Crosstalk Between ER Stress, Autophagy and Inflammation

The endoplasmic reticulum (ER) is not only responsible for protein synthesis and folding but also plays a critical role in sensing cellular stress and maintaining cellular homeostasis. Upon sensing the accumulation of unfolded proteins due to perturbation in protein synthesis or folding, specific intracellular signaling pathways are activated, which are collectively termed as unfolded protein response (UPR). UPR expands the capacity of the protein folding machinery, decreases protein synthesis and enhances ER-associated protein degradation (ERAD) which degrades misfolded proteins through the proteasomes. More recent evidences suggest that UPR also amplifies cytokines-mediated inflammatory responses leading to pathogenesis of inflammatory diseases. UPR signaling also activates autophagy; a lysosome-dependent degradative pathwaythat has an extended capacity to degrade misfolded proteins and damaged ER. Thus, activation of autophagy limits inflammatory response and provides cyto-protection by attenuating ER-stress. Here we review the mechanisms that couple UPR, autophagy and cytokine-induced inflammation that can facilitate the development of novel therapeutic strategies to mitigate cellular stress and inflammation associated with various pathologies.

Automated summary

The endoplasmic reticulum (ER) is crucial for protein synthesis, folding, sensing cellular stress and maintaining cellular homeostasis. The unfolded protein response (UPR) expands protein folding capacity, reduces protein synthesis, enhances ER-associated protein degradation (ERAD), and amplifies cytokine-mediated inflammatory responses. UPR also activates autophagy, which limits inflammation and provides cyto-protection by attenuating ER-stress.