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通过靶向NEMO-泛素相互作用的小分子抑制经典NF-κB信号通路

Inhibition of Canonical NF-κB Signaling by a Small Molecule Targeting NEMO-Ubiquitin Interaction.

作者信息

Vincendeau Michelle, Hadian Kamyar, Messias Ana C, Brenke Jara K, Halander Jenny, Griesbach Richard, Greczmiel Ute, Bertossi Arianna, Stehle Ralf, Nagel Daniel, Demski Katrin, Velvarska Hana, Niessing Dierk, Geerlof Arie, Sattler Michael, Krappmann Daniel

机构信息

Research Unit Cellular Signal Integration, Helmholtz Zentrum München für Gesundheit und Umwelt, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München für Gesundheit und Umwelt, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

出版信息

Sci Rep. 2016 Jan 7;6:18934. doi: 10.1038/srep18934.

DOI:10.1038/srep18934
PMID:26740240
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4703965/
Abstract

The IκB kinase (IKK) complex acts as the gatekeeper of canonical NF-κB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKα and IKKβ and the regulatory subunit NEMO/IKKγ. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-κB activation in response to TNFα, but not IL-1β stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB). Using biochemical and NMR experiments we demonstrate that iNUB binds to NEMOUBAN and competes for interaction with methionine-1-linked linear ubiquitin chains. iNUB inhibited NF-κB activation upon UBAN-dependent TNFα and TCR/CD28, but not UBAN-independent IL-1β stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-κB activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-κB signaling.

摘要

IκB激酶（IKK）复合物作为经典NF-κB信号通路的守门人，从而调节免疫、炎症和癌症。它由催化亚基IKKα和IKKβ以及调节亚基NEMO/IKKγ组成。在此，我们表明NEMO中的泛素结合结构域（UBAN）对于IKK/NF-κB响应TNFα而非IL-1β刺激的激活至关重要。通过筛选天然化合物文库，我们鉴定出一种蒽醌衍生物，它作为NEMO-泛素结合抑制剂（iNUB）发挥作用。利用生化和核磁共振实验，我们证明iNUB与NEMO UBAN结合并竞争与甲硫氨酸-1连接的线性泛素链的相互作用。iNUB抑制了依赖UBAN的TNFα和TCR/CD28刺激后的NF-κB激活，但不抑制不依赖UBAN的IL-刺激。此外，iNUB选择性地杀死依赖慢性B细胞受体触发的IKK/NF-κB激活的淋巴瘤细胞。因此，iNUB破坏了NEMO-泛素蛋白质-蛋白质相互作用界面，从而抑制生理和病理NF-κB信号传导。 1β1β

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/41a3e9432837/srep18934-f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/d022871521dc/srep18934-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/704e5f3fc1a7/srep18934-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/02172942d680/srep18934-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/41a3e9432837/srep18934-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/79fcee24fe6d/srep18934-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/9f1b5ec092b0/srep18934-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/ba80f5abe4a8/srep18934-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/d022871521dc/srep18934-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/704e5f3fc1a7/srep18934-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/02172942d680/srep18934-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ae5/4703965/41a3e9432837/srep18934-f7.jpg

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