Vesicle-mediated export from the ER: COPII coat function and regulation

Abstract

Vesicle trafficking from the endoplasmic reticulum (ER) is a vital cellular process in all eukaryotes responsible for moving secretory cargoes from the ER to the Golgi apparatus. To accomplish this feat, the cell employs a set of conserved cytoplasmic coat proteins - the coat protein II (COPII) complex - that recruit cargo into nascent buds and deform the ER membrane to drive vesicle formation. While our understanding of COPII coat mechanics has developed substantially since its discovery, we have only recently begun to appreciate the factors that regulate this complex and, in turn, ER-to-Golgi trafficking. Here, we describe these factors and their influences on COPII vesicle formation. Properties intrinsic to the GTP cycle of the coat, as well as coat structure, have critical implications for COPII vesicle trafficking. Extrinsic factors in the cytosol can modulate COPII activity through direct interaction with the coat or with scaffolding components, or by changing composition of the ER membrane. Further, lumenal and membrane-bound cargoes and cargo receptors can influence COPII-mediated trafficking in equally profound ways. Together, these factors work in concert to ensure proper cargo movement in this first step of the secretory pathway. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.

Keywords: CLSD; COPII; Cargo export; Cargo receptor; ER; ER exit sites; ERES; ERK; Endoplasmic reticulum; GAP; GEF; GPI-AP; GST; GTPase activating protein; MAPK; PH; PtdIns4P; TANGO1; TFG-1; TRK-fused gene 1; VSVG; Vesicle; bst; bypass-of-sec-thirteen; cTAGE5; coat protein II complex; cranio–lentinculo–sutural dysplasia; cutaneous T-cell lymphoma-associated antigen 5; endoplasmic reticulum; extracellular signal-regulated kinase; glutathione S-transferase; glycosylphophatidylinositol-anchored protein; guanine nucleotide exchange factor; mitogen activated protein kinase; phosphatidylinositol 4-phosphate; pleckstrin homology; transport and Golgi organization 1; vesicular stomatitis virus G protein.

Figure 1. COPII assembly at the ER and regulation by cytosolic factors

COPII coat formation at the ER is initiated by recruitment of Sar to the membrane in the GTP-bound state, enhanced by Sec12 GEF activity. Sar1-GTP recruits Sec23/24 heterodimer through interaction with Sec23. At the ER, Sec24 recruits cargo into pre-budding complexes. Sec13/31 complex is recruited to the inner coat layer through interactions with Sec23. Sec13/31 assembly into the coat drives membrane curvature, facilitating membrane deformation. Lumenal cargoes diffuse into the nascent bud or are recruited through cargo receptor proteins. Vesicle release from the ER is achieved in a manner related to Sar1 GTP hydrolysis. Released COPII vesicles typically fall within a 60 to 100 nanometer range. Sec16 facilitates COPII vesicle formation at the ER, likely through scaffolding COPII components and contributing to ERES structure. Interactions of COPII and COPII-associated components with domains of Sec16 are shown in the box in the upper left. Non-COPII proteins that affect COPII vesicle formation are shown in red italics, with red arrows indicating their proposed targets.

Figure 2. Cargo and cargo receptors as COPII regulators

A. Concentration of lumenally oriented asymmetric cargo and cargo receptors at ERES confers a local membrane environment less amenable to bending and thus requires the full rigidity of the Sec13/31 cage. B. TANGO1 competes with Sec13/31 for binding of Sec23/24, thus stalling GTP hydrolysis. This allows for polymerization of a larger coat for trafficking of procollagen. C. A variety of other cargo receptors may also have regulatory roles. Erv14 may act as a chaperone for its plasma membrane-localized cargo. Receptors for cargo that could interact with the coat directly are also appealing candidates for regulatory roles.