ER stress: Autophagy induction, inhibition and selection

TLDR

Accumulation of unfolded proteins in the ER triggers stress that activates the unfolded protein response and induces macroautophagy, a lysosome‑mediated degradation pathway, yet the molecular cues governing whether autophagy is stimulated or inhibited remain largely unknown. This review aims to summarize the crosstalk and signaling networks between ER stress and autophagy in mammalian systems. It also highlights current knowledge on selective autophagy and its connection to ER stress.

Abstract

An accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to stress conditions. To mitigate such circumstances, stressed cells activate a homeostatic intracellular signaling network cumulatively called the unfolded protein response (UPR), which orchestrates the recuperation of ER function. Macroautophagy (hereafter autophagy), an intracellular lysosome-mediated bulk degradation pathway for recycling and eliminating wornout proteins, protein aggregates, and damaged organelles, has also emerged as an essential protective mechanism during ER stress. These 2 systems are dynamically interconnected, and recent investigations have revealed that ER stress can either stimulate or inhibit autophagy. However, the stress-associated molecular cues that control the changeover switch between induction and inhibition of autophagy are largely obscure. This review summarizes the crosstalk between ER stress and autophagy and their signaling networks mainly in mammalian-based systems. Additionally, we highlight current knowledge on selective autophagy and its connection to ER stress.