Crosstalk Between ER Stress, Autophagy and Inflammation

Abstract

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.

Keywords: ER-stress; autophagy; cytokines; inflammation; unfolded protein response.

Figure 1

Inflammatory/Cytokine signaling regulated by UPR. Upon ER stress, the ER chaperone BiP dissociates from its complex with IRE1, PERK and ATF6 which results in the activation of the three arms of the UPR pathway as shown in the figure. All the three arms of the UPR regulates the production of inflammatory cytokines via different mechanisms which converge on NF-κB activation. PERK also regulates TXNIP through the induction of ATF5 which in turn modulates NLRP3 inflammasome resulting in enhanced inflammation. Calcium disruption induced ER stress activates STING pathway resulting in the production of IFN-1.

Figure 2

Crosstalk between ER stress, autophagy and inflammation. The arms of UPR activating inflammation also intersect with pathways regulating autophagy. The possible points of intersection are shown in the illustration.