Abstract
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.
Highlights
Masaya Fukushi 10, Takashi Irie 10, Daisuke Tsuruta 7, Shinji Sakamoto 8, Keiji Tanaka[5], Yasushi Saeki 5, Shuya Fukai 2,3 & Fuminori Tokunaga 1✉
We reported that HOIPIN-1 and HOIPIN-8 (Fig. 1a) suppress the linear ubiquitin chain assembly complex (LUBAC)-induced linear ubiquitination and nuclear factor-κB (NF-κB) target gene expression[28,29]
We found that the Sendai virus (SeV)-induced expression of interferon regulatory factor 3 (IRF3)-target genes was suppressed by HOIPINs in MEF cells (Fig. 2i)
Summary
Masaya Fukushi 10, Takashi Irie 10, Daisuke Tsuruta 7, Shinji Sakamoto 8, Keiji Tanaka[5], Yasushi Saeki 5, Shuya Fukai 2,3 & Fuminori Tokunaga 1✉. 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. 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. The linear ubiquitin chain assembly complex (LUBAC), composed of the HOIL-1L ( known as RBCK1), HOIP (RNF31), and SHARPIN, generates the Met1-linked linear polyubiquitin chain[7,8]. Upon stimulation by proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), LUBAC is recruited to cytokine receptors through binding to K63-linked polyubiquitin chains[13], and conjugates linear ubiquitin chains to NEMO, RIP1, and FADD14–16. Genetic mutations of LUBAC subunits and linear ubiquitin-binding proteins induce various disorders[20]
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