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Biochemical Society Transactions (2015) Volume 43, part 1

Procollagen export from the endoplasmic reticulum Vivek Malhotra*†‡1 , Patrik Erlmann*†‡ and Cristina Nogueira*†‡ *Cell and Developmental Biology Programme, Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003 Barcelona, Spain †Universitat Pompeu Fabra (UPF), Placa ¸ de la Merce` 10, 08002 Barcelona, Spain ‡Institucio´ Catalana de Recerca i Estudis Avancats ¸ (ICREA), Passeig Llu´ıs Companys 23, 08010 Barcelona, Spain

Abstract Collagens are secreted into the extracellular space where they assemble into a large complex protein network to form basement membrane and extracellular matrix. Collagens are therefore essential for cell attachment, tissue organization and the overall survival of all multicellular organisms. Collagens are synthesized in the endoplasmic reticulum (ER) but they are too big to fit into a conventional coat protein complex II (COPII) transport carrier of 60–90 nm average diameter. How are these molecules exported from the ER and then transported along the secretory pathway? We describe here the involvement of special packing machinery composed of hetero oligomers of transport and Golgi organization 1 (TANGO1) and cutaneous T-cell lymphoma-associated antigen 5 (cTAGE5) in the export of procollagen VII from the ER.

Introduction Secretory and plasma membrane (PM) proteins that are synthesized into the ER are packed into COPII vesicles of 60–90 nm average diameter and transported to the Golgi apparatus [1]. Trafficking of cargoes across the Golgi is a contentious topic. There is data on the involvement of COPI vesicles, tubules, continuities across the cisternae of the Golgi stacks and cargo transport by non-vesicular or cisternal maturation [2–5]. Export of proteins from late Golgi for secretion or delivery to the PM is mediated by a number of distinct carriers and those that have been described in greater detail include carriers of the trans-Golgi network (TGN) to the cell surface (CARTS) [6] and clathrin-coated vesicles [7]. The export from the TGN to the PM can be via or independent of endosomes. In polarized cells, different carriers deliver cargoes to the apical and basolateral surface respectively [8]. Specialized secretory cells pack cargoes, such as mucins and insulin, into granules that mature to condense cargoes and release them by fusion with PM in a signal-dependent manner [9,10]. Although the mechanisms of biogenesis of clathrin, COPI- and COPII-coated vesicles are known in considerable detail, an understanding of mechanisms that create other vesicles and transport processes mentioned above remains poorly understood. The secreted collagens and lipoprotein particles called chylomicrons are also transported from the ER, but they are too big to fit into generic COPII and COPI vesicles. Is trafficking of procollagen I by COPII vesicles [11], Key words: collagen, COPII, secretion, SNARE, TANGO. Abbreviations: CARTS, carriers of the TGN to the cell surface; COP, coatomer protein; cTAGE5, cutaneous T-cell lymphoma-associated antigen 5; ER, endoplasmic reticulum; ERGIC, ER–Golgi intermediate compartment; HRP, horseradish peroxidase; PM, plasma membrane; PRD, prolinerich domain; SH3, Src homology 3; ss, signal sequence; TANGO, transport and Golgi organization; TGN, trans-Golgi network. 1 To whom correspondence should be addressed (email [email protected]).

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megacarriers [12] or by cisternal maturation [2]? Upon exiting the TGN, collagen I is excluded from CARTS [6]. How are these molecules transported from the TGN to PM? All in all, it is fair to state that the secretion of collagens that make up 25–30 % of our dry body weight is not entirely clear.

TANGO1 is required for procollagen VII and IV export from ER A genome-wide screen of proteins required for secretion of signal sequence (ss)-containing plant protein horseradish peroxidase (HRP) by Drosophila S2 cells revealed the involvement of a number of new gene products [13]. These TANGO (transport and Golgi organization) proteins include a protein called TANGO1/MIA3 whose knockdown by siRNA affected secretion of procollagen VII from mammalian cells [14]. Strangely, export of the equally bulky procollagen I was largely unaffected upon TANGO1 knockdown. TANGO1 is located at the ER exit sites and interacts with SEC23A and SEC24C of COPII coats through its proline-rich domain (PRD). The SH3 (Src homology 3) domain of TANGO1 in the lumen of the ER binds procollagen VII. Deletion of TANGO1 in mice produces pups that are smaller in size, lack mineralized bones and die soon after birth. The pups also exhibit skin abnormalities and are defective in secreting a number of collagens [15]. TANGO1 is also required for secretion of the only collagen expressed in Drosophila (collagen IV). Interestingly, in polarized tissues of the fruitfly, TANGO1 is confined to basal ER exit sites [16,17]. These findings underscore the physiological relevance of TANGO1 in procollagen VII and procollagen IV export from the ER. In mammals, TANGO1 is expressed in all cells except cells of haemopoietic origin [18]. Cells of the liver and small Biochem. Soc. Trans. (2015) 43, 104–107; doi:10.1042/BST20140286

