Dissecting the functional divergence of DCAF11 isoforms in protein degradation.

Abstract

DCAF11 is a substrate receptor of the Cullin-RING ligase 4 (CRL4) ubiquitin ligase complex and an emerging effector supporting targeted protein degradation. DCAF11 exists as two major isoforms, but their functional differences remain incompletely understood. Here, we show that DCAF11 isoforms 1 and 2 assemble into CRL4 complexes with similar efficiency and exhibit largely overlapping endogenous substrate profiles, including proteins implicated in electrophile detoxification. In contrast, they differ in their compatibility with small-molecule degraders: covalent PROTACs engage both isoforms, whereas a non-covalent molecular glue selectively utilizes isoform 1. These findings reveal isoform-dependent control of protein degradation and highlight opportunities for isoform-selective targeting.