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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.

SUBMITTER: Kupka S

PROVIDER: S-EPMC5009064 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes.

Kupka Sebastian S De Miguel Diego D Draber Peter P Martino Luigi L Surinova Silvia S Rittinger Katrin K Walczak Henning H

Cell reports 20160818 9

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 ...[more]

PMID: 27545878

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

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SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death.

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PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome

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| S-SCDT-EMBOJ-2019-102201 | biostudies-other

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

Project description:TNF-a is a key regulator of innate immune and proinflammatory responses. However, the composition of the TNF-a 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-a stimulation induces widespread protein phosphorylation and that the scope of phosphorylation expands in a temporal manner. TNF-a 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 TNFRSC. 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-jB and inhibits TNF-a-induced necroptosis, pointing to an important function of SPATA2 in modulating the outcomes of TNF-a signaling. Taken together, our study draws a detailed map of TNF-a signaling, identifies SPATA2 as a novel component of TNF-a signaling, and provides a rich resource for further functional investigations.

2016-06-09 | PXD003627 | Pride

SPATA2 and CYLD inhibit T cell infiltration into colorectal cancer <i>via</i> regulation of IFN-γ/STAT1 axis.

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| S-EPMC9756846 | biostudies-literature

CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling.

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| S-EPMC4819907 | biostudies-literature

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2013-06-20 | E-GEOD-48122 | biostudies-arrayexpress

STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NF-kB signaling

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| S-SCDT-10_1038-S44318-024-00291-2 | biostudies-other

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