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bioRxiv · 10.1101/2025.08.14.670414

Cul5Wsb2 uses BCL2 proteins as co-receptors to target Bim for degradation.

Vaysse-Zinkhofer, W.·Alcindor, E.·Garaffo, N.·Toczyski, D. P.
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Abstract

Anti-apoptotic BCL2 family proteins (e.g. BCL-XL) protect cells by binding and inhibiting pro-apoptotic proteins (e.g. BIM). Although CUL5WSB2 was linked to apoptosis regulation, its substrate and mechanism were unknown. We find that BCL2 proteins recruit BIM to CUL5WSB2 for degradation. 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 two 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 and 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.

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Vaysse-Zinkhofer, W., Alcindor, E., Garaffo, N., Toczyski, D. P.. 2025-08-14. Cul5Wsb2 uses BCL2 proteins as co-receptors to target Bim for degradation.. https://doi.org/10.1101/2025.08.14.670414

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