A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses.
A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses.
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DOI：
10.1016/j.celrep.2013.08.025
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发表时间：
2013-10-17
期刊：
影响因子：
8.8
通讯作者：
Greenberg RA
中科院分区：
文献类型：
--
作者：
Zheng H;Gupta V;Patterson-Fortin J;Bhattacharya S;Katlinski K;Wu J;Varghese B;Carbone CJ;Aressy B;Fuchs SY;Greenberg RA
赖氨酸63连接的泛素（K63-Ub）链代表了一种特殊的泛素拓扑结构，介导蛋白酶体无关的信号传导事件。去泛素化酶（DUB） BRCC36分离成独特的核和细胞质复合物，对K63-Ub水解具有特异性。RAP80将五成员核BRCC36复合体靶向DNA双链断裂处的K63-Ub链。另一种四成员BRCC36复合物（BRISC）缺乏已知的靶向片段。在这里，我们确定丝氨酸羟甲基转移酶（SHMT）作为一个迄今为止未被认识的组件，履行这一功能。SHMT在与1型干扰素（IFN）受体链1 （IFNAR1）结合的K63-Ub链上指导BRISC活性。briscc - shmt2复合物定位并去泛素化积极参与的IFNAR1，从而限制其K63-Ub介导的内化和溶酶体降解。BRISC缺陷细胞和小鼠对IFN的反应减弱，并受到IFN相关免疫病理的保护。这些研究揭示了DUB调节的新机制，并建议使用BRISC抑制剂治疗由IFN反应升高驱动的病理生理过程。
Lysine63-linked ubiquitin (K63-Ub) chains represent a particular ubiquitin topology that mediates proteasome-independent signaling events. The deubiquitinating enzyme (DUB) BRCC36 segregates into distinct nuclear and cytoplasmic complexes that are specific for K63-Ub hydrolysis. RAP80 targets the five-member nuclear BRCC36 complex to K63-Ub chains at DNA double-strand breaks. The alternative four-member BRCC36 containing complex (BRISC) lacks a known targeting moiety. Here we identify Serine Hydroxymethyltransferase (SHMT) as a heretofore-unappreciated component that fulfills this function. SHMT directs BRISC activity at K63-Ub chains conjugated to the type 1 interferon (IFN) receptor chain 1 (IFNAR1). BRISC-SHMT2 complexes localize to and deubiquitinate actively engaged IFNAR1, thus limiting its K63-Ub mediated internalization and lysosomal degradation. BRISC deficient cells and mice exhibit attenuated responses to IFN and are protected from IFN-associated immunopathology. These studies reveal a novel mechanism of DUB regulation, and suggest a therapeutic use of BRISC inhibitors for treating pathophysiologic processes driven by elevated IFN responses.
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影响因子：
8.7
作者：
Piehler J;Thomas C;Garcia KC;Schreiber G
通讯作者：
Schreiber G
影响因子：
7.8
作者：
Kumar, K. G. Suresh;Barriere, Herve;Carbone, Christopher J.;Liu, Jianghuai;Swaminathan, Gayathri;Xu, Ping;Li, Ying;Baker, Darren P.;Peng, Junmin;Lukacs, Gergely L.;Fuchs, Serge Y.
通讯作者：
Fuchs, Serge Y.
DOI：
10.3109/08977194.2012.669382
发表时间：
2012-06
期刊：
Growth factors (Chur, Switzerland)
影响因子：
--
作者：
Fuchs SY
通讯作者：
Fuchs SY
影响因子：
16
作者：
Cohn, Martin A.;Kowal, Przemyslaw;D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
影响因子：
11.4
作者：
Cooper, Eric M.;Cutcliffe, Colleen;Cohen, Robert E.
通讯作者：
Cohen, Robert E.