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ARTICLE IN PRESS
YSCDB-1576; No. of Pages 2
Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
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Editorial
Nuclear envelope proteins in health and diseases
The nuclear envelope (NE), a hallmark of eukaryotic cells, is a highly organized double membrane that encloses the nuclear genome. The NE is a specialized cisterna of endoplasmic reticulum (ER) with the outer (ONM) and the inner (INM) nuclear membranes separating the nuclear from the cytoplasmic compartments, interconnecting through nuclear pore complexes and associated with the nuclear lamina, a fibrous meshwork of intermediate filaments lying underneath the INM [1]. Despite its essential position in the cell, the exact structure, composition and functions of the NE are yet not fully deciphered. Twenty years ago, the molecular genetics era shed light on NE components, with the identification of a hitherto new NE protein, the emerin, to be the first INM protein involved in a rare human genetic disease, the X-linked form of Emery–Dreifuss muscular dystrophy (EDMD) [2,3]. This very first link between the NE and diseases was followed a few years after with the implication of A-type lamins, components of the nuclear lamina, in the autosomal forms of EDMD, making EDMD the first disease of the NE [4,5]. But this was only the discovery of the “tip of the iceberg”. Indeed, since these first identifications, A-type lamins have been implicated in a wide range of rare diseases, with more than 10 different types of Laminopathies described, affecting either specifically one tissue type (striated muscle, adipose tissue, peripheral nerve) or several tissues in a systemic manner (premature aging syndromes) [6]. Other NE components and interacting partners, such as the B-type lamins, Lamin B receptor (LBR), ZMPSTE24, TorsinA, MAN1, LAP2␣, LAP1. . . have been also linked to different diseases [6–8]. As a result, the NE is now positioned on the interface between cell biology and medicine. The constant “back-and-forth” between these two disciplines has allowed not only the identification of new components of the NE – some being implicated in diseases (e.g. nesprins, SUN. . .) [9,10], the others being good candidates for yet unidentified human diseases [11] – but also the deciphering of some of their functions taking advantage of the complementarities of both the healthy and diseased contexts, and this for the benefit of patients. As the field is still rapidly growing, it has been a challenge to restrict my choice to a few topics for this special issue of Seminars in Cell & Developmental Biology. The eight reviews cover different components of the NE, different types of disorders ranging from rare to more commons, and also different approaches used to explore their roles and dysfunctions, making the NE a real paradigm from basic science to translational medicine. Koch and Holaska [12] focus on emerin functions and the current thinking for how loss or mutations in emerin cause EDMD. Emerin has now been shown to have diverse functions, including the regulation of gene expression, cell signaling, nuclear structure
and chromatin architecture. Their review highlights open questions concerning emerin’s roles in cell and nuclear biology. For the A-type lamins, the three main types of laminopathies are presented, i.e. the striated muscle laminopathies comprising different forms of muscular dystrophy and cardiomyopathy [13,14], the premature aging syndromes [15] and the NE-related lipodystrophies [16]. A-type lamins are components of the nuclear lamina, which mediates nuclear stiffness and anchors chromatin to the nuclear periphery. A-type lamins are also found in the nuclear interior, i.e. in the nucleoplasm where they interact among others with lamina-associated polypeptide 2␣ (LAP2␣) [14]. In the context of the striated muscles, Azibani et al. [13] focus on studies performed on knock-out and knock-in Lmna mouse models, which have led to decipher some of the lamin A/C functions in striated muscles and to the first preclinical trials of pharmaceutical therapies. Gesson et al. [14] review the roles of LAP2␣ in the regulation of nucleoplasmic pool of A-type lamins highlighting the potential function of the nucleoplasmic A-type lamins and LAP2␣ as regulators of adult stem cell function and tissue homeostasis and discussing potential implications of this concept in the context of striated muscle laminopathies and premature aging syndromes. Cau et al. [15] present an extensive review on the premature aging syndromes. They dissect in deep the clinical and genetic spectrum of these ultra rare disorders, the current knowledge of the NE and nucleoplasm components involved and their