Vaysse-Zinkhöfer Wilhelm, Catherine Alcindor Enya Marie, Garaffo Nicholas, Toczyski David Paul
Department of Biochemistry, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA.
bioRxiv. 2025 Aug 14:2025.08.14.670414. doi: 10.1101/2025.08.14.670414.
Apoptosis helps eliminate damaged or unnecessary cells. Anti-apoptotic BCL2 family proteins protect cells by binding and inhibiting pro-apoptotic proteins. Our study reveals that BCL2 proteins also target Bim for degradation by serving to recruit Bim to the E3 ubiquitin ligase Cul5. Wsb2 recognizes Bcl-xl through a motif conserved between Bcl-xl, Bcl-w and Bcl2, but not Mcl1. Disruption of this interaction through mutation of either Bcl-xl or Wsb2 blocks the binding of Wsb2 to the Bcl-xl/Bim dimer. Wsb2 also associates with the Mcl1/Bim dimer through a separate Wsb2 interface, suggesting that Wsb2 has evolved independent means to target Bim. While Wsb2 is not essential in most cells, it is essential in cells derived from tumors of the nervous system, and knockdown of Wsb2 in these lines causes death by apoptosis. This work uncovers a novel mechanism of apoptosis regulation, with implications for developing therapies against neuroblastomas and other cancers reliant on this pathway for survival.
细胞凋亡有助于清除受损或多余的细胞。抗凋亡的BCL2家族蛋白通过结合并抑制促凋亡蛋白来保护细胞。我们的研究表明，BCL2蛋白还通过将Bim招募到E3泛素连接酶Cul5来靶向降解Bim。Wsb2通过Bcl-xl、Bcl-w和Bcl2之间保守的基序识别Bcl-xl，但不识别Mcl1。通过Bcl-xl或Wsb2的突变破坏这种相互作用会阻断Wsb2与Bcl-xl/Bim二聚体的结合。Wsb2还通过一个独立的Wsb2界面与Mcl1/Bim二聚体结合，这表明Wsb2已经进化出独立的方式来靶向Bim。虽然Wsb2在大多数细胞中并非必不可少，但在源自神经系统肿瘤的细胞中却是必不可少的，并且在这些细胞系中敲低Wsb2会导致细胞凋亡死亡。这项工作揭示了一种新的细胞凋亡调节机制，对开发针对神经母细胞瘤和其他依赖该途径生存的癌症的治疗方法具有启示意义。
