SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death
Schlicher L, Wissler M, Preiss F, Brauns-Schubert P, Jakob C, Dumit V, Borner C, Dengjel J, Maurer U.
K63- and Met1-linked ubiquitylation are crucial posttranslational modifications for TNF receptor signaling. These non-degradative ubiquitylations are counteracted by deubiquitinases (DUBs), such as the enzyme CYLD, resulting in an appropriate signal strength, but the regulation of this process remains incompletely under- stood. Here, we describe an interaction partner of CYLD, SPATA2, which we identified by a mass spectrometry screen. We find that SPATA2 interacts via its PUB domain with CYLD, while a PUB inter- action motif (PIM) of SPATA2 interacts with the PUB domain of the LUBAC component HOIP. SPATA2 is required for the recruitment of CYLD to the TNF receptor signaling complex upon TNFR stimula- tion. Moreover, SPATA2 acts as an allosteric activator for the K63- and M1-deubiquitinase activity of CYLD. In consequence, SPATA2 substantially attenuates TNF-induced NF-kB and MAPK signaling. Conversely, SPATA2 is required for TNF-induced complex II forma- tion, caspase activation, and apoptosis. Thus, this study identifies SPATA2 as an important factor in the TNF signaling pathway with a substantial role for the effects mediated by the cytokine.
