Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases

Abstract

Most proteins destined for the extracellular space or various intracellular compartments must traverse the intracellular secretory pathway. The first step is the recruitment and transport of cargoes from the endoplasmic reticulum (ER) lumen to the Golgi apparatus by coat protein complex II (COPII), consisting of five core proteins. Additional ER transmembrane proteins that aid cargo recruitment are referred to as cargo receptors. Gene duplication events have resulted in multiple COPII paralogs present in the mammalian genome. Here, we review the functions of each COPII protein, human disorders associated with each paralog, and evidence for functional conservation between paralogs. We also provide a summary of current knowledge regarding two prototypical cargo receptors in mammals, LMAN1 and SURF4, and their roles in human health and disease.

Figure 1. COPII coat assembly on the ER membrane.

SEC12 recruits GDP-bound SAR1 to ER exit sites (ERESs) and acts as a guanine nucleotide exchange factor for SAR1. GTP-bound SAR1 inserts its hydrophobic N-terminus into the ER membrane and recruits SEC23-SEC24 heterodimers to the ER exit site via direct interaction with SEC23. SEC24 mediates cargo recruitment via direct physical interaction with transmembrane proteins through their cytoplasmic tails or with soluble cargoes via cargo receptors. SEC23 also functions as the GTPase-activating protein for SAR1 and stimulates SAR1 GTP hydrolysis. Finally, SEC13-SEC31 heterotetramers are recruited as the outer coat to complete the coat assembly process.

Figure 2. ER to Golgi transport of secreted proteins.

Secretory proteins in the ER lumen are recruited into the COPII vesicle/tubule by COPII coat proteins. In the vesicular transport model, the vesicle buds from the ER and travels to the ERGIC/cis-Golgi network with COPII coat proteins accompanying the vesicle. In the tubular transport model, cargo proteins are transported in a continuous interwoven tubular network instead of discrete vesicles. COPII proteins remain on the ER membrane and function as a gatekeeper restricting entry of secretory proteins into tubules.