The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC
The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC
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DOI：
10.1038/s41556-020-0517-9
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发表时间：
2020-05-11
影响因子：
21.3
通讯作者：
Iwai, Kazuhiro
中科院分区：
文献类型：
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作者：
Fuseya, Yasuhiro;Fujita, Hiroaki;Iwai, Kazuhiro
Fuseya等人。发现HOIL-1L催化LUBAC三个亚基上的单泛素化，从而削弱LUBAC的功能及其在感染防御和皮炎发病中的作用。由HOIP、Sharpin和HOIL-1L组成的线性泛素链组装复合体(LUBAC)通过产生线性泛素链促进核因子-kappa B的激活和保护细胞死亡。LUBAC含有两个环-IBR-环(RBR)泛素连接酶(E3)，HOIP-RBR负责催化线性泛素化。我们发现HOIL-1L RBR在调节LUBAC中起着至关重要的作用。HOIL-1L RBR与LUBAC的所有亚基结合，然后HOIP介导的线性链结合到LUBAC上，这些线性链减弱了LUBAC的功能。将E3缺陷的HOIL-1L突变体引入细胞可增强线性泛素化，从而保护细胞免受沙门氏菌感染，并治愈因Sharpin丢失导致的LUBAC水平降低而导致的皮炎。我们的结果揭示了一种E3连接酶的调节模式，在这种模式中，LUBAC中的辅助E3通过为自线性泛素化提供首选底物来下调主要的E3。因此，抑制HOIL-1L E3是治疗严重感染或免疫缺陷的一种有前途的策略。
Fuseya et al. show that HOIL-1L catalyses monoubiquitination on all three LUBAC subunits, thereby impairing the function of LUBAC and its role in infection defence and dermatitis pathogenesis.The linear ubiquitin chain assembly complex (LUBAC), which consists of HOIP, SHARPIN and HOIL-1L, promotes NF-kappa B activation and protects against cell death by generating linear ubiquitin chains. LUBAC contains two RING-IBR-RING (RBR) ubiquitin ligases (E3), and the HOIP RBR is responsible for catalysing linear ubiquitination. We found that HOIL-1L RBR plays a crucial role in regulating LUBAC. HOIL-1L RBR conjugates monoubiquitin onto all LUBAC subunits, followed by HOIP-mediated conjugation of linear chains onto monoubiquitin, and these linear chains attenuate the functions of LUBAC. The introduction of E3-defective HOIL-1L mutants into cells augmented linear ubiquitination, which protected the cells against Salmonella infection and cured dermatitis caused by reduced LUBAC levels due to SHARPIN loss. Our results reveal a regulatory mode of E3 ligases in which the accessory E3 in LUBAC downregulates the main E3 by providing preferred substrates for autolinear ubiquitination. Thus, inhibition of HOIL-1L E3 represents a promising strategy for treating severe infections or immunodeficiency.