2. Academic Validation
  3. SPATA2 links CYLD to the TNF-α receptor signaling complex and modulates the receptor signaling outcomes

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

  • EMBO J. 2016 Sep 1;35(17):1868-84. doi: 10.15252/embj.201694300.
Sebastian A Wagner 1,  Shankha Satpathy 2,  Petra Beli 3,  Chunaram Choudhary 4
Affiliations

Affiliations

  • 1 Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Medicine, Hematology/Oncology, Goethe University School of Medicine, Frankfurt, Germany German Cancer Consortium (DKTK), Heidelberg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany swagner@med.uni-frankfurt.de chuna.choudhary@cpr.ku.dk.
  • 2 Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 3 Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Institute of Molecular Biology (IMB), Mainz, Germany.
  • 4 Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark swagner@med.uni-frankfurt.de chuna.choudhary@cpr.ku.dk.
PMID: 27307491 DOI: 10.15252/embj.201694300
Abstract

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.

Keywords

CYLD; LUBAC; SPATA2; TNF‐RSC; necroptosis.

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