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Biochem Biophys Res Commun. 2019 Feb 12;509(3):700-706. doi: 10.1016/j.bbrc.2018.12.164. Epub 2019 Jan 2.

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

Author information

1
Biological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, 569-1125, Japan.
2
Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.
3
Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, 569-1125, Japan.
4
Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan. Electronic address: ftokunaga@med.osaka-cu.ac.jp.

Abstract

Nuclear factor-κB (NF-κB) is a crucial transcription factor family involved in the regulation of immune and inflammatory responses and cell survival. The linear ubiquitin chain assembly complex (LUBAC), composed of the HOIL-1L, HOIP, and SHARPIN subunits, specifically generates Met1-linked linear ubiquitin chains through the ubiquitin ligase activity in HOIP, and activates the NF-κB pathway. We recently identified a chemical inhibitor of LUBAC, which we named HOIPIN-1 (HOIP inhibitor-1). To improve the potency of HOIPIN-1, we synthesized 7 derivatives (HOIPIN-2∼8), and analyzed their effects on LUBAC and NF-κB activation. Among them, HOIPIN-8 suppressed the linear ubiquitination activity by recombinant LUBAC at an IC50 value of 11 nM, corresponding to a 255-fold increase over that of HOIPIN-1. Furthermore, as compared with HOIPIN-1, HOIPIN-8 showed 10-fold and 4-fold enhanced inhibitory activities on LUBAC- and TNF-α-induced NF-κB activation respectively, without cytotoxicity. These results indicated that HOIPIN-8 is a powerful tool to explore the physiological functions of LUBAC.

KEYWORDS:

Cytokine; Enzyme inhibitor; Inflammation; NF-κB; Ubiquitin

PMID:
30611571
DOI:
10.1016/j.bbrc.2018.12.164

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