XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP

Area of Science:

• Cellular Biology
• Molecular Oncology
• Cancer Research

Background:

• X-linked inhibitor of apoptosis-associated factor-1 (XAF1) is a tumor suppressor often inactivated in human cancers.
• XAF1's role in endoplasmic reticulum (ER) stress response and the unfolded protein response (UPR) is not well understood.

Purpose of the Study:

• To investigate the function of XAF1 in ER stress response.
• To elucidate the molecular mechanisms by which XAF1 influences UPR-mediated cell fate.
• To determine the role of XAF1 in tumor suppression under ER stress conditions.

Main Methods:

• Investigated XAF1's interaction with ER stress sensor GRP78 and its destabilization via ZNF313.
• Analyzed XAF1's regulation of PERK-Nrf2 signaling and its effect on CHIP E3 ligase activity.
• Assessed the impact of XAF1 on IRE1α phosphorylation and UPR signaling pathways.
• Utilized tumor xenograft models to evaluate XAF1's role in tumor regression under ER stress.
• Examined XAF1 and GRP78 expression correlation in human cancer cell lines and primary breast carcinomas.

Main Results:

• XAF1 sensitizes cells to ER stress, promoting apoptosis over autophagy by destabilizing GRP78.
• XAF1 expression is activated by PERK-Nrf2 signaling and inhibits adaptive UPR by destabilizing CHIP, thus blocking IRE1α phosphorylation.
• XAF1-deficient tumors show reduced regression upon ER stress induction compared to wild-type tumors.
• An inverse correlation between XAF1 and GRP78 expression was observed in human cancers.

Conclusions:

• XAF1 acts as a critical regulator of ER stress sensitivity and UPR signaling outcomes.
• XAF1 inactivation disrupts tumor suppression, contributing to tumorigenesis by impairing ER stress-induced apoptosis.
• XAF1's mechanism involves modulating key components of the UPR, including GRP78, CHIP, and IRE1α.