
WSB2は、CRL5 E3ユビキチンリガーゼ複合体の基質受容体として機能し、NOXAタンパク質の分解を促進することで、BCL-2ファミリータンパク質阻害剤に対する細胞の感受性を調節する。


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Anti-apoptotic BCL-2 family proteins are frequently overexpressed in various cancers, contributing to the initiation and development of cancer, as well as intrinsic or acquired resistance to therapy. Although BCL-2 family protein inhibitors, such as Venetoclax, have demonstrated efficacy in hematological neoplasms, their effectiveness as single agents in solid tumors is limited. Identifying alternative molecular targets that can overcome intrinsic resistance to BCL-2 family protein inhibitors is of great clinical importance. Here, we present evidence of strong synthetic lethal interactions between WSB2, a relatively unexplored substrate-binding receptor of the Cullin 5-RBX2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, and multiple anti-apoptotic BCL-2 family proteins. Mechanistically, an assembled CRL5WSB2 E3 ubiquitin ligase complex targets NOXA, a pro-apoptotic BCL-2 family protein, for degradation via the ubiquitin-proteasomal pathway. Ablation of WSB2 leads to a remarkable accumulation of NOXA proteins in cultured cell lines and knockout mouse organs. While WSB2 deficiency alone has a minimal effect on spontaneous apoptosis, it renders cancer cells more susceptible to apoptosis when anti-apoptotic BCL-2 family proteins are genetically depleted or pharmacologically inhibited. These findings establish WSB2 as a critical regulator of mitochondrial apoptosis and highlight the dysregulation of the WSB2-NOXA regulatory axis as a contributing factor to apoptosis resistance in cancer cells. Synergistically targeting WSB2 and anti-apoptotic BCL-2 family proteins holds promising clinical potential in the treatment of human cancers.

### Competing Interest Statement

The authors have declared no competing interest.

Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors

bcl-2-ファミリータンパク質阻害剤に対する合成致死性を誘導するwsb2-介在性noxa分解の障害


BCL-2 ファミリータンパク質阻害剤に対する合成致死性を誘導するWSB2 介在性NOXA分解の障害
