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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Vydané v:	Molecular cell Ročník 63; číslo 6; s. 990 - 1005
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 15.09.2016
Predmet:	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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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4164
DOI:	10.1016/j.molcel.2016.08.001