pathophysiological mechanisms that had led in less than 10 years to several clinical trials for progeria children. They particularly highlighted how improving our knowledge of these syndromes and searching for innovative and efficient therapies may significantly not only expand the affected childrens’ lifespan and preserve their quality of life but also improve our understanding of aging-related disorders, physiological aging and other physiological processes such as those involved in oncogenesis. Guénantin et al. [16] report on lipodystrophic syndromes, affecting the adipose tissue, linked to alteration of A-type and B-type lamins, and present the clinical, tissular and cellular characteristics of these disorders as well as their hypothetical pathophysiological mechanisms. To complete the nuclear lamina defects, Hutchison [8] reviews B-type lamins in health and disease. The gene encoding lamin B1 causes leukodystrophy, an adult onset neurodegenerative disorder, when duplicated and had been implicated as a susceptibility gene in neural tube defects. For over two decades, B-type lamins were thought to have roles in fundamental processes including correct assembly of nuclear envelopes, DNA replication, transcription and cell survival. Recent studies have questioned these roles and have
http://dx.doi.org/10.1016/j.semcdb.2014.04.023 1084-9521/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Bonne G. Nuclear envelope proteins in health and diseases. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.023
G Model YSCDB-1576; No. of Pages 2
ARTICLE IN PRESS Editorial / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
2
instead emphasized the role of these proteins in tissue building, tissue integrity and cellular senescence. The review highlights how different model systems have contributed to our understanding of the functions of B-type lamins and which of those functions are critical for human health and disease. Shin et al. [7] present an interesting view of the role of the Lamina-associated polypeptide 1 (LAP1) in the tissue specificity of some NE-related diseases. Indeed, as mentioned above, mutations in genes encoding widely expressed NE proteins often lead to diseases that manifest in specific tissues. LAP1, an integral protein of the INM expressed in most cells and tissues interacts with lamins, torsinA and emerin suggesting it may serve as a key node for transducing signals across the NE. Based on recent in vivo studies in genetically modified mice supporting functional links between LAP1 and both torsinA and emerin, Shin et al. propose that tissueselective NE-diseases may result, at least in part, from the selective disruption of discrete NE protein complexes. Finally, the review by Cartwright and Karakesisoglou [17] make the “link” between the NE and the cytoplasm with their comprehensive review of Nesprins in health and disease. Indeed, the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex is an evolutionary conserved structure that spans the entire NE, and integrates the nuclear interior with the cytoskeleton, in order to support a diverse array of fundamental biological processes. Nesprins (Nuclear Envelope SPectrin Repeat proteINS) are key components of the LINC complex. Initially described as large integral NE proteins, they are far more complex as their genes generate many variants, which occupy various sub-cellular compartments suggesting functions beyond the NE and LINC complex. The involvement of nesprins in diseases, i.e. cancer, myopathies, arthrogryposis, neurological disorders and hearing loss, has further expanded our knowledge of their functions. Cartwright and Karakesisoglou review the huge complexity of the nesprins family, providing an in-depth account of their structure, molecular interactions and cellular functions and speculating about possible pathomechanisms underlying nesprin-associated diseases. Altogether, the reviews of this special issue of Seminars in Cell & Developmental Biology dramatically demonstrate how essential is merging healthy and disease contexts for the exploration of the structures and functions of the nuclear envelope proteins. Within twenty years, the landscape of the NE and of its related compartment, the nucleoplasm has greatly changed, but still we have only started to unravel the “tip of the iceberg”. I am convinced that in the near future thanks to the current intensive research in the field, the NE will be fully recognized, no more as a “simple” double lipid bilayer separating the nuclear from the cytoplasmic compartments, but as a real hub platform functionally inter-connecting these cell compartments. I sincerely hope you will enjoy this special issue. References [1] Hetzer MW. The nuclear envelope. Cold Spring Harb Perspect Biol 2010;2:a000539.
