration of the nigrostriatal dopaminergic system (Voutilainen et al., 2011). CDNF has also a significant neuroprotective and neurorestorative effect in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD (Airavaara et al., 2012). In PD, ER stress is well known activated and modulation of the UPR in neurodegeneration is a promising target for future therapeutic treatments (Halliday and Mallucci, 2014). But whether protective and restorative effect of CDNF on PD is related with ER stress still need more studies in detail. 6. How can ER stress regulate MANF secretion? As an ER stress-inducible genes, MANF plays important roles in ER stress response. But what is responsible for the rapid secretion of MANF in response to ER stress? Now there are mainly two explains, KDEL receptor and GRP78. Glembotski has suggested a hypothetical KDEL receptor competition model for MANF secretion in response to ER stress (Glembotski, 2011). It is possible that under basal unstressed conditions, MANF expression is low and the C-terminal RTDL sequence can be recognized by the KDEL receptor to retain MANF intracellularly. However, upon ER stress, levels of ER stress response gene products that have both C-terminal KDEL
10
(e.g.GRP78) and RTDL (e.g. MANF) proteins increase, while KDEL receptor levels do not change (Llewellyn et al., 1997). Compared with the canonical KDEL sequence, there is only 40-80% percent binding capability of the RTDL sequence with KDEL receptor (Raykhel et al., 2007). KDEL proteins with a high affinity for the KDEL receptor can compete better for binding to the KDEL receptor than RTDL proteins. Thus, KDEL proteins are efficiently retained in the ER but in the case of MANF, inefficient retention in the ER during ER stress leads to an increase in its secretion. But in another study, KDEL receptor at the cell surface increase after thapsigargin-induced ER stress and the C-terminal RTDL sequence of MANF is necessary and sufficient for MANF trafficking, cell surface binding and response to ER stress in neuronal cell types (Henderson et al., 2013). Furthermore, this group also find the C-terminal of MANF, alanine-serine-alanine-arginine-threonine-aspartic acid-leucine (ASARTDL), is sensitive to ER calcium homeostasis (Henderson et al., 2014). Proteins with ASARTDL terminal has lower affinity for the KDEL receptor and is more likely to be released after Ca2+ depletion. All of these findings suggest that interaction between C-terminal sequence and KDEL receptor is important for regulating MANF secretion. In addition to KDEL receptor, MANF can also be retained in the SR/ER via its calcium-dependent interaction with the SR/ER-resident protein, GRP78, in cultured ventricular myocytes and HeLa cells, both of which secrete proteins via the constitutive pathway (Glembotski et al., 2012). In this study, MANF can form complex with GRP78 and this complex formation is not dependent upon the C-terminal RTDL of MANF but sensitive to changes in calcium concentrations. SR/ER calcium depletion triggered MANF secretion by decreasing its retention. Under conditions of normal SR/ER calcium, MANF is retained by calcium-dependent binding to GRP78. When
11
SR/ER calcium is decreased, MANF retention by GRP78 is decreased. So The KDEL receptor and GRP78 comprise two separate MANF retention mechanisms. All of these results indicate that calcium may play important role in MANF retention, whether in the affinity of C-terminal sequence with KDEL receptor or in the complex of MANF formed with GRP78, but the exact mechanism still need further studies. 7. Conclusions In summary, MANF and CDNF are exceptional proteins with very different N- and C-terminal domains. The unique structure suggests their unique function. Especially MANF, as an ER stress-inducible genes, plays important roles during ER stress in cells. All of these findings provide insight into the mechanism of MANF and CDNF in protection of progressive diseases associated with ER dysfunction, such as PD and diabetes, which makes them a highly potential therapeutic agent.
Conflict of interest All authors have no conflict of interests.
Acknowledgements The present work was
supported by Shandong Province Natural Science
Foundation (No. ZR2012HL24) and A Project of Yantai City Science and Technology Development Program (No. 2013WS224).
Fig. 1. Amino acid sequence alignment and crystal structure of MANF and CDNF (Lindstrom et
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al., 2013). A) Amino acid sequence alignment of HsMANF and HsCDNF. Numbering corresponds to HsMANF amino acid residues. Signal sequence (ss), N-terminal domain and C-terminal domain are coloured in orange, blue and green, respectively. The eight conserved cysteines are indicated with asterisks. C-terminal CXXC (purple) and RTDL/KTEL (red) motifs are rectangled. B) Crystal structure of HsMANF. CXXC and RTDL motifs are indicated.
