MECHANISTIC INTERPLAY BETWEEN ER STRESS AND AUTOPHAGY: INTEGRATIVE CONTROL OF PROTEOSTASIS AND CELLULAR HOMEOSTASIS

Abstract

The endoplasmic reticulum (ER) is crucial for protein folding, post-translational modifications, calcium storage, and lipid production. Disruptions in these functions cause an accumulation of unfolded or misfolded proteins, leading to ER stress and triggering the unfolded protein response (UPR). The UPR aims to restore balance by modulating translational attenuation, increasing the transcription of chaperones, and activating degradation pathways. However, if the stress is intense or prolonged, these adaptive responses shift towards apoptosis. Of the three UPR pathways, the PERK–eIF2α–ATF4–CHOP and IRE1–XBP1 pathways are key in connecting ER stress to autophagy, while ATF6 helps maintain proteostasis by controlling the transcription of ER quality components.

Autophagy functions as a critical compensatory mechanism during ER stress, facilitating the clearance of aggregated proteins and damaged organelles to re-establish the cellular balance. Crosstalk between the UPR and autophagic machinery occurs through multiple signalling nodes, including the AMPK–mTOR axis, ubiquitin–proteasome system, and calcium-mediated signalling pathways. The disruption of these interactions contributes to several pathological states, including cancer, neurodegenerative disorders, and metabolic diseases. This review integrates current insights into the molecular interplay between ER stress and autophagy, emphasizing their coordination through ER-associated degradation (ERAD), lipophagy, and metabolic signalling. Understanding these interconnected pathways offers potential therapeutic opportunities to modulate proteostasis and improve cellular resilience under stressful conditions.