[2] Bione S, Maestrini E, Rivella S, Manchini M, Regis S, Romei G, et al. Identification of a novel X-linked gene responsible for Emery–Dreifuss muscular dystrophy. Nature Genet 1994;8:323–7. [3] Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, et al. Emerin deficiency at the nuclear membrane in patients with Emery–Dreifuss muscular dystrophy. Nature Genet 1996;12:254–9. [4] Bonne G, Di Barletta MR, Varnous S, Becane H-M, Hammouda EH, Merlini L, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nature Genet 1999;21:285–8. [5] di Barletta MR, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, et al. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery–Dreifuss muscular dystrophy. Am J Hum Genet 2000;66:1407–12. [6] Worman HJ, Bonne G. Laminopathies”: a wide spectrum of human diseases. Exp Cell Res 2007;313:2121–33. [7] Shin JY, Dauer WT, Worman HJ. Lamina-associated polypeptide 1: Protein interactions and tissue-selective functions. Sem Cell Dev Biol 2014, http://dx.doi.org/10.1016/j.semcdb.2014.01.010. [8] Hutchison CJ. B-type lamins in health and disease. Sem Cell Dev Biol 2013, http://dx.doi.org/10.1016/j.semcdb.2013.12.012. [9] Attali R, Warwar N, Israel A, Gurt I, McNally E, Puckelwartz M, et al. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet 2009;18:3462–70. [10] Li P, Meinke P, Huong le TT, Wehnert M, Noegel AA. Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies. Hum Mutat 2014;35:452–61. [11] Schirmer EC, Florens L, Guan T, Yates 3rd JR, Gerace L. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science 2003;301:1380–2. [12] Koch AJ, Holaska JM. Emerin in health and disease. Sem Cell Dev Biol 2013, http://dx.doi.org/10.1016/j.semcdb.2013.12.008. [13] Azibani F, Muchir A, Vignier N, Bonne G, Bertrand AT. Striated muscle laminopathies. Sem Cell Dev Biol 2014. [14] Gesson K, Vidak S, Foisner R. Lamina-associated polypeptide (LAP)2alpha and nucleoplasmic lamins in adult stem cell regulation and disease. Sem Cell Dev Biol 2013. [15] Cau P, Navarro C, Harhouri K, et al. Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective. Sem Cell Dev Biol 2014. [16] Guenantin AC, Briand N, Bidault G, et al. Nuclear envelope-related lipodystrophies. Sem Cell Dev Biol 2013. [17] Cartwright S, Karakesisoglou I. Nesprins in health and disease. Sem Cell Dev Biol 2013, http://dx.doi.org/10.1016/j.semcdb.2013.12.010.
Gisèle Bonne a,b,∗ Sorbonne Universités, UPMC Univ Paris 06, INSERM U974, CNRS FRE 3617, Center of Research in Myology, Institut de Myologie, Paris F-75013, France b Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris F-75013, France a
∗ Correspondence
to: Center of Research in Myology, UPMC – Inserm UMRS 974, CNRS FRE3617, Institut de Myologie, G.H. Pitié-Salpêtrière, 47, boulevard de l’Hopital, F-75 651 Paris Cedex 13, France. Tel.: +33 1 42 16 57 23; fax: +33 1 42 16 57 00. E-mail address: [email protected] Available online xxx
Please cite this article in press as: Bonne G. Nuclear envelope proteins in health and diseases. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.023
ARTICLE IN PRESS
YSCDB-1576; No. of Pages 2
Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb
Editorial
Nuclear envelope proteins in health and diseases
The nuclear envelope (NE), a hallmark of eukaryotic cells, is a highly organized double membrane that encloses the nuclear genome. The NE is a specialized cisterna of endoplasmic reticulum (ER) with the outer (ONM) and the inner (INM) nuclear membranes separating the nuclear from the cytoplasmic compartments, interconnecting through nuclear pore complexes and associated with the nuclear lamina, a fibrous meshwork of intermediate filaments lying underneath the INM [1]. Despite its essential position in the cell, the exact structure, composition and functions of the NE are yet not fully deciphered. Twenty years ago, the molecular genetics era shed light on NE components, with the identification of a hitherto new NE protein, the emerin, to be the first INM protein involved in a rare human genetic disease, the X-linked form of Emery–Dreifuss muscular dystrophy (EDMD) [2,3]. This very first link between the NE and diseases was followed a few years after with the implication of A-type lamins, components of the nuclear lamina, in the autosomal forms of EDMD, making EDMD the first disease of the NE [4,5]. But this was only the discovery of the “tip of the iceberg”. Indeed, since these first identifications, A-type lamins have been implicated in a wide range of rare diseases, with more than 10 different types of Laminopathies described, affecting either specifically one tissue type (striated muscle, adipose tissue, peripheral nerve) or several tissues in a systemic manner (premature aging syndromes) [6]. Other NE components and interacting partners, such as the B-type lamins, Lamin B receptor (LBR), ZMPSTE24, TorsinA, MAN1, LAP2␣, LAP1. . . have been also linked to different diseases [6–8]. As a result, the NE is now positioned on the interface between cell biology and medicine. The constant “back-and-forth” between these two disciplines has allowed not only the identification of new components of the NE – some being implicated in diseases (e.g. nesprins, SUN. . .) [9,10], the others being good candidates for yet unidentified human diseases [11] – but also the deciphering of some of their functions taking advantage of the complementarities of both the healthy and diseased contexts, and this for the benefit of patients. As the field is still rapidly growing, it has been a challenge to restrict my choice to a few topics for this special issue of Seminars in Cell & Developmental Biology. The eight reviews cover different components of the NE, different types of disorders ranging from rare to more commons, and also different approaches used to explore their roles and dysfunctions, making the NE a real paradigm from basic science to translational medicine. Koch and Holaska [12] focus on emerin functions and the current thinking for how loss or mutations in emerin cause EDMD. Emerin has now been shown to have diverse functions, including the regulation of gene expression, cell signaling, nuclear structure
