Less is better: various means to reduce protein load in the endoplasmic reticulum

Abstract

The endoplasmic reticulum (ER) is an important organelle that controls the intracellular and extracellular environments. The ER is responsible for folding almost one-third of the total protein population in the eukaryotic cell. Disruption of ER-protein folding is associated with numerous human diseases, including metabolic disorders, neurodegenerative diseases, and cancer. During ER perturbations, the cells deploy various mechanisms to increase the ER-folding capacity and reduce ER-protein load by minimizing the number of substrates entering the ER to regain homeostasis. These mechanisms include signaling pathways, degradation mechanisms, and other processes that mediate the reflux of ER content to the cytosol. In this review, we will discuss the recent discoveries of five different ER quality control mechanisms, including the unfolded protein response (UPR), ER-associated-degradation (ERAD), pre-emptive quality control, ER-phagy and ER to cytosol signaling (ERCYS). We will discuss the roles of these processes in decreasing ER-protein load and inter-mechanism crosstalk.

Keywords: COPII; ERAD; ERCYS; ER‐Phagy; ER‐pQC; UPR.

Fig. 1

Schematic showing various mechanisms to relieve the ER of its content during stress. (A) The UPR: (a) RIDD results in degradation of mRNAs encoding for proteins in the secretory pathway and induces XBP1s target genes, (b) PERK inhibits global protein translation by phosphorylation of eIF2α and increases ATF4 target genes, and (c) ATF6 induces genes involved in increasing the ER‐protein folding capacity; (B) the ERAD eliminates misfolded proteins from the ER by directing their degradation to the proteasome. (C) The pre‐emptive quality control mechanism (ER‐pQC) reroutes synthesized proteins to the cytosol for proteasomal degradation. (D) ER‐phagy removes part of the damaged ER‐containing misfolded proteins (E) ERCYS induces reflux of soluble ER‐resident proteins to the cytosol, where they gain new function.