TBK1 and IKK epsilon prevent TNF-induced cell death by RIPK1 phosphorylation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F18%3A00502261" target="_blank" >RIV/68378050:_____/18:00502261 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1038/s41556-018-0229-6" target="_blank" >http://dx.doi.org/10.1038/s41556-018-0229-6</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41556-018-0229-6" target="_blank" >10.1038/s41556-018-0229-6</a>

Result language

angličtina

Original language name

TBK1 and IKK epsilon prevent TNF-induced cell death by RIPK1 phosphorylation

Original language description

The linear-ubiquitin chain assembly complex (LUBAC) modulates signalling via various immune receptors. In tumour necrosis factor (TNF) signalling, linear (also known as M1) ubiquitin enables full gene activation and prevents cell death. However, the mechanisms underlying cell death prevention remain ill-defined. Here, we show that LUBAC activity enables TBK1 and IKK epsilon recruitment to and activation at the TNF receptor 1 signalling complex (TNFR1-SC). While exerting only limited effects on TNF-induced gene activation, TBK1 and IKKe are essential to prevent TNF-induced cell death. Mechanistically, TBK1 and IKK epsilon phosphorylate the kinase RIPK1 in the TNFR1-SC, thereby preventing RIPK1-dependent cell death. This activity is essential in vivo, as it prevents TNF-induced lethal shock. Strikingly, NEMO (also known as IKK gamma), which mostly, but not exclusively, binds the TNFR1-SC via M1 ubiquitin, mediates the recruitment of the adaptors TANK and NAP1 (also known as AZI2). TANK is constitutively associated with both TBK1 and IKKe, while NAP1 is associated with TBK1. We discovered a previously unrecognized cell death checkpoint that is mediated by TBK1 and IKK epsilon, and uncovered an essential survival function for NEMO, whereby it enables the recruitment and activation of these non-canonical IKKs to prevent TNF-induced cell death.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30102 - Immunology

Project

<a href="/en/project/GJ17-27355Y" target="_blank" >GJ17-27355Y: Elucidation of molecular mechanisms guiding assembly and function of IL-17-receptor signaling complex.</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nature Cell Biology

ISSN

1465-7392

e-ISSN

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Volume of the periodical

20

Issue of the periodical within the volume

12

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

1389-1399

UT code for WoS article

000451328500011

EID of the result in the Scopus database

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