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Review
. 2018 Aug;150(2):119-131.
doi: 10.1007/s00418-018-1689-2. Epub 2018 Jun 18.

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

Janine McCaughey  1 , David J Stephens  2
Affiliations
Review

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

Janine McCaughey et al. Histochem Cell Biol. 2018 Aug.

Abstract

The export of newly synthesized proteins from the endoplasmic reticulum is fundamental to the ongoing maintenance of cell and tissue structure and function. After co-translational translocation into the ER, proteins destined for downstream intracellular compartments or secretion from the cell are sorted and packaged into transport vesicles by the COPII coat protein complex. The fundamental discovery and characterization of the pathway has now been augmented by a greater understanding of the role of COPII in diverse aspects of cell function. We now have a deep understanding of how COPII contributes to the trafficking of diverse cargoes including extracellular matrix molecules, developmental signalling proteins, and key metabolic factors such as lipoproteins. Structural and functional studies have shown that the COPII coat is both highly flexible and subject to multiple modes of regulation. This has led to new discoveries defining roles of COPII in development, autophagy, and tissue organization. Many of these newly emerging features of the canonical COPII pathway are placed in a context of procollagen secretion because of the fundamental interest in how a coat complex that typically generates 80-nm transport vesicles can package a cargo reported to be over 300 nm. Here we review the current understanding of COPII and assess the current consensus on its role in packaging diverse cargo proteins.

Keywords: COPII; Endoplasmic reticulum; Golgi, procollagen; Vesicle.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
COPII-dependent packaging. (1) At ERES Sec16 binds the membrane protein Sec12, which acts as a GEF for Sar1–GDP promoting GDP–GTP exchange. Active Sar1–GTP then binds the ER membrane. (2) The inner COPII components Sec23/24 are recruited and Sec24 binds cargo proteins from the ER lumen. (3) TFG and Sec16 help organize the ERES to which Sec13/Sec31 are recruited by binding to the inner coat complex. (4) A COPII vesicle begins to form as the membrane deforms, Sar1–GTP accumulates at the base of this structure and undergoes conformational changes through GTP-hydrolysis induced by Sec23–Sec24 together with Sec13–Sec31. (5) The COPII vesicle containing the cargo proteins is released from the ER and traffics to the ERGIC. (6) Fusion with the ERGIC membrane takes place after uncoating of the vesicle. (7) Subsequently, cargo proteins are transported from the ERGIC to the Golgi
Fig. 2
Fig. 2
Proposed role of TANGO1 and cTAGE5. (1) cTAGE5 binds Sec12 and concentrates it to the ERES. TANGO1 binds Hsp47 through its ER-luminal SH3-domain, directing procollagen to ERES. (2) Efficient Sar1–GTP/GDP cycling is facilitated by sedlin and Sec12. The COPII prebudding complex is further regulated by TANGO1 together with cTAGE5 that bind to the COPII inner layer. The NRZ tethering complex is recruited by TANGO1/cTAGE5 and recruits ERGIC membranes to the forming COPII complex. TANGO1/cTAGE5 assemble the fusion machinery SLY1 and syntaxin18 that drive incorporation of ERGIC membranes into the vesicle to allow procollagen incorporation into the carrier (3). Some uncertainty remains as to the precise structure of procollagen trimers on exit from the ER such that larger COPII-coated carriers might not be necessary
Fig. 3
Fig. 3
Post-translational modification of the COPII coat for efficient coat assembly. COPII vesicles can be modified in several ways. (A) Monoubiquitylation of Sec31A is facilitated by the CUL3-KLHL12 ubiquitin ligase in a calcium-dependent manner and helps regulate COPII size. This process can be reversed by USP8. ALG-2, a subunit of the KLHL12 complex, facilitates enrichment and assembly of TFG at ERES. (B) O-glycosylation through addition of O-N-acetylglucosamine to Sec24 and Sec23 is important for organization and regulation of the COPII complex. (Ci) Phosphorylation of Sec23/24 through CK1δ and PP6 confers directionality on COPII vesicles from ER to Golgi, while phosphorylation by CK2. (Cii) Inhibits association of Sec31 with the membrane. Sec24 phosphorylation is also involved in autophagy. All of these processes are necessary for efficient COPII assembly
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