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Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion. The Journal of biological chemistry 287, 25893-25904. Halliday, M., Mallucci, G.R., 2014. Targeting the unfolded protein response in neurodegeneration: A new approach to therapy. Neuropharmacology 76 Pt A, 169-174. Hellman, M., Arumae, U., Yu, L.Y., Lindholm, P., Peranen, J., Saarma, M., Permi, P., 2011. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. The Journal of biological chemistry 286, 2675-2680. Hellman, M., Peranen, J., Saarma, M., Permi, P., 2010. 1H, 13C and 15N resonance assignments of the human mesencephalic astrocyte-derived neurotrophic factor. Biomolecular NMR assignments 4, 215-217. Henderson, M.J., Richie, C.T., Airavaara, M., Wang, Y., Harvey, B.K., 2013. Mesencephalic astrocyte-derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. The Journal of biological chemistry 288, 4209-4225. Henderson, M.J., Wires, E.S., Trychta, K.A., Richie, C.T., Harvey, B.K., 2014. SERCaMP: a carboxy-terminal protein modification that enables monitoring of ER calcium homeostasis. Molecular biology of the cell 25, 2828-2839. Higa, A., Chevet, E., 2012. Redox signaling loops in the unfolded protein response. Cell Signal 24, 1548-1555. Krensky, A.M., Clayberger, C., 2009. Biology and clinical relevance of granulysin. Tissue Antigens 73, 193-198. Lindahl, M., Danilova, T., Palm, E., Lindholm, P., Voikar, V., Hakonen, E., Ustinov, J., Andressoo, J.O., Harvey, B.K., Otonkoski, T., Rossi, J., Saarma, M., 2014. MANF is indispensable for the proliferation and survival of pancreatic beta cells. Cell reports 7, 366-375. Linde, C.M., Grundstrom, S., Nordling, E., Refai, E., Brennan, P.J., Andersson, M., 2005. Conserved structure and function in the granulysin and NK-lysin peptide family. Infect Immun 73, 6332-6339. Lindholm, P., Peranen, J., Andressoo, J.O., Kalkkinen, N., Kokaia, Z., Lindvall, O., Timmusk, T., Saarma, M., 2008. MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Molecular and cellular neurosciences 39, 356-371. Lindholm, P., Saarma, M., 2010. Novel CDNF/MANF family of neurotrophic factors. Developmental neurobiology 70, 360-371. Lindholm, P., Voutilainen, M.H., Lauren, J., Peranen, J., Leppanen, V.M., Andressoo, J.O., Lindahl, M., Janhunen, S., Kalkkinen, N., Timmusk, T., Tuominen, R.K., Saarma, M., 2007. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 448, 73-77. Lindstrom, R., Lindholm, P., Kallijarvi, J., Yu, L.Y., Piepponen, T.P., Arumae, U., Saarma, M., Heino, T.I., 2013. Characterization of the structural and functional determinants of MANF/CDNF in Drosophila in vivo model. PloS one 8, e73928. Llewellyn, D.H., Roderick, H.L., Rose, S., 1997. KDEL receptor expression is not coordinatedly up-regulated with ER stress-induced reticuloplasmin expression in HeLa cells. Biochemical and biophysical research communications 240, 36-40. Marciniak, S.J., Ron, D., 2006. Endoplasmic reticulum stress signaling in disease. Physiol Rev 86, 1133-1149. Mizobuchi, N., Hoseki, J., Kubota, H., Toyokuni, S., Nozaki, J., Naitoh, M., Koizumi, A., Nagata, K., 2007. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element.
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Neuroscience 29, 9651-9659. Wang, H., Ke, Z., Alimov, A., Xu, M., Frank, J.A., Fang, S., Luo, J., 2014. Spatiotemporal expression of MANF in the developing rat brain. PloS one 9, e90433. Yang, W., Shen, Y., Chen, Y., Chen, L., Wang, L., Wang, H., Xu, S., Fang, S., Fu, Y., Yu, Y., Shen, Y., 2014. Mesencephalic astrocyte-derived neurotrophic factor prevents neuron loss via inhibiting ischemia-induced apoptosis. Journal of the neurological sciences 344, 129-138. Yu, Y.Q., Liu, L.C., Wang, F.C., Liang, Y., Cha, D.Q., Zhang, J.J., Shen, Y.J., Wang, H.P., Fang, S., Shen, Y.X., 2010. Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 30, 79-91. Zitvogel, L., Kroemer, G., 2010. The multifaceted granulysin. Blood 116, 3379-3380.
Table 1 Widespread distribution of MANF and CDNF in adult mouse tissues
Brain
Heart
Kidney
Liver
Lung
Skeletal muscle
Salivary gland
Testis
mRNA
L
M
M
H
L
L
H
H
protein
L
L
L
H
L
L
H
H
mRNA
M
H
M
M
M
H
M
H
protein
L
H
L
M
M
H
M
H
MANF
CDNF
H: high level; M: middle level; L: low level
16
Figure
Table
