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

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

Original languageEnglish
JournalE M B O Journal
Volume35
Issue number17
Pages (from-to)1868-1884
ISSN0261-4189
DOIs
Publication statusPublished - 1 Sep 2016

ID: 162643966