Small-molecule inhibitors of linear ubiquitin chain assembly complex (LUBAC), HOIPINs, suppress NF-κB signaling

Katsuya, Ken; Oikawa, Daisuke; Iio, Kiyosei; Obika, Shingo; Hori, Yuji; Urashima, Toshiki; Ayukawa, Kumiko; Tokunaga, Fuminori

doi:10.1016/j.bbrc.2018.12.164

Cited by 48 publications

(65 citation statements)

References 32 publications

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“…Moreover, the IL-1β-induced NF-κB activation, demonstrated by the phosphorylation of IKKα/β, p105, and p65, was suppressed by HOIPINs. As reported 29 , the inhibitory effects of HOIPIN-8 were more potent than those of HOIPIN-1. Similarly, HOIPIN-1 dose-dependently suppressed TNF-αinduced NF-κB activation and gene expression in A549 cells ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 68%

“…We reported that HOIPIN-1 and HOIPIN-8 ( Fig. 1a) suppress the LUBAC-induced linear ubiquitination and NF-κB target gene expression 28,29 . Among reported LUBAC inhibitors, BAY11-7082 and gliotoxin showed potent cytotoxicity ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 90%

“…We have developed eight types of HOIP inhibitors (HOIPIN-1-HOIPIN-8) 29 . The HOIPIN-1-and HOIPIN-8-bound structures of HOIP explain the differences in the inhibition activities of the eight HOIP inhibitors with petit-LUBAC ( Supplementary Fig.…”

Section: Hoipins Inhibit the Ring-hect-hybrid Reaction Of Lubacmentioning

confidence: 99%

“…We identified a thiol-reactive, α,β-unsaturated carbonyl-containing chemical compound, named HOIPIN-1 from HOIP inhibitor-1, as a LUBAC inhibitor 28 . Furthermore, we developed seven derivatives of HOIPIN-1, and found that HOIPIN-8 is the most potent LUBAC inhibitor among them 29 . However, the detailed molecular mechanism and the pharmacological effects of HOIPINs have remained elusive.…”

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confidence: 99%

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Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses

et al. 2020

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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 Cterminal 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.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 90%

Section: Hoipins Inhibit the Ring-hect-hybrid Reaction Of Lubacmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses

et al. 2020

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“…For analysis of native LUBAC formation, the Invitrogen Blue Native Gel system (Invitrogen, BN2007, BN2008) was regulates the host response. While several chemical inhibitors as well as peptides that bind HOIP have been used to inhibit LUBAC activity in cell culture (70)(71)(72)(73) and in vitro assays (74,75) and support the targetablility of LUBAC, we have demonstrated that complete loss of HOIP is detrimental during IAV infection; however, some destabilization of LUBAC through loss of HOIL-1L is beneficial. Thus, novel compounds that target LUBAC stability to modulate LUBAC activity may be therapeutically beneficial for the treatment of hyperinflammatory response during IAV infection, where a modest degree of host response is necessary.…”

Section: Discussionmentioning

confidence: 65%

Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection

Brazee¹,

Morales‐Nebreda²,

Magnani³

et al. 2020

Journal of Clinical Investigation

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Linear ubiquitination‐induced necrotic tumor remodeling elicits immune evasion

et al. 2023

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Tumor‐elicited inflammation confers tumorigenic properties, including cell death resistance, proliferation, or immune evasion. To focus on inflammatory signaling in tumors, we investigated linear ubiquitination, which enhances the nuclear factor‐κB signaling pathway and prevents extrinsic programmed cell death under inflammatory environments. Here, we showed that linear ubiquitination was augmented especially in tumor cells around a necrotic core. Linear ubiquitination allowed melanomas to tolerate the hostile tumor microenvironment and to extend a necrosis‐containing morphology. Loss of linear ubiquitination resulted in few necrotic lesions and growth regression, further leading to repression of innate anti‐PD‐1 therapy resistance signatures in melanoma as well as activation of interferon responses and antigen presentation that promote immune‐mediated tumor eradication. Collectively, linear ubiquitination promotes tumor‐specific tissue remodeling and the ensuing immune evasion.

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Small-molecule inhibitors of linear ubiquitin chain assembly complex (LUBAC), HOIPINs, suppress NF-κB signaling

Cited by 48 publications

References 32 publications

Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses

Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses

Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection

Linear ubiquitination‐induced necrotic tumor remodeling elicits immune evasion

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