SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling.
SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling.
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DOI：
10.1016/j.molcel.2016.08.001
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发表时间：
2016-09-15
期刊：
影响因子：
16
通讯作者：
Gyrd-Hansen, Mads
中科院分区：
文献类型：
--
作者：
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
线性泛素链组装复合物（LUBAC）调节免疫信号，其功能受脱泛素酶OTULIN和CYLD调控，这两种酶与催化亚基HOIP相关。然而，CYLD与HOIP相互作用的机制尚不清楚。我们在这里发现CYLD通过精子发生相关蛋白2 （SPATA2）与HOIP相互作用。SPATA2通过其非规范的PUB结构域与CYLD相互作用，该结构域以CYLD b -box依赖的方式结合催化CYLD USP结构域。值得注意的是，SPATA2结合激活了cyld介导的泛素链水解。SPATA2还包含一个保守的PUB相互作用基序，选择性地停靠到HOIP PUB结构域。在细胞中，SPATA2被募集到TNF受体1信号复合体，并且是CYLD募集所必需的。SPATA2的缺失会增加LUBAC底物的泛素化，并导致NOD2信号传导增强。我们的数据显示SPATA2是CYLD和HOIP的高亲和力结合伙伴，也是lubac介导的NF-κB信号传导的调节成分。SPATA2介导CYLD向LUBAC和TNF受体1复合物的募集SPATA2与CYLD形成高亲和力复合物并刺激CYLD的活性SPATA2与OTULIN一样，使用保守的PIM停靠在HOIP PUB结构域SPATA2限制LUBAC底物的泛素化以调节炎症信号Elliott等人的研究表明SPATA2将CYLD与LUBAC桥接以调节底物泛素化和炎症信号。结构和生化工作定义了SPATA2-CYLD和SPATA2-HOIP接口，揭示了spata2介导的CYLD激活，并首次揭示了LUBAC复合物的化学计量学。
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. CYLD recruitment to LUBAC and the TNF receptor 1 complex is mediated by SPATA2 SPATA2 forms a high-affinity complex with CYLD and stimulates CYLD’s activity SPATA2, like OTULIN, uses a conserved PIM to dock to the HOIP PUB domain SPATA2 limits ubiquitination of LUBAC substrates to regulate inflammatory signaling Elliott et al. show that SPATA2 bridges CYLD with LUBAC to regulate substrate ubiquitination and inflammatory signaling. Structural and biochemical work defines SPATA2-CYLD and SPATA2-HOIP interfaces, reveals SPATA2-mediated CYLD activation, and provides first insights into stoichiometry of LUBAC complexes.
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DOI：
10.1084/jem.20062694
发表时间：
2007-06-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Reiley WW;Jin W;Lee AJ;Wright A;Wu X;Tewalt EF;Leonard TO;Norbury CC;Fitzpatrick L;Zhang M;Sun SC
通讯作者：
Sun SC
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
16
作者：
Damgaard, Rune Busk;Nachbur, Ueli;Gyrd-Hansen, Mads
通讯作者：
Gyrd-Hansen, Mads
影响因子：
16
作者：
Li H;Lim KS;Kim H;Hinds TR;Jo U;Mao H;Weller CE;Sun J;Chatterjee C;D'Andrea AD;Zheng N
通讯作者：
Zheng N
影响因子：
64.8
作者：
Ikeda, Fumiyo;Deribe, Yonathan Lissanu;Skanland, Sigrid S.;Stieglitz, Benjamin;Grabbe, Caroline;Franz-Wachtel, Mirita;van Wijk, Sjoerd J. L.;Goswami, Panchali;Nagy, Vanja;Terzic, Janos;Tokunaga, Fuminori;Androulidaki, Ariadne;Nakagawa, Tomoko;Pasparakis, Manolis;Iwai, Kazuhiro;Sundberg, John P.;Schaefer, Liliana;Rittinger, Katrin;Macek, Boris;Dikic, Ivan
通讯作者：
Dikic, Ivan