Export Control: Post-transcriptional Regulation of the COPII Trafficking Pathway

Abstract

The coat protein complex II (COPII) mediates forward trafficking of protein and lipid cargoes from the endoplasmic reticulum. COPII is an ancient and essential pathway in all eukaryotes and COPII dysfunction underlies a range of human diseases. Despite this broad significance, major aspects of COPII trafficking remain incompletely understood. For example, while the biochemical features of COPII vesicle formation are relatively well characterized, much less is known about how the COPII system dynamically adjusts its activity to changing physiologic cues or stresses. Recently, post-transcriptional mechanisms have emerged as a major mode of COPII regulation. Here, we review the current literature on how post-transcriptional events, and especially post-translational modifications, govern the COPII pathway.

Keywords: COPII; autophagy; membrane trafficking; post-translation modification; signaling/signaling pathways.

FIGURE 1

Overview of COPII vesicle formation. COPII vesicle formation proceeds through a series of steps: (1) Sar1 is recruited to the ER membrane at ER exit sites (ERES), marked by Sec16. Using the GEF Sec12, Sar1 exchanges GDP for GTP and inserts an α-helix into the ER membrane, promoting curvature. (2) Sec23 and Sec24 heterodimers are recruited to ERES, binding Sar1 to form the pre-budding complex. Cargo is loaded into the forming vesicle through direct interaction with Sec24, interaction with a Sec24-binding adaptor protein or bulk flow. (3) Lastly, Sec13 and Sec31 heterotetramers assemble around the forming vesicle, promoting further membrane curvature and scission.

FIGURE 2

Spatiotemporal control of COPII budding and fusion by Sec23 phosphorylation. (A) Phosphorylation of Sec23 by Hrr25 in yeast and CK1δ in mammalian cells prevents interaction with Sar1, inhibiting budding. The phosphatases Sit4/PP6 dephosphorylate Sec23, allowing for COPII vesicle formation. (B) Golgi/ERGIC membrane-localized pools of Hrr25/CK1δ phosphorylate Sec23, promoting vesicle uncoating and subsequent fusion with the target membrane. Addition of IC261, an Hrr25/CK1δ inhibitor, prevents COPII uncoating and fusion.

FIGURE 3

Reciprocal modification of Sec24 by O-GlcNAcylation and phosphorylation. During interphase, Sec24C is O-GlcNAc-modified. As the cell enters mitosis, Sec24C is deglycosylated and phosphorylated. Phosphorylated Sec24C is deficient in membrane association. Phosphoproteomics results suggest that Aurora and/or Polo-like kinase (PLK) may be responsible for phosphorylating Sec24C during mitosis, but this remains speculative.

FIGURE 4

Multi-modal regulation of the ERES scaffolding protein Sec16. (A) ERK2 phosphorylates Sec16 on T415 and promotes ERES assembly. (B) ULK1 and ULK2 phosphorylate Sec16A and Sec16B. Sec16 phosphorylation promotes Sec16-Sec24 interaction. (C) Upon starvation, dPARP16 promotes MARylation of Sec16, which leads to the formation of Sec bodies, composed of Sec16, Sec23, Sec24, and Sec31.

FIGURE 5

Regulation of COPII trafficking by cargo PTMs. (A) Insulin stimulation, which activates the PI3K pathway, induces the phosphorylation of sterol regulatory element binding proteins (SREBP) by Akt. Phosphorylation increases the affinity of the SREBP-1c/SREBP cleavage-activating protein (SCAP) complex for Sec23/Sec24 and promotes COPII-dependent trafficking to the Golgi. (B) The acyltransferase Porcupine is necessary for the palmitoylation of Wnt, which enhances its binding to preformed Wntless/Sec12 complexes and facilitates Wnt secretion by COPII.