Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
Commun Biol. 2020 Apr 3;3(1):163. doi: 10.1038/s42003-020-0882-8.
The NF-κB and interferon antiviral signaling pathways play pivotal roles in inflammatory and innate immune responses. The LUBAC ubiquitin ligase complex, composed of the HOIP, HOIL-1L, and SHARPIN subunits, activates the canonical NF-κB pathway through Met1-linked linear ubiquitination. We identified small-molecule chemical inhibitors of LUBAC, HOIPIN-1 and HOIPIN-8. Here we show that HOIPINs down-regulate not only the proinflammatory cytokine-induced canonical NF-κB pathway, but also various pathogen-associated molecular pattern-induced antiviral pathways. Structural analyses indicated that HOIPINs inhibit the RING-HECT-hybrid reaction in HOIP by modifying the active Cys885, and residues in the C-terminal LDD domain, such as Arg935 and Asp936, facilitate the binding of HOIPINs to LUBAC. HOIPINs effectively induce cell death in activated B cell-like diffuse large B cell lymphoma cells, and alleviate imiquimod-induced psoriasis in model mice. These results reveal the molecular and cellular bases of LUBAC inhibition by HOIPINs, and demonstrate their potential therapeutic uses.
NF-κB 和干扰素抗病毒信号通路在炎症和先天免疫反应中发挥关键作用。LUBAC 泛素连接酶复合物由 HOIP、HOIL-1L 和 SHARPIN 亚基组成，通过 Met1 连接的线性泛素化激活经典 NF-κB 通路。我们鉴定了 LUBAC、HOIPIN-1 和 HOIPIN-8 的小分子化学抑制剂。在这里，我们表明 HOIPINs 不仅下调了促炎细胞因子诱导的经典 NF-κB 通路，还下调了各种病原体相关分子模式诱导的抗病毒通路。结构分析表明，HOIPINs 通过修饰活性 Cys885 以及 LDD 结构域中的 C 末端残基（如 Arg935 和 Asp936）来抑制 HOIP 的 RING-HECT 杂合反应，从而促进 HOIPINs 与 LUBAC 的结合。HOIPINs 可有效诱导激活的 B 细胞样弥漫性大 B 细胞淋巴瘤细胞死亡，并减轻模型小鼠中咪喹莫特诱导的银屑病。这些结果揭示了 HOIPINs 抑制 LUBAC 的分子和细胞基础，并证明了它们在治疗中的潜在用途。
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