Gasdermin D is a novel effector in the extrinsic apoptosis pathway

Informations projet

Inflapoptosis

N° de convention de subvention: 838252

DOI

10.3030/838252

Projet clôturé le 30 Septembre 2020

Date de signature de la CE 10 Avril 2019

Date de début 1 Septembre 2019

Date de fin 31 Août 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 191 149,44

Contribution de l’UE

€ 191 149,44

Coordonné par

UNIVERSITE DE LAUSANNE
Switzerland

Periodic Reporting for period 1 - Inflapoptosis (Gasdermin D is a novel effector in the extrinsic apoptosis pathway)

Période du rapport: 2019-09-01 au 2021-08-31

Résumé du contexte et des objectifs généraux du projet

Gasdermin D (GSDMD) is a recently described pore-forming protein that is important for host defence against infection. However, emerging studies also implicate GSDMD in a variety of inflammatory diseases through poorly characterised mechanisms.
The aim of this study is to investigate the molecular and cellular mechanisms by which GSDMD promote inflammatory disease, so that better drug candidates can be identified in future. Here, we characterised the molecular mechanisms by which GSDMD promotes
tumour necrosis factor(TNF)-driven diseases. We show that caspase-8-dependent GSDMD activation promotes TNF-driven