title: SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes.
abstract: Recruitment of the deubiquitinase CYLD to signaling complexes is mediated by its interaction with HOIP, the catalytically active component of the linear ubiquitin chain assembly complex (LUBAC). Here, we identify SPATA2 as a constitutive direct binding partner of HOIP that bridges the interaction between CYLD and HOIP. SPATA2 recruitment to TNFR1- and NOD2-signaling complexes is dependent on HOIP, and loss of SPATA2 abolishes CYLD recruitment. Deficiency in SPATA2 exerts limited effects on gene activation pathways but diminishes necroptosis induced by tumor necrosis factor (TNF), resembling loss of CYLD. In summary, we describe SPATA2 as a previously unrecognized factor in LUBAC-dependent signaling pathways that serves as an adaptor between HOIP and CYLD, thereby enabling recruitment of CYLD to signaling complexes.
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kupka
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: De Miguel
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Draber
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1BF, UK.
authors.forename: Luigi
authors.initials: L
authors.lastname: Martino
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Surinova
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1BF, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rittinger
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: h.walczak@ucl.ac.uk.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
mesh_terms: D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D000074749:Deubiquitinating Enzyme CYLD; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D061251:Primary Cell Culture; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011506:Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; C425523:SPATA2 protein, human; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD