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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

<a href="/cs/project/GJ17-27355Y" target="_blank" >GJ17-27355Y: Studium molekulárních mechanismů regulujících složení a funkci IL-17 receptorového signálního komplexu.</a><br>

Návaznosti

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

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Nature Cell Biology

ISSN

1465-7392

e-ISSN

—

Svazek periodika

20

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

1389-1399

Kód UT WoS článku

000451328500011

EID výsledku v databázi Scopus

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