Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation.
Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation.
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DOI：
10.1016/j.celrep.2021.110175
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发表时间：
2021-12-28
期刊：
影响因子：
8.8
通讯作者：
Horvath CM
中科院分区：
文献类型：
--
作者：
Lenoir JJ;Parisien JP;Horvath CM
赖氨酸63连接的多聚泛素（K63-Ub）链激活一系列细胞免疫和炎症信号传导途径，包括哺乳动物的抗病毒反应。干扰素和抗病毒基因由形成K63-Ub链的TRAF家族泛素连接酶触发。LGP 2是TRAF介导的K63-Ub的反馈抑制剂，可以干扰多种免疫信号传导途径。我们的研究结果表明，LGP 2抑制K63-Ub的协会和螯合的K63-Ub结合酶，Ubc13/UBE2N。LGP 2解旋酶亚结构域Hel2i介导蛋白质相互作用，其接合并抑制Ubc13/UBE2N，影响对一系列K63-Ub连接酶蛋白的控制，包括TRAF6、TRIM25和RNF125，所有这些蛋白质都被LGP 2灭活。这些发现为LGP 2介导的负调控建立了一个统一的机制，该机制可以调节多种K63-Ub信号通路。Mrs. et al.鉴定了免疫调节蛋白LGP 2用于抑制IRF 3和NF-κ B活化的机制。LGP2通过结合和隔离K63缀合酶Ubc13/UBE2N来阻断免疫信号传导所需的K63聚泛素化，影响广泛的抗病毒、细胞因子和免疫信号传导途径。
Lysine 63-linked polyubiquitin (K63-Ub) chains activate a range of cellular immune and inflammatory signaling pathways, including the mammalian antiviral response. Interferon and antiviral genes are triggered by TRAF family ubiquitin ligases that form K63-Ub chains. LGP2 is a feedback inhibitor of TRAF-mediated K63-Ub that can interfere with diverse immune signaling pathways. Our results demonstrate that LGP2 inhibits K63-Ub by association with and sequestration of the K63-Ub-conjugating enzyme, Ubc13/UBE2N. The LGP2 helicase subdomain, Hel2i, mediates protein interaction that engages and inhibits Ubc13/UBE2N, affecting control over a range of K63-Ub ligase proteins, including TRAF6, TRIM25, and RNF125, all of which are inactivated by LGP2. These findings establish a unifying mechanism for LGP2-mediated negative regulation that can modulate a variety of K63-Ub signaling pathways. Lenoir et al. identify the mechanism that the immune regulatory protein, LGP2, uses to inhibit IRF3 and NF-κB activation. LGP2 blocks K63 polyubiquitination required for immune signaling by binding and sequestering the K63-conjugating enzyme, Ubc13/UBE2N, affecting a wide range of antiviral, cytokine, and immune signaling pathways.
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