2. Academic Validation
  3. SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling

SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling

  • Mol Cell. 2016 Sep 15;63(6):990-1005. doi: 10.1016/j.molcel.2016.08.001.
Paul R Elliott 1,  Derek Leske 2,  Matous Hrdinka 2,  Katrin Bagola 2,  Berthe K Fiil 2,  Stephen H McLaughlin 1,  Jane Wagstaff 1,  Norbert Volkmar 2,  John C Christianson 2,  Benedikt M Kessler 3,  Stefan M V Freund 1,  David Komander 4,  Mads Gyrd-Hansen 5
Affiliations

Affiliations

  • 1 Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
  • 2 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
  • 3 TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
  • 4 Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: dk@mrc-lmb.cam.ac.uk.
  • 5 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. Electronic address: mads.gyrd-hansen@ludwig.ox.ac.uk.
PMID: 27591049 DOI: 10.1016/j.molcel.2016.08.001
Abstract

The linear ubiquitin chain assembly complex (LUBAC) regulates immune signaling, and its function is regulated by the deubiquitinases OTULIN and CYLD, which associate with the catalytic subunit HOIP. However, the mechanism through which CYLD interacts with HOIP is unclear. We here show that CYLD interacts with HOIP via spermatogenesis-associated protein 2 (SPATA2). SPATA2 interacts with CYLD through its non-canonical PUB domain, which binds the catalytic CYLD USP domain in a CYLD B-box-dependent manner. Significantly, SPATA2 binding activates CYLD-mediated hydrolysis of ubiquitin chains. SPATA2 also harbors a conserved PUB-interacting motif that selectively docks into the HOIP PUB domain. In cells, SPATA2 is recruited to the TNF Receptor 1 signaling complex and is required for CYLD recruitment. Loss of SPATA2 increases ubiquitination of LUBAC substrates and results in enhanced NOD2 signaling. Our data reveal SPATA2 as a high-affinity binding partner of CYLD and HOIP, and a regulatory component of LUBAC-mediated NF-κB signaling.

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