线性泛素链组装复合物（LUBAC）的小分子抑制剂，HOIPINs，抑制 NF-κB 信号通路。

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

机构信息

Biological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, 569-1125, Japan.

Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.

出版信息

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

DOI:10.1016/j.bbrc.2018.12.164

PMID:30611571

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 IC 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.

摘要

核因子-κB（NF-κB）是一个关键的转录因子家族，参与免疫和炎症反应以及细胞存活的调节。线性泛素链组装复合物（LUBAC）由 HOIL-1L、HOIP 和 SHARPIN 亚基组成，通过 HOIP 的泛素连接酶活性特异性地产生 Met1 连接的线性泛素链，并激活 NF-κB 途径。我们最近鉴定了 LUBAC 的一种化学抑制剂，我们将其命名为 HOIPIN-1（HOIP 抑制剂-1）。为了提高 HOIPIN-1 的效力，我们合成了 7 种衍生物（HOIPIN-2∼8），并分析了它们对 LUBAC 和 NF-κB 激活的影响。其中，HOIPIN-8 在 IC 值为 11 nM 时抑制重组 LUBAC 的线性泛素化活性，与 HOIPIN-1 相比增加了 255 倍。此外，与 HOIPIN-1 相比，HOIPIN-8 对 LUBAC 和 TNF-α诱导的 NF-κB 激活的抑制活性分别增强了 10 倍和 4 倍，而没有细胞毒性。这些结果表明，HOIPIN-8 是探索 LUBAC 生理功能的有力工具。