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Figure 1 The structural organization of TANGO1/MIA3 and its homologue cTAGE5/MIA2 The structural domains of TANGO1, MIA2 and cTAGE5 as annotated in the UniProtKB database. TM, transmembrane domain; ss, signal sequence.

intestine express, in addition to TANGO1, a TANGO1like protein called MIA2. Both TANGO1 and MIA2 have similar structural features (Figure 1) and localize to the ER exit sites [19]. A spliced variant of MIA2, called cutaneous Tcell lymphoma-associated antigen 5 (cTAGE5), in addition to liver and small intestine can be found in a wide range of tissue culture cell lines. cTAGE5 and TANGO1 interact through their second coiled-coil domain [20]. The first coiled-coil domain of cTAGE5 binds and recruits SEC12 to ER exit sites without affecting SEC12–GEF (guanine–nucleotideexchange factor) activity [21]. Knockdown of cTAGE5 by siRNA also arrests procollagen VII in the ER [20]. The exact role of MIA2 at ER exit sites is unclear, but a mouse harbouring a point mutation in its SH3-like domain was found to contain less cholesterol (40 % of control) and HDL (high-density lipoprotein; ∼20 %) in the blood [19]. However, as mentioned above, cells that express MIA2 also express TANGO1 and cTAGE5, so the meaning of a defect in circulating cholesterol in mice expressing mutant MIA2 remains unclear.

Procollagen VII export from the ER requires fusion of membranes Cross-linking of cellular proteins followed by immunoprecipitation of TANGO1 from mammalian cells revealed its interaction with SLY1. SLY1 is known for its role in protein transport between ER and Golgi and its interaction with the ER-specific t-SNAREs (target soluble N-ethylmaleimidesensitive fusion protein-attachment protein) Syntaxin 17 and Syntaxin 18 [22,23]. Interestingly, siRNA mediated knockdown of SLY1 and Syntaxin 18, but not Syntaxin 17, inhibited export of procollagen VII from the ER. Knockdown of Syntaxin 18, Syntaxin 17 or SLY1 did not affect general protein secretion, export of procollagen I from the ER or retrograde protein transport [24]. On the basis of the collective data, we propose the following scheme for the export of procollagen VII from the ER (Figure 2). TANGO1 binds procollagen VII in the ER lumen and interacts with SEC23/24 on the cytoplasmic side. cTAGE5 bound to TANGO1 recruits SEC12 to ER exit sites, which brings more SEC23/24 thus engaging additional

TANGO1–cTAGE5–cargo complexes. These interactions thus concentrate procollagen VII at ER exit sites. Membrane fusion proteins SLY1 and ER-localized Syntaxin 18 are then engaged at this site for fusion of membranes from a downstream compartment such as ERGIC (ER–Golgi intermediate compartment) or Golgi. As a result, the procollagen-VII-enriched ER patch grows into a large bud. TANGO1–cTAGE5–SEC12–SEC23/24 remains at the neck of the growing bud. Upon loading, a given amount of procollagen VII, TANGO1 separates from procollagen VII and from SEC23/24, which promotes recruitment of SEC13/31 that triggers fission of a mega procollagen VII-containing transport carrier from the ER. TANGO1– cTAGE5 is not incorporated into the departing procollagen VII-containing transport carriers. We cannot rule out the possibility that the large bud enriched in procollagen VII fuses directly with a Golgi cisternae without the involvement of a mega transport carrier. Altogether, we conclude the following: (i) The data suggest that procollagens are sorted in the ER but why sort these proteins in the ER if they meet again at the Golgi for further trafficking along the secretory pathway? The sorting at the ER might be an indication that these proteins follow separate pathways to perhaps different sides of a polarized cell, for example, collagen VII and collagen IV are secreted to the basal side and their sorting in the ER by TANGO1 might be necessary for their trafficking by a separate pathway form the ER. It is also possible that collagens travel at distinct times across the secretory pathway or to distinct cisternae of the Golgi en route to secretion from cells. (ii) Formation of ‘mega’ carriers at the ER to export procollagen VII requires accretion of membranes from ERGIC or an early Golgi compartment by a SLY1–Syntaxin 18 dependent membrane fusion event. (ii) To date, the best characterized proteins exported by TANGO1–cTAGE5 are collagen VII (in mammals) and collagen IV (in the fruitfly). Mice lacking TANGO1 gene are defective in the secretion of a number of collagens including I, II, III, IV, VII and IX [15]. It is, however, not known whether these collagens bind TANGO1. Knockdown of TANGO1 in fruitfly cells inhibits export of artificial cargoes such  C The

