SPATA2 links CYLD to the TNF-{alpha} receptor signaling complex and modulates the receptor signaling outcomes

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-B 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.

Source: EMBO Journal - August 31, 2016 Category: Molecular Biology Authors: Wagner, S. A., Satpathy, S., Beli, P., Choudhary, C. Tags: Immunology, Post-translational Modifications, Proteolysis & Proteomics, Signal Transduction Articles Source Type: research