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

Abstract

X-linked inhibitor of apoptosis-associated factor-1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in many human cancers. Despite accumulating evidence for the pro-apoptotic role for XAF1 under various stressful conditions, its involvement in endoplasmic reticulum (ER) stress response remains undefined. Here, we report that XAF1 increases cell sensitivity to ER stress and acts as a molecular switch in unfolded protein response (UPR)-mediated cell-fate decisions favoring apoptosis over adaptive autophagy. Mechanistically, XAF1 interacts with and destabilizes ER stress sensor GRP78 through the assembly of zinc finger protein 313 (ZNF313)-mediated destruction complex. Moreover, XAF1 expression is activated through PERK-Nrf2 signaling and destabilizes C-terminus of Hsc70-interacting protein (CHIP) ubiquitin E3 ligase, thereby blocking CHIP-mediated K63-linked ubiquitination and subsequent phosphorylation of inositol-required enzyme-1α (IRE1α) that is involved in in the adaptive ER stress response. 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.

Multifaceted proteome analysis at solubility, redox, and expression dimensions for target identification

“…3c ). In XAF1 that is known to be transcriptionally activated by oxidative stress 38 , we found oxidation of Cys112 upon IFN stimulation. As expected, the IFN-α treatment led to changes in the REXpression and solubility of many known and putative ISGs ( Fig.…”

Identification of modules and key genes associated with breast cancer subtypes through network analysis

“…Interestingly, its expression has been relevant in the pathogenesis of BC due to its role in motility, invasion, metastasis, and a poor response to chemotherapy and radiotherapy 138 , 139 . Additionally, XAF1 counteracts the inhibitory effect of apoptosis (13 degrees) 140 , IFIT2 involve positive regulation of the apoptotic process and response to the virus (13 degrees) 141 , RSAD2 is an interferon-inducible antiviral protein (13 degrees), and OAS2 involved in the innate immune response to viral infection (13 degrees) 142 . The Basal B network consists of 40 nodes and 28 edges.…”

XAF1 promotes colorectal cancer metastasis via VCP–RNF114–JUP axis

“…These interactions make it suitable for XAF1 to function as a VCP adaptor protein to regulate the deubiquitination and stability of RNF114. It is reported that XAF1 interacts with ER stress sensor glucose-regulated protein (GRP78) via the C-terminal region, leading to the degradation of GRP78 in an RNF114-dependent manner ( Lee et al, 2022 ). XAF1 interacts with ERα and BRCA1 via the ZF domains 5/6 and 4, respectively, and destabilizes ERα through the assembly of BRCA1-mediated destruction complex and promotes estrogen-induced apoptosis ( Lim et al, 2022 ).…”