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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

Similar Datasets

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

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| S-EPMC5031558 | biostudies-literature

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

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

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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-EPMC6960439 | biostudies-literature

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

Project description:The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate Caspase-1 and drive the maturation of proinflammatory cytokines IL-1beta and IL-18. The NLRP3 inflammasome activity must be tightly controlled because its over-activation is implicated in the pathogenesis of inflammatory diseases. Here we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances the NLRP3 inflammasome activity both in macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits CYLD to the centrosome where they deubiquitinate polo-like kinase 4 (PLK4), a key regulator of centrosome duplication, to facilitate its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, a step required for NLRP3 inflammasome activation. Pharmacological or shRNA-mediated inhibition of PLK4 or lack of NEK7 phosphorylation at Ser204 augments its interaction with NLRP3, leading to increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal pathway-mediated regulation of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3-associated inflammatory diseases.

| 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.

Project description:IntroductionColorectal cancer (CRC) is largely refractory to currently available immunotherapies such as blockade of programmed cell death protein-1 (PD-1).ResultsIn this study, we identified SPATA2 and its protein partner CYLD as novel regulators of CXC-ligand 10 (CXCL10), a T-cell-attractant chemokine, in CRC. By specifically deleting SPATA2 and CYLD in human and mouse CRC cell lines, we showed that these two proteins inhibit STAT1 accumulation and activation and subsequently CXCL10 expression in tumor cells. At steady-state, STAT1 is highly ubiquitinated in a SPATA2/CYLD-dependent manner. Finally, we demonstrated that tumor-specific deletion of SPATA2 and CYLD enhances anti-PD-1 response in vivo.DiscussionOur data suggest that SPATA2 and CYLD represent two potential novel targets for treatment of immune-excluded, PD-1-resistant tumors.

| 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

REST–Mediated Recruitment of Polycomb Repressor Complexes in Mammalian Cells

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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

Project description:STING activation by cyclic dinucleotides in mammals induces IRF3- and NF-kB -mediated gene expression in mammals, as well as lipidation of LC3B at Golgi-related membranes. While mechanisms of the IRF3 response are well understood, the mechanisms of NF-kB activation via STING remain unclear. We report that STING activation induces linear/M1-linked ubiquitin chain (M1-Ub) formation and recruitment of the LUBAC E3 ligase, HOIP, to LC3B-associated Golgi membranes where ubiquitin is also localized. Loss of HOIP prevents formation of M1-Ub ubiquitin chains and reduces STING-induced NF-kB and IRF3 signaling in human THP1 monocytes and mouse bone marrow-derived macrophages, without affecting STING activation. STING-induced LC3B lipidation is not required for M1-Ub chain formation or for immune-related gene expression, but the recently reported STING function in neutralizing Golgi pH may be involved. Thus, LUBAC synthesis of M1-linked ubiquitin chains mediates STING-induced innate-immune signaling.

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

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