Trends in Cell Biology
ReviewER-to-Golgi Transport: A Sizeable Problem
Section snippets
Oversized Cargo: Too Big for COPII?
Efficient extracellular matrix (ECM) formation is essential for normal development. The early stages of metazoan embryo development, tissue organisation, and, for example, bone formation place high demands on the secretory system. Secretory cargo like collagens, aggrecan, fibronectin, fibrillin, and laminins (Table 1) exit the endoplasmic reticulum (ER) and traffic to the Golgi apparatus prior to reaching their destination, the extracellular space. Transport of proteins from the ER to the Golgi
The Case for Large Carriers
Fibrillar collagens are expressed in diverse species from sponges to humans and can thus be linked with evolutionary steps leading to multicellularity [19]. The most abundant collagen in humans is a fibrillar type I, which has been described as a rigid [10], rod-shaped trimer with a length of about 300 nm 9, 20. Procollagen IV is the major network-forming collagen of basement membranes, with an estimated overall length of 430 nm but with considerable flexibility arising from interruptions in
TANGO1 in ER-to-Golgi Transport of Collagens
The transport and Golgi organisation protein (TANGO1, encoded by the MIA3 gene) plays a key role in ER-to-Golgi trafficking of large proteins and has drawn increasing attention in recent years. TANGO1, an ER-resident transmembrane protein localising to ERESs in mammalian cells [16], was originally identified as a factor required for conventional secretion [49]. TANGO-related proteins have also been implicated directly in the formation of large COPII carriers that enable procollagen transport
Alternative Modes of ER–Golgi Trafficking of Large Cargoes
Large COPII carriers have yet to be identified in cells expressing endogenous protein levels. Primary fibroblasts do not contain any evident large COPII structures 11, 71. Most of the experiments resulting in large carriers were performed in cells overexpressing KLHL12 and or procollagens in transformed cell lines 11, 12. Furthermore, the micron-size punctate structures positive for Sec23 and procollagen in mouse osteoblasts are also positive for markers of autophagy and ubiquitin [72]. These
Concluding Remarks and Future Perspectives
The classical COPII pathway is considered by many to generate small, 80-nm vesicles (Figure 2Ai, Key Figure) insufficient for procollagen transport. More semi-flexible procollagen polymers might be able to fit into carriers only slightly larger than 80 nm COPII vesicles (Figure 2Aii), and this has some experimental support [18], while other models propose the formation of larger carriers (Figure 2Aiii). To determine how large cargo proteins can be transported from the ER to the ERGIC and/or
Acknowledgments
We thank Nicola Stevenson for critical reading of the manuscript. Our laboratory is supported by grants from the Medical Research Council (MRC) (MR/P000177/1) and the Biotechnology and Biological Sciences Research Council (BB/N000420/1). J.M. is funded by a postgraduate scholarship from the University of Bristol. The funders had no role in the writing of this review.
Glossary
- Coat complex type II (COPII)
- a multiprotein complex that assembles in a GTP-dependent manner on the cytosolic face of the ER to concentrate cargo and initiate transport carrier formation.
- Endoplasmic reticulum exit site (ERES)
- comprising the transitional ER, budding structures, and the first post-ER membranes of the ERGIC.
- ER–Golgi intermediate compartment (ERGIC)
- the first post-ER compartment; plays a key role in the models of large-vesicle formation. It could act to maintain the physical
References (128)
COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum
Cell
(1994)Trafficking mechanisms of extracellular matrix macromolecules: insights from vertebrate development and human diseases
Int. J. Biochem. Cell Biol.
(2014)Exiting the ER: what we know and what we don’t
Trends Cell Biol.
(2014)Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils
J. Biol. Chem.
(1991)Structural implications from an electronmicroscopic comparison of procollagen V with procollagen I, pC-collagen I, procollagen IV, and a Drosophila procollagen
J. Biol. Chem.
(1982)Regulation of the CUL3 ubiquitin ligase by a calcium-dependent co-adaptor
Cell
(2016)TANGO1 facilitates cargo loading at endoplasmic reticulum exit sites
Cell
(2009)Environmentally controlled curvature of single collagen proteins
Biophys. J.
(2018)Type I procollagens containing substitutions of aspartate, arginine, and cysteine for glycine in the pro alpha 1 (I) chain are cleaved slowly by N-proteinase, but only the cysteine substitution introduces a kink in the molecule
J. Biol. Chem.
(1992)Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells
J. Biol. Chem.
(2015)
Procollagen binds to both prolyl 4-hydroxylase/protein disulfide isomerase and HSP47 within the endoplasmic reticulum in the absence of ascorbate
FEBS Lett.
Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone
Semin. Cell Dev. Biol.
Substrate recognition of collagen-specific molecular chaperone HSP47. Structural requirements and binding regulation
J. Biol. Chem.
The endoplasmic reticulum-resident collagen chaperone Hsp47 interacts with and promotes the secretion of decorin, fibromodulin, and lumican
J. Biol. Chem.
The SEC23–SEC31 interface plays critical role for export of procollagen from the endoplasmic reticulum. J
Biol. Chem.
Structural basis for cargo regulation of COPII coat assembly
Cell
Coat flexibility in the secretory pathway: a role in transport of bulky cargoes
Curr. Opin. Cell Biol.
Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle
Cell
Drosophila Dumpy is a gigantic extracellular protein required to maintain tension at epidermal–cuticle attachment sites
Curr. Biol.
ER-to-Golgi carriers arise through direct en bloc protrusion and multistage maturation of specialized ER exit domains
Dev. Cell
Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta
Bone
Procollagen traverses the Golgi stack without leaving the lumen of cisternae: evidence for cisternal maturation
Cell
TFG promotes organization of transitional ER and efficient collagen secretion
Cell Rep.
Visualizing intracellular organelle and cytoskeletal interactions at nanoscale resolution on millisecond timescales
Cell
Sec16 is a determinant of transitional ER organization
Curr. Biol.
The genetic basis of a craniofacial disease provides insight into COPII coat assembly
Dev. Cell
Insights into COPII coat nucleation from the structure of Sec23.Sar1 complexed with the active fragment of Sec31
Dev. Cell
COPII-coated vesicle formation reconstituted with purified coat proteins and chemically defined liposomes
Cell
Imaging of procollagen transport reveals COPI-dependent cargo sorting during ER-to-Golgi transport in mammalian cells
J. Cell Sci.
COPII-dependent ER export in animal cells: adaptation and control for diverse cargo
Histochem. Cell Biol.
The pathway of collagen secretion
Annu. Rev. Cell Dev. Biol.
COPII and the regulation of protein sorting in mammals
Nat. Cell Biol.
Synthesis and secretion of collagen by cells of connective tissue, bone, and dentin
Anat. Rec.
COPII-coated membranes function as transport carriers of intracellular procollagen I
J. Cell Biol.
TANGO1 recruits ERGIC membranes to the endoplasmic reticulum for procollagen export
eLife
SLY1 and syntaxin 18 specify a distinct pathway for procollagen VII export from the endoplasmic reticulum
eLife
Sedlin controls the ER export of procollagen by regulating the Sar1 cycle
Science
Mechanisms for exporting large-sized cargoes from the endoplasmic reticulum
Cell. Mol. Life Sci.
The evolution of extracellular matrix
Mol. Biol. Cell
The collagenopathies: review of clinical phenotypes and molecular correlations
Curr. Rheumatol. Rep.
Mutations in collagen genes: causes of rare and some common diseases in humans
FASEB J.
Precursors of collagen secreted by cultured human fibroblasts
Proc. Natl. Acad. Sci. U. S. A.
A major collagen-binding protein of chick embryo fibroblasts is a novel heat shock protein
J. Cell Biol.
Type I collagen in Hsp47-null cells is aggregated in endoplasmic reticulum and deficient in N-propeptide processing and fibrillogenesis
Mol. Biol. Cell
Accumulation of type IV collagen in dilated ER leads to apoptosis in Hsp47-knockout mouse embryos via induction of CHOP
J. Cell Sci.
Intracellular interaction of collagen-specific stress protein HSP47 with newly synthesized procollagen
J. Cell Biol.
Direct in vitro and in vivo evidence for interaction between Hsp47 protein and collagen triple helix
J. Biol. Chem.
Hsp47: a molecular chaperone that interacts with and stabilizes correctly-folded procollagen
EMBO J.
Procollagen export from the endoplasmic reticulum
Biochem. Soc. Trans.
Cell-free generation of COPII-coated procollagen I carriers
Bio Protoc.
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2021, Matrix Biology PlusCitation Excerpt :HSP47 aids the translocation of collagen from the rough ER via the ERGIC (ER Golgi Intermediate Compartment) to the Golgi for secretion to the ECM, by acting as an anchor between the TANGO1 protein and collagen to allow packaging of collagen in secretory vesicles (Fig. 1) [32]. For an in depth review on the secretion of large cargo proteins we refer the reader to [33]. Folded collagen in the Golgi then undergoes cleavage with cleavage of the C-propeptide by procollagen C-proteinases (which are identical to the BMP-1/tolloid proteinase) that is required for fibrillogenesis (Fig. 1) [22].