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Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses
Communications Biology ( IF 5.2 ) Pub Date : 2020-04-03 , DOI: 10.1038/s42003-020-0882-8
Daisuke Oikawa , Yusuke Sato , Fumiaki Ohtake , Keidai Komakura , Kazuki Hanada , Koji Sugawara , Seigo Terawaki , Yukari Mizukami , Hoang T. Phuong , Kiyosei Iio , Shingo Obika , Masaya Fukushi , Takashi Irie , Daisuke Tsuruta , Shinji Sakamoto , Keiji Tanaka , Yasushi Saeki , Shuya Fukai , Fuminori Tokunaga

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.



中文翻译:

HOIPINs介导的LUBAC抑制和先天免疫反应的分子基础

NF-κB和干扰素抗病毒信号通路在炎症和先天免疫反应中起关键作用。由HOIP,HOIL-1L和SHARPIN亚基组成的LUBAC泛素连接酶复合物通过Met1连接的线性泛素化激活经典的NF-κB途径。我们确定了LUBAC,HOIPIN-1和HOIPIN-8的小分子化学抑制剂。在这里,我们显示,HOIPINs不仅下调促炎性细胞因子诱导的经典NF-κB途径,而且下调各种病原体相关的分子模式诱导的抗病毒途径。结构分析表明,HOIPIN通过修饰活性Cys885抑制HOIP中的RING-HECT杂交反应,C末端LDD域中的残基(例如Arg935和Asp936)促进HOIPIN与LUBAC的结合。HOIPINs在活化的B细胞样弥漫性大B细胞淋巴瘤细胞中有效诱导细胞死亡,并减轻模型小鼠咪喹莫特诱发的牛皮癣。这些结果揭示了HOIPIN抑制LUBAC的分子和细胞基础,并证明了其潜在的治疗用途。

更新日期:2020-04-24
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