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Figure 2 A model for procollagen VII secretion from the ER TANGO1 bound to procollagen VII interacts with cTAGE5 that recruits SEC12 to an ER exit site. The PRDs of TANGO and cTAGE5 interact with SEC23/24 and prevent or delay the recruitment of SEC13/31.This allows a patch of ER to concentrated procollagen VII. This patch then recruits SLY1 and Syntaxin 18. SLY1 and Syntaxin 18 then recruit membranes from a compartment like the ERGIC. Fusion of ERGIC membranes with the ER patch promotes growth into a mega procollagen-enriched structure or a bud. Once a threshold quantity of procollagen is packed into this bud, TANGO1 dissociates from procollagen VII, which results in the separation of PRD from SEC23/24 on the cytoplasmic domain. SEC13/31 is then recruited to SEC23/24. This could have two possible outcomes: (i) the big bud containing collagen undergoes separation by fission, or (ii) the bud enriched in collagen VII fuses directly with the cisternae of the Golgi without the formation of a distinct carrier for subsequent trafficking along the Golgi stack.

ss-HRP and ss-luciferase that have no structural similarities to procollagen VII and IV [13,25]. It is likely that there are distinct export routes from the ER. Although endogenous secretory proteins such as collagen VII are exported via a specific path, artificial secretory proteins like ss-HRP and ssluciferase have no sorting signals and therefore exit by any route that is available. Blocking one pathway, such as that controlled by TANGO1, slows downs or blocks one of the possible exit routes.

Other proteins involved in procollagen export from the ER Knockdown of the ubiquitin ligase Cul3 by siRNA or shRNA in mouse embryonic fibroblasts was found to inhibit collagen IV secretion. Overexpression of a specific Cul3 adaptor protein, KLH12, in human fibroblast cell line IMR90 increased secretion of procollagen I and KLHL12 was present on large membranes of 200–500 nm diameter that also contained SEC31. SEC31 was found to be ubiquitinated  C The

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by Cul3–KLHL12 [12]. On the basis of these data, it has been suggested that mono-ubiquitination of SEC31 by Cul3–KLHL12 generates a larger COPII coat to generate a mega vesicle for the export of procollagen IV (mice) and procollagen I (human cell lines) from the ER. However, the site in SEC31 that is mono-ubiquitinated and involved in this process is not known. It is also not known whether this reaction generates a mega COPII-coated vesicle en route for secretion, whether the 200–500 nm KLHL12– SEC31 coated membrane bounded compartments contain collagen and finally whether collagen I and collagen IV are exported by the same pathway. More importantly, how does the cytoplasmic Cul3–KLHL12 communicate across the ER membrane with the secretory procollagen I and procollagen IV [26]? A protein called Sedlin is recruited to ER exit sites via TANGO1-dependent pathway and reported to regulate the cycling of Sar1–GTPase. This event is proposed to help generate carriers to commensurate with the size of procollagen I at the ER. How TANGO1 recruits Sedlin to ER exit sites is not known [27]. Even more importantly,

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TANGO1 is not involved in the export of procollagen I from the ER, so how this reaction then controls the activity of Sedlin for Sar1–GTPase remains unclear. The new findings are beginning to reveal insights and, not surprisingly, presenting new challenges on the mechanism of procollagen export from the ER. How cells control the quantity and timely release of collagens will help understand the functional assembly of extracellular matrix and the attachment of cells to basement membranes.

Funding This work is supported by the Deutsche Forschungsgemeinschaft (DFG), German Research Foundation fellowship [grant number ER 681/1-1 (to P.E.)]; the Plan Nacional [grant number BFU200800414]; the Consolider [grant number CSD2009-00016]; the Agencia ` de Gestio´ d’Ajuts Universitaris i de Recerca (AGAUR)-Catalan Government [grant number SGR2009-1488]; and the European Research Council [grant number 268692] to V.M.

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Procollagen export from the endoplasmic reticulum.

Collagens are secreted into the extracellular space where they assemble into a large complex protein network to form basement membrane and extracellul...
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