Molecular Interaction of Endoplasmic Reticulum Stress and Autophagy: Mechanisms, Signaling Pathways, and Implications for Cellular Homeostasis
MA Yunhe1,2, GU Yuexi2, ZHANG Ziyu3, WANG Ruobing1, ZHANG Tao1*
ER stress (endoplasmic reticulum stress) is a protective response elicited by certain cellular stresses, including hypoxia, and nutrient deprivation. This response relies on three branches of the UPR (unfolded protein response): IRE1α-XBP1, PERK-eIF2α and ATF6α, which collectively inhibit total protein synthesis, thereby alleviating ER burden and preserving cellular homeostasis. ER stress can also induce autophagy to clear unfolded or misfolded proteins. The UPR and autophagy interact at multiple levels: for example, the IRE1α-TRAF2-JNK axis can release Beclin-1 via JNK-mediated phosphorylation of Bcl-2, thereby activating the ATG14-VPS34-Beclin-1 complex to synthesize PI3P for autophagy initiation. Calcium dyshomeostasis induced by ER stress can activate AMPK through SOCE (store-operated calcium entry), thereby inhibiting mTORC1 to induce autophagy. Moreover, AMPK and mTORC1 together integrate energy and nutritional status to synergistically regulate autophagy activity. ER stress preferentially induces selective autophagy, especially ER-phagy, which aids in the destruction of misfold- ed proteins and surplus ER membranes, thereby maintaining cellular homeostasis. However, excessive or prolonged stress can hinder lysosomal function, thereby inhibiting the proper progression of the autophagy process, resulting in pathological cellular damage. This review will delineate the molecular mechanisms of autophagy induced by ER stress, as well as their interactions, along with the implications of dysregulated ER stress and autophagy in aging, neurodegenerative diseases and cancer, which will provide potential innovative strategies for the prevention and treatment of these diseases.
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