SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes

Recruitment of the deubiquitinase CYLD to signaling complexes is mediated by its interaction with HOIP, the catalytically active component of the linear ubiquitin chain assembly complex (LUBAC). Here, we identify SPATA2 as a constitutive direct binding partner of HOIP that bridges the interaction between CYLD and HOIP. SPATA2 recruitment to TNFR1- and NOD2-signaling complexes is dependent on HOIP, and loss of SPATA2 abolishes CYLD recruitment. Deficiency in SPATA2 exerts limited effects on gene activation pathways but diminishes necroptosis induced by tumor necrosis factor (TNF), resembling loss of CYLD. In summary, we describe SPATA2 as a previously unrecognized factor in LUBAC-dependent signaling pathways that serves as an adaptor between HOIP and CYLD, thereby enabling recruitment of CYLD to signaling complexes. [Display omitted] •SPATA2 bridges the interaction between HOIP and CYLD•CYLD recruitment to the TNFR1-signaling complex requires SPATA2•Loss of SPATA2 phenocopies absence of CYLD in TNFR1 signaling Kupka et al. show that the previously demonstrated interaction of CYLD with HOIP, which is required for recruitment of CYLD into signaling complexes, is indirect and mediated by SPATA2. Loss of SPATA2 abrogates recruitment of CYLD to signaling complexes and consequently mimics CYLD deficiency with regards to gene activation and necroptosis induced by TNF.