and chromatin architecture. Their review highlights open questions concerning emerin’s roles in cell and nuclear biology. For the A-type lamins, the three main types of laminopathies are presented, i.e. the striated muscle laminopathies comprising different forms of muscular dystrophy and cardiomyopathy [13,14], the premature aging syndromes [15] and the NE-related lipodystrophies [16]. A-type lamins are components of the nuclear lamina, which mediates nuclear stiffness and anchors chromatin to the nuclear periphery. A-type lamins are also found in the nuclear interior, i.e. in the nucleoplasm where they interact among others with lamina-associated polypeptide 2␣ (LAP2␣) [14]. In the context of the striated muscles, Azibani et al. [13] focus on studies performed on knock-out and knock-in Lmna mouse models, which have led to decipher some of the lamin A/C functions in striated muscles and to the first preclinical trials of pharmaceutical therapies. Gesson et al. [14] review the roles of LAP2␣ in the regulation of nucleoplasmic pool of A-type lamins highlighting the potential function of the nucleoplasmic A-type lamins and LAP2␣ as regulators of adult stem cell function and tissue homeostasis and discussing potential implications of this concept in the context of striated muscle laminopathies and premature aging syndromes. Cau et al. [15] present an extensive review on the premature aging syndromes. They dissect in deep the clinical and genetic spectrum of these ultra rare disorders, the current knowledge of the NE and nucleoplasm components involved and their pathophysiological mechanisms that had led in less than 10 years to several clinical trials for progeria children. They particularly highlighted how improving our knowledge of these syndromes and searching for innovative and efficient therapies may significantly not only expand the affected childrens’ lifespan and preserve their quality of life but also improve our understanding of aging-related disorders, physiological aging and other physiological processes such as those involved in oncogenesis. Guénantin et al. [16] report on lipodystrophic syndromes, affecting the adipose tissue, linked to alteration of A-type and B-type lamins, and present the clinical, tissular and cellular characteristics of these disorders as well as their hypothetical pathophysiological mechanisms. To complete the nuclear lamina defects, Hutchison [8] reviews B-type lamins in health and disease. The gene encoding lamin B1 causes leukodystrophy, an adult onset neurodegenerative disorder, when duplicated and had been implicated as a susceptibility gene in neural tube defects. For over two decades, B-type lamins were thought to have roles in fundamental processes including correct assembly of nuclear envelopes, DNA replication, transcription and cell survival. Recent studies have questioned these roles and have
http://dx.doi.org/10.1016/j.semcdb.2014.04.023 1084-9521/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Bonne G. Nuclear envelope proteins in health and diseases. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.023
G Model YSCDB-1576; No. of Pages 2
ARTICLE IN PRESS Editorial / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
2
instead emphasized the role of these proteins in tissue building, tissue integrity and cellular senescence. The review highlights how different model systems have contributed to our understanding of the functions of B-type lamins and which of those functions are critical for human health and disease. Shin et al. [7] present an interesting view of the role of the Lamina-associated polypeptide 1 (LAP1) in the tissue specificity of some NE-related diseases. Indeed, as mentioned above, mutations in genes encoding widely expressed NE proteins often lead to diseases that manifest in specific tissues. LAP1, an integral protein of the INM expressed in most cells and tissues interacts with lamins, torsinA and emerin suggesting it may serve as a key node for transducing signals across the NE. Based on recent in vivo studies in genetically modified mice supporting functional links between LAP1 and both torsinA and emerin, Shin et al. propose that tissueselective NE-diseases may result, at least in part, from the selective disruption of discrete NE protein complexes. Finally, the review by Cartwright and Karakesisoglou [17] make the “link” between the NE and the cytoplasm with their comprehensive review of Nesprins in health and disease. Indeed, the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex is an evolutionary conserved structure that spans the entire NE, and integrates the nuclear interior with the cytoskeleton, in order to support a diverse array of fundamental biological processes. Nesprins (Nuclear Envelope SPectrin Repeat proteINS) are key components of the LINC complex. Initially described as large integral NE proteins, they are far more complex as their genes generate many variants, which occupy various sub-cellular compartments suggesting functions beyond the NE and LINC complex. The involvement of nesprins in diseases, i.e. cancer, myopathies, arthrogryposis, neurological disorders and hearing loss, has further expanded our knowledge of their functions. Cartwright and Karakesisoglou review the huge complexity of the nesprins family, providing an in-depth account of their structure, molecular interactions and cellular functions and speculating about possible pathomechanisms underlying nesprin-associated diseases. Altogether, the reviews of this special issue of Seminars in Cell & Developmental Biology dramatically demonstrate how essential is merging healthy and disease contexts for the exploration of the structures and functions of the nuclear envelope proteins. Within twenty years, the landscape of the NE and of its related compartment, the nucleoplasm has greatly changed, but still we have only started to unravel the “tip of the iceberg”. I am convinced that in the near future thanks to the current intensive research in the field, the NE will be fully recognized, no more as a “simple” double lipid bilayer separating the nuclear from the cytoplasmic compartments, but as a real hub platform functionally inter-connecting these cell compartments. I sincerely hope you will enjoy this special issue. References [1] Hetzer MW. The nuclear envelope. Cold Spring Harb Perspect Biol 2010;2:a000539.
