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.