SPATA2 links CYLD to the TNF a receptor signaling complex and modulates the receptor signaling outcomes
TNF a is a key regulator of innate immune and proinflammatory responses. However, the composition of the TNF a receptor associated signaling complexes (TNF RSC) and the architecture of the downstream signaling networks are incompletely understood. We employed quantitative mass spectrometry to demonstrate that TNF a stimulation induces widespread protein phosphorylation and that the scope of phosphorylation expands in a temporal manner. TNF a stimulation also induces rapid ubiquitylation of components of the TNF RSC. Temporal analysis of the TNF RSC composition identified SPATA2 as a novel component of the TNF RSC. The predicted PUB domain in the N terminus of SPATA2 interacts with the USP domain of CYLD, whereas the C terminus of SPATA2 interacts with HOIP. SPATA2 is required for recruitment of CYLD to the TNF RSC. Downregulation of SPATA2 augments transcriptional activation of NF kB and inhibits TNF a induced necroptosis, pointing to an important function of SPATA2 in modulating the outcomes of TNF a signaling. Taken together, our study draws a detailed map of TNF a signaling, identifies SPATA2 as a novel component of TNF a signaling, and provides a rich resource for further functional investigations.
The EMBO journal