BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

Significance BRCA1 associated protein 1 (BAP1) is a tumor suppressor and its inactivating mutations frequently occur in a subset of human cancers. This study reveals an unexpected finding that loss of BAP1 compromises the cellular adaptability to metabolic stress, and links BAP1 to unfolded protein response to regulate cell survival under metabolic stress. We also report the first line of in vivo evidence that Bap1 KO mice experienced unresolved endoplasmic reticulum stress in the kidney. Our study not only provides mechanical insights for BAP1 functions in cell survival upon metabolic stress through endoplasmic reticulum stress signaling, but also may provide a conceptual framework for further understanding BAP1 function in cancer. The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.

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