Trends in Cell Biology
Volume 29, Issue 12, December 2019, Pages 940-953
Journal home page for Trends in Cell Biology

Review
ER-to-Golgi Transport: A Sizeable Problem

https://doi.org/10.1016/j.tcb.2019.08.007Get rights and content

Highlights

  • Export of cargo from the ER requires an adaptable system to accommodate cargoes of diverse size and shape.

  • In metazoans, the secretion of collagens has been widely studied due to their large size.

  • TANGO1 has emerged as a key player in assembling COPII-dependent machinery to drive export from the ER.

  • The interplay between TANGO1 and the chaperone Hsp47 is central to understanding this process.

  • New data and resulting models have challenged the ‘large carrier’ model and have led to questions of whether complete coating of carriers with COPII is needed.

Metazoans require efficient and ordered secretion of extracellular matrix (ECM) to coordinate cell and tissue function. Many ECM proteins are atypically large and their demand during key stages of development presents a major challenge to the canonical secretion machinery. While many of the molecular players in this pathway are known, little is understood about how they are integrated in time and space. Recent advances in gene engineering and super-resolution microscopy have underscored the spatiotemporal organisation of the endoplasmic reticulum (ER)–Golgi interface. These findings are challenging long-held models of vesicular transport of large matrix proteins, such as procollagen, and are implicating less well-defined carriers and direct interconnections between organelles. Here, we discuss current models describing the dynamics and mechanisms of ER–Golgi transport.

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)

  • N. Hosokawa et al.

    Procollagen binds to both prolyl 4-hydroxylase/protein disulfide isomerase and HSP47 within the endoplasmic reticulum in the absence of ascorbate

    FEBS Lett.

    (2000)
  • S. Ito et al.

    Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone

    Semin. Cell Dev. Biol.

    (2017)
  • T. Koide

    Substrate recognition of collagen-specific molecular chaperone HSP47. Structural requirements and binding regulation

    J. Biol. Chem.

    (1999)
  • Y. Ishikawa

    The endoplasmic reticulum-resident collagen chaperone Hsp47 interacts with and promotes the secretion of decorin, fibromodulin, and lumican

    J. Biol. Chem.

    (2018)
  • S.D. Kim

    The SEC23–SEC31 interface plays critical role for export of procollagen from the endoplasmic reticulum. J

    Biol. Chem.

    (2012)
  • S.M. Stagg

    Structural basis for cargo regulation of COPII coat assembly

    Cell

    (2008)
  • J. Hutchings et al.

    Coat flexibility in the secretory pathway: a role in transport of bulky cargoes

    Curr. Opin. Cell Biol.

    (2019)
  • M.C. Lee

    Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle

    Cell

    (2005)
  • M.B. Wilkin

    Drosophila Dumpy is a gigantic extracellular protein required to maintain tension at epidermal–cuticle attachment sites

    Curr. Biol.

    (2000)
  • A.A. Mironov

    ER-to-Golgi carriers arise through direct en bloc protrusion and multistage maturation of specialized ER exit domains

    Dev. Cell

    (2003)
  • M. Balasubramanian

    Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta

    Bone

    (2017)
  • L. Bonfanti

    Procollagen traverses the Golgi stack without leaving the lumen of cisternae: evidence for cisternal maturation

    Cell

    (1998)
  • J. McCaughey

    TFG promotes organization of transitional ER and efficient collagen secretion

    Cell Rep.

    (2016)
  • Y. Guo

    Visualizing intracellular organelle and cytoskeletal interactions at nanoscale resolution on millisecond timescales

    Cell

    (2018)
  • P.L. Connerly

    Sec16 is a determinant of transitional ER organization

    Curr. Biol.

