SPATA2 links CYLD to the TNF-? receptor signaling complex and modulates the receptor signaling outcomes.

ABSTRACT: TNF-? is a key regulator of innate immune and proinflammatory responses. However, the composition of the TNF-? 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-? stimulation induces widespread protein phosphorylation and that the scope of phosphorylation expands in a temporal manner. TNF-? 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-?B and inhibits TNF-?-induced necroptosis, pointing to an important function of SPATA2 in modulating the outcomes of TNF-? signaling. Taken together, our study draws a detailed map of TNF-? signaling, identifies SPATA2 as a novel component of TNF-? signaling, and provides a rich resource for further functional investigations.

SUBMITTER: Wagner SA 

PROVIDER: S-EPMC5007551 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature