BIK泛素化的調控決定細胞壓力反應下生與死的命運以及抗腫瘤的活性

Abstract

屬於BH3-only的促進細胞凋亡蛋白BIK會受到泛素-蛋白酶體系統調控。然而，這種調控的根本機制及其生理功能仍然不清楚。在此，我們發現了一個泛素連接酶CRL5ASB11介導BIK泛素化/降解的機制。在內質網壓力下，ASB11被XBP1轉錄激活，從而促進BIK的泛素化，與p97的相互作用以及蛋白降解。相反地，基因損害藥物通過上調p53來下調IRE1/XBP1，導致BIK穩定。這樣相反的ASB11介導BIK泛素化調控，部分參與了內質網壓力下的適應性反應以及DNA損傷下的凋亡反應。透過IRE1抑制劑阻斷泛素化途徑可穩定活性突變體的BIK並增加它對三陰性乳腺癌的抗腫瘤功效。我們的研究發現一個BIK的泛素連接酶，通過內質網壓力和DNA損傷揭示了正反向BIK泛素化的調控機制，並且涉及一個抗癌策略，透過共同施用標靶BIK的泛素化途徑以及活性BIK。

The BH3-only pro-apoptotic protein BIK is regulated by ubiquitin-proteasome system. However, the underlying mechanism of this regulation and its physiological functions remain elusive. Here, we identify a BIK ubiquitination/degradation mechanism mediated by ubiquitin ligase CRL5ASB11. Under ER stress, ASB11 is transcriptionally activated by XBP1, thereby stimulating BIK ubiquitination, interaction with p97, and proteolysis. Conversely, genotoxic agents act through p53 to downregulate IRE1/XBP1 axis, leading to BIK stabilization. These opposite regulations of ASB11-medaited BIK ubiquitination participate in part to the adaptive response to ER stress and apoptotic response to DNA damage. Blockage of this ubiquitination pathway by IRE1 inhibitors stabilizes BIK active mutant and increases its anti-tumor efficacy in triple negative breast cancers. Our study identifies a BIK ubiquitin ligase, uncovers the opposite regulations of this BIK ubiquitination by ER stress and DNA damage, and implicate an anti-cancer strategy by targeting BIK ubiquitination pathway in combined with administration of active BIK.