Wwp2 targets SRG3, a scaffold protein of the SWI/SNF-like BAF complex, for ubiquitination and degradation.

SRG3 plays essential roles both in early mouse embryogenesis and in extra-embryonic vascular development. As one of the core components of the SWI/SNF-like BAF complex, SRG3 serves as the scaffold protein and its protein level controls the stability of the BAF complex, which controls diverse physiological processes through transcriptional regulation. However, little is known about how the protein level of SRG3 is regulated in mammalian cells. Previously, we identified a murine ubiquitin ligase (Wwp2) and demonstrated that it interacts with pluripotency-associated key transcription factor Oct4 and RNA polymerase II large subunit Rpb1, promoting their ubiquitination and degradation. Here, we report that Wwp2 acts as a ubiquitin ligase of SRG3. Our results show that Wwp2 and SRG3 form protein complexes and co-localize in the nucleus in mammalian cells. The interaction is mediated through the WW domain of Wwp2 and the PPPY motif of SRG3, respectively. Importantly, Wwp2 promotes ubiquitination and degradation of SRG3 through the ubiquitin-proteasome system. The expression of a catalytically inactive mutant of Wwp2 abolishes SRG3 ubiquitination. Collectively, our study opens up a new avenue to understand how the protein level of SRG3 is regulated in mammalian cells.