Directing Traffic: Regulation of COPI Transport by Post-translational Modifications

Abstract

The coat protein complex I (COPI) is an essential, highly conserved pathway that traffics proteins and lipids between the endoplasmic reticulum (ER) and the Golgi. Many aspects of the COPI machinery are well understood at the structural, biochemical and genetic levels. However, we know much less about how cells dynamically modulate COPI trafficking in response to changing signals, metabolic state, stress or other stimuli. Recently, post-translational modifications (PTMs) have emerged as one common theme in the regulation of the COPI pathway. Here, we review a range of modifications and mechanisms that govern COPI activity in interphase cells and suggest potential future directions to address as-yet unanswered questions.

Keywords: COPI vesicle trafficking; coatomer; glycosylation; interphase; myristoylation; phosphorylation; post-translational modifications; ubiquitination.

FIGURE 1

PKA-mediated phosphorylation regulates COPI trafficking. (A) Phosphorylation of KDELR by PKA on the Golgi membrane promotes its interaction with COPI (teal) and ArfGAP, regulating its recycling to the ER through COPI-dependent trafficking. (B) Phosphorylation of the potassium channel KCNK3 by PKA promotes 14-3-3β binding, displacing β-COP at the Golgi membrane and blocking retrieval to the ER allowing anterograde trafficking of the channel to the cell membrane. Single arrows indicate functional interaction. Double-headed arrows indicate translocation. COP, coat protein complex I; KCNK3, potassium channel subfamily K member 3; KDELR, KDEL receptor; P, phosphorylation; PKA, protein kinase A.

FIGURE 2

Src-mediated phosphorylation influences COPI trafficking. (A) During ER stress, Src associates with Ire1 and phosphorylates the ArfGAP ASAP1, leading to recruitment of Arf1-GTP to the Golgi membrane. (B) At the ERGIC, Src phosphorylates PKCι/λ, which is required by Rab2 to recruit β-COP for retrograde trafficking. Single arrows indicate functional interaction. Double-headed arrows indicate translocation. Arf, adenosine diphosphate-ribosylation factor; ASAP1, ArfGAP containing SH3, ANK repeat and PH domains; ERGIC, ER-Golgi intermediate compartment; GAP, GTPase activating protein; GBF1, Golgi-specific brefeldin A-resistance GEF 1; GEF, guanine nucleotide exchange factor; Ire1α, inositol-requiring 1; PKC, protein kinase C; Rab2, small GTPase; Src, non-receptor tyrosine kinase (name derived from “sarcoma”).

FIGURE 3

Regulation of COPI trafficking by ubiquitination. (A) In yeast, ubiquitination of the SNARE Snc1 allows for coatomer binding through β′- and α-COP, leading to recycling to the plasma membrane. (B) Androgen receptor signaling by dihydrotestosterone has been found to activate the ubiquitin ligase PIRH2, which targets ε-COP for proteasomal degradation. Single arrows indicate functional interaction. Double-headed arrows indicate translocation. AR, androgen receptor; DHT, dihydrotestosterone; PIRH2, p53-induced RING-H2 protein; PM, plasma membrane; Snc1, synaptobrevin homolog 1; Ub, ubiquitination.

FIGURE 4

N-glycosylation of p24δ5 is required for ERD2 recycling in Arabidopsis. N-glycosylation of the COPI cargo p24δ5 promotes ERD2 binding and retrograde trafficking. Single arrows indicate functional interaction. Double-headed arrows indicate translocation. ERD2, ER lumen protein-retaining receptor 2; N, N-glycosylation.

FIGURE 5

Pathogens manipulate COPI trafficking during infection. (A) The Shigella flexneri type III effector protein IpaJ cleaves the myristoylated N-terminus of Arf1 during infection, disrupting its membrane association and COPI trafficking. (B) During hepatitis C virus infection, phosphorylation of GBF1 is triggered by host IRGM and a kinase, likely AMPK, leading to prolonged Arf1 activation and disruption of normal trafficking. Single arrows indicate functional interaction. Double-headed arrows indicate translocation. AMPK, adenosine monophosphate-activated protein kinase; HCV, hepatitis C virus; IpaJ, invasion plasmid antigen J (Shigella); IRGM, immunity-related GTPase M.