Disease-Associated Factors at the Endoplasmic Reticulum-Golgi Interface

Abstract

The endoplasmic reticulum (ER)-Golgi interface is essential for directing the transport of proteins synthesized in the ER to the Golgi apparatus via the ER-Golgi intermediate compartment, as well as for recycling proteins back to the ER. This transport is facilitated by various components, including COPI and COPII coat protein complexes and the transport protein particle complex. Recently, the ER-Golgi transport pathway has gained attention due to emerging evidence of nonvesicular transport mechanisms and the regulation of trafficking through liquid-liquid phase separation. Numerous diseases have been linked to mutations in proteins localized at the ER-Golgi interface, highlighting the need for comprehensive analysis of these conditions. This review examines the disease phenotypes associated with dysfunctional ER-Golgi transport factors and explores their cellular effects, providing insights into potential therapeutic strategies.

Keywords: COPI; COPII; ER exit site; ERGIC; Golgi; TRAPP complex; disease‐associated factor; endoplasmic reticulum; liquid‐phase separation; nonvesicular transport.

FIGURE 1

Model of COPII vesicle formation at the ER exit site. The ER exit site is a specialized region of the ER membrane formed by TANGO1 and Sec16. In mammals, TANGO1 forms a complex with cTAGE5 and Sec12, which activates the small GTPase, Sar1. Activated Sar1 binds to the Sec23/24 complex, which then recruits the Sec13/31 complex, leading to COPII vesicle assembly. TFG localizes to the region between the ER and ERGIC, facilitating transport via COPII vesicles.

FIGURE 2

Schematic of COPI vesicle formation. Arf1 is activated by GBF1 on the Golgi membrane, converting it to its GTP‐bound state, which in turn recruits the COPI coatomer complex. The COPI coatomer complex comprises the following subunits: Alpha (COPA), beta 1 (COPB1), beta 2 (COPB2), delta (COPD), epsilon (COPE), gamma 1 (COPG1), gamma 2 (COPG2), zeta 1 (COPZ1) and zeta 2 (COPZ2) that form the COPI vesicle.

FIGURE 3

Recycling factors between the ER and Golgi. ERGIC‐53 recognizes specific glycans on cargo proteins and mediates their transport from the ER to ERGIC. ERGIC‐53 contains a C‐terminal motif that interacts with the COPI coatomer complex, enabling its recycling from ERGIC back to the ER via COPI vesicles. The KDEL receptor, a seven‐transmembrane‐domain protein, recognizes KDEL motifs commonly found in ER‐resident proteins and facilitates their transport from the Golgi or ERGIC to the ER, while recycling itself between the ER and Golgi.

FIGURE 4

Composition of the TRAPPIII complex. The mammalian TRAPPIII complex, which plays a role in membrane transport between the ER and Golgi, consists of a core complex (TRAPPC1, TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC4, TRAPPC5 and TRAPPC6) along with TRAPPC8, TRAPPC11, TRAPPC12 and TRAPPC13.