The Back and Forth of Cargo Exit from the Endoplasmic Reticulum

Abstract

Endoplasmic reticulum (ER) to Golgi trafficking is an essential step in sorting mature, correctly folded, processed and assembled proteins (cargo) from immature proteins and ER-resident proteins. However, the mechanisms governing trafficking selectivity, specificity and regulation are not yet fully understood. To date, three complementary mechanisms have been described that enable regulation of this trafficking step: ER retention of immature proteins in the ER; selective uptake of fully mature proteins into Golgi-bound vesicles; and retrieval from the Golgi of immature cargo that has erroneously exited the ER. Together, these three mechanisms allow incredible specificity and enable the cell to carry out protein quality control and regulate protein processing, oligomerization and expression. This review will focus on the current knowledge of selectivity mechanisms acting during the ER-to-Golgi sorting step and their significance in health and disease. The review will also highlight several key questions that have remained unanswered and discuss the future frontiers.

COPII Coat Composition Is Actively Regulated by Luminal Cargo Maturation

“…However, it is unclear how the COPII coat works together with cargo receptors to select fully assembled proteins into forming vesicles [1][2][3]. In this study, we provide direct new mechanistic insight into the previously unknown mode of action of ER cargo receptors.…”

“…Active concentration into vesicles of those cargo molecules that cannot directly interact with Sec24p, like soluble secretory proteins, requires specialized transmembrane proteins, which act as adaptors or cargo receptors by linking cargo with the COPII coat. However, neither the precise mechanism by which cargo receptors select mature from immature secretory proteins nor how this selection is coupled to COPII vesicle biogenesis are well understood [1][2][3].…”

Getting membrane proteins on and off the shuttle bus between the endoplasmic reticulum and the Golgi complex

“…As ER residency is based on two distinct processes -the exclusion of resident proteins from ERES and the retrieval through retrograde transport of those residents that have escaped from the ER (Spang, 2013;Geva and Schuldiner, 2014) -either one of these processes could, in principle, be influenced by TMD length. Indeed, Rer1p, a cargo receptor involved in retrograde transport, recognizes the TMD of escaped membrane proteins of the ER (Sato et al, 2003), and the artificially lengthened TMD of cytochrome P450 2C1 (see Box 2) interferes with retrieval of the altered protein from the Golgi (Szczesna-Skorupa and Kemper, 2000).…”

“…An extended role for receptor-mediated cargo capture at ERES As summarized above, a sizeable portion of secretory membrane cargo proteins carry export signals that are recognized by the COPII Sec24 subunit (Ma and Jan, 2002;Dancourt and Barlowe, 2010;Geva and Schuldiner, 2014) or by cargo receptors such as Erv14 (Bökel et al, 2006;Herzig et al, 2012;Pagant et al, 2015). I suggest here that the signal-mediated capture of membrane protein cargoes not only serves the purpose of efficient export of the captured cargoes themselves but that it also plays a much more general role, in that it creates a microdomain in the bilayer into which membrane proteins that are devoid of export signals partition according to the length of their TMD (Fig.…”

The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK)

“…The selection, delivery, and degradation of misfolded proteins in this compartment proceeds through the ER associated degradation (ERAD) pathway. Quality control "decisions" that operate at later steps in the secretory pathway, such as in the Golgi apparatus, the endosome, and the plasma membrane, have also been identified in eukaryotic cells (6)(7)(8). However, the relative influence of each system on specific client proteins is rarely investigated.…”