[2] Bione S, Maestrini E, Rivella S, Manchini M, Regis S, Romei G, et al. Identification of a novel X-linked gene responsible for Emery–Dreifuss muscular dystrophy. Nature Genet 1994;8:323–7. [3] Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, et al. Emerin deficiency at the nuclear membrane in patients with Emery–Dreifuss muscular dystrophy. Nature Genet 1996;12:254–9. [4] Bonne G, Di Barletta MR, Varnous S, Becane H-M, Hammouda EH, Merlini L, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nature Genet 1999;21:285–8. [5] di Barletta MR, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, et al. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery–Dreifuss muscular dystrophy. Am J Hum Genet 2000;66:1407–12. [6] Worman HJ, Bonne G. Laminopathies”: a wide spectrum of human diseases. Exp Cell Res 2007;313:2121–33. [7] Shin JY, Dauer WT, Worman HJ. Lamina-associated polypeptide 1: Protein interactions and tissue-selective functions. Sem Cell Dev Biol 2014, http://dx.doi.org/10.1016/j.semcdb.2014.01.010. [8] Hutchison CJ. B-type lamins in health and disease. Sem Cell Dev Biol 2013, http://dx.doi.org/10.1016/j.semcdb.2013.12.012. [9] Attali R, Warwar N, Israel A, Gurt I, McNally E, Puckelwartz M, et al. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet 2009;18:3462–70. [10] Li P, Meinke P, Huong le TT, Wehnert M, Noegel AA. Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies. Hum Mutat 2014;35:452–61. [11] Schirmer EC, Florens L, Guan T, Yates 3rd JR, Gerace L. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science 2003;301:1380–2. [12] Koch AJ, Holaska JM. Emerin in health and disease. Sem Cell Dev Biol 2013, http://dx.doi.org/10.1016/j.semcdb.2013.12.008. [13] Azibani F, Muchir A, Vignier N, Bonne G, Bertrand AT. Striated muscle laminopathies. Sem Cell Dev Biol 2014. [14] Gesson K, Vidak S, Foisner R. Lamina-associated polypeptide (LAP)2alpha and nucleoplasmic lamins in adult stem cell regulation and disease. Sem Cell Dev Biol 2013. [15] Cau P, Navarro C, Harhouri K, et al. Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective. Sem Cell Dev Biol 2014. [16] Guenantin AC, Briand N, Bidault G, et al. Nuclear envelope-related lipodystrophies. Sem Cell Dev Biol 2013. [17] Cartwright S, Karakesisoglou I. Nesprins in health and disease. Sem Cell Dev Biol 2013, http://dx.doi.org/10.1016/j.semcdb.2013.12.010.
Gisèle Bonne a,b,∗ Sorbonne Universités, UPMC Univ Paris 06, INSERM U974, CNRS FRE 3617, Center of Research in Myology, Institut de Myologie, Paris F-75013, France b Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris F-75013, France a
∗ Correspondence
to: Center of Research in Myology, UPMC – Inserm UMRS 974, CNRS FRE3617, Institut de Myologie, G.H. Pitié-Salpêtrière, 47, boulevard de l’Hopital, F-75 651 Paris Cedex 13, France. Tel.: +33 1 42 16 57 23; fax: +33 1 42 16 57 00. E-mail address: [email protected] Available online xxx
Please cite this article in press as: Bonne G. Nuclear envelope proteins in health and diseases. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.023