    (2005)
  • J.C. Fromme

    The genetic basis of a craniofacial disease provides insight into COPII coat assembly

    Dev. Cell

    (2007)
  • X. Bi

    Insights into COPII coat nucleation from the structure of Sec23.Sar1 complexed with the active fragment of Sec31

    Dev. Cell

    (2007)
  • K. Matsuoka

    COPII-coated vesicle formation reconstituted with purified coat proteins and chemically defined liposomes

    Cell

    (1998)
  • D.J. Stephens et al.

    Imaging of procollagen transport reveals COPI-dependent cargo sorting during ER-to-Golgi transport in mammalian cells

    J. Cell Sci.

    (2002)
  • J. McCaughey et al.

    COPII-dependent ER export in animal cells: adaptation and control for diverse cargo

    Histochem. Cell Biol.

    (2018)
  • V. Malhotra et al.

    The pathway of collagen secretion

    Annu. Rev. Cell Dev. Biol.

    (2015)
  • G. Zanetti

    COPII and the regulation of protein sorting in mammals

    Nat. Cell Biol.

    (2011)
  • C.P. Leblond

    Synthesis and secretion of collagen by cells of connective tissue, bone, and dentin

    Anat. Rec.

    (1989)
  • A. Gorur

    COPII-coated membranes function as transport carriers of intracellular procollagen I

    J. Cell Biol.

    (2017)
  • A.J. Santos

    TANGO1 recruits ERGIC membranes to the endoplasmic reticulum for procollagen export

    eLife

    (2015)
  • C. Nogueira

    SLY1 and syntaxin 18 specify a distinct pathway for procollagen VII export from the endoplasmic reticulum

    eLife

    (2014)
  • R. Venditti

    Sedlin controls the ER export of procollagen by regulating the Sar1 cycle

    Science

    (2012)
  • K. Saito et al.

    Mechanisms for exporting large-sized cargoes from the endoplasmic reticulum

    Cell. Mol. Life Sci.

    (2015)
  • S. Ozbek

    The evolution of extracellular matrix

    Mol. Biol. Cell

    (2010)
  • R. Jobling

    The collagenopathies: review of clinical phenotypes and molecular correlations

    Curr. Rheumatol. Rep.

    (2014)
  • H. Kuivaniemi

    Mutations in collagen genes: causes of rare and some common diseases in humans

    FASEB J.

    (1991)
  • B. Goldberg

    Precursors of collagen secreted by cultured human fibroblasts

    Proc. Natl. Acad. Sci. U. S. A.

    (1972)
  • K. Nagata

    A major collagen-binding protein of chick embryo fibroblasts is a novel heat shock protein

    J. Cell Biol.

    (1986)
  • Y. Ishida

    Type I collagen in Hsp47-null cells is aggregated in endoplasmic reticulum and deficient in N-propeptide processing and fibrillogenesis

    Mol. Biol. Cell

    (2006)
  • T. Marutani

    Accumulation of type IV collagen in dilated ER leads to apoptosis in Hsp47-knockout mouse embryos via induction of CHOP

    J. Cell Sci.

    (2004)
  • M. Satoh

    Intracellular interaction of collagen-specific stress protein HSP47 with newly synthesized procollagen

    J. Cell Biol.

    (1996)
  • T. Ono

    Direct in vitro and in vivo evidence for interaction between Hsp47 protein and collagen triple helix

    J. Biol. Chem.

    (2012)
  • M. Tasab

    Hsp47: a molecular chaperone that interacts with and stabilizes correctly-folded procollagen

    EMBO J.

    (2000)
  • V. Malhotra

    Procollagen export from the endoplasmic reticulum

    Biochem. Soc. Trans.

    (2015)
  • L. Yuan

    Cell-free generation of COPII-coated procollagen I carriers

    Bio Protoc.

    (2017)
  • Cited by (44)

    • Intra-Golgi Transport

      2022, Encyclopedia of Cell Biology: Volume 1-6, Second Edition
    • Four decades in the making: Collagen III and mechanisms of vascular Ehlers Danlos Syndrome

      2021, Matrix Biology Plus
      Citation 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].

    View all citing articles on Scopus
    View full text