Version 1
: Received: 15 March 2022 / Approved: 17 March 2022 / Online: 17 March 2022 (10:59:09 CET)
How to cite:
Lee, K.; Hong, H.; Lim, J.; Ko, K.; Lee, M.; Chi, S. XAF1 Inactivation Increases Tumor Cell Resistance to Endoplasmic Reticulum Stress-Induced Apoptosis Through Stabilization of GRP78 and CHIP. Preprints2022, 2022030251. https://doi.org/10.20944/preprints202203.0251.v1
Lee, K.; Hong, H.; Lim, J.; Ko, K.; Lee, M.; Chi, S. XAF1 Inactivation Increases Tumor Cell Resistance to Endoplasmic Reticulum Stress-Induced Apoptosis Through Stabilization of GRP78 and CHIP. Preprints 2022, 2022030251. https://doi.org/10.20944/preprints202203.0251.v1
Lee, K.; Hong, H.; Lim, J.; Ko, K.; Lee, M.; Chi, S. XAF1 Inactivation Increases Tumor Cell Resistance to Endoplasmic Reticulum Stress-Induced Apoptosis Through Stabilization of GRP78 and CHIP. Preprints2022, 2022030251. https://doi.org/10.20944/preprints202203.0251.v1
APA Style
Lee, K., Hong, H., Lim, J., Ko, K., Lee, M., & Chi, S. (2022). XAF1 Inactivation Increases Tumor Cell Resistance to Endoplasmic Reticulum Stress-Induced Apoptosis Through Stabilization of GRP78 and CHIP. Preprints. https://doi.org/10.20944/preprints202203.0251.v1
Chicago/Turabian Style
Lee, K., Min-Goo Lee and Sung-Gil Chi. 2022 "XAF1 Inactivation Increases Tumor Cell Resistance to Endoplasmic Reticulum Stress-Induced Apoptosis Through Stabilization of GRP78 and CHIP" Preprints. https://doi.org/10.20944/preprints202203.0251.v1
Abstract
Despite accumulating evidence for the pro-apoptotic role for X-linked inhibitor of apoptosis-associated factor 1 (XAF1), its involvement in endoplasmic reticulum (ER) stress response remains undefined. Here, we report that XAF1 enhances cell sensitivity to ER stress and acts as a switch in unfolded protein response (UPR)-mediated cell-fate decisions favoring apoptosis over adaptive autophagy. XAF1 interacts with and destabilizes ER stress sensor GRP78 through the assembly of zinc finger protein 313-mediated destruction complex. Moreover, XAF1 gene transcription is activated by ER stress through PERK-Nrf2 signaling to direct an adaptive to apoptotic switch of stress response by blocking C-terminus of Hsc70-interacting protein (CHIP)-mediated K63-linked ubiquitination and subsequent phosphorylation of inositol-required enzyme-1α (IRE1α). In tumor xenograft assays, XAF1-/- tumors display substantially lower regression compared to XAF1+/+ tumors in response to cytotoxic dose of ER stress inducer. XAF1 and GRP78 expression show an inverse correlation in human cancer cell lines and primary breast carcinomas. Collectively this study uncovers an important role for XAF1 as a linchpin to govern the sensitivity to ER stress and the outcomes of UPR signaling, illuminating the mechanistic consequence of XAF1 inactivation in tumorigenesis.
Keywords
ER stress; XAF1; GRP78; ZNF313; CHIP
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.