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

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 inte...

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Bibliographic Details
Published in:Molecular cell Vol. 63; no. 6; pp. 990 - 1005
Main Authors: Elliott, Paul R, Leske, Derek, Hrdinka, Matous, Bagola, Katrin, Fiil, Berthe K, McLaughlin, Stephen H, Wagstaff, Jane, Volkmar, Norbert, Christianson, John C, Kessler, Benedikt M, Freund, Stefan M V, Komander, David, Gyrd-Hansen, Mads
Format: Journal Article
Language:English
Published: United States 15.09.2016
Subjects:
Amino Acid Sequence
Binding Sites
Cloning, Molecular
Crystallography, X-Ray
Deubiquitinating Enzyme CYLD
Endopeptidases - chemistry
Endopeptidases - genetics
Endopeptidases - immunology
Escherichia coli - genetics
Escherichia coli - metabolism
Gene Expression
Gene Expression Regulation
Humans
Immunity, Innate
Kinetics
Molecular Docking Simulation
NF-kappa B - chemistry
NF-kappa B - genetics
NF-kappa B - immunology
Nod2 Signaling Adaptor Protein - chemistry
Nod2 Signaling Adaptor Protein - genetics
Nod2 Signaling Adaptor Protein - immunology
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Proteins - chemistry
Proteins - genetics
Proteins - immunology
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - immunology
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction
Substrate Specificity
Tumor Suppressor Proteins - chemistry
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - immunology
Ubiquitin - chemistry
Ubiquitin - genetics
Ubiquitin - immunology
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - immunology
ISSN:1097-4164
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Summary: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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ISSN:1097-4164
DOI:10.1016/j.molcel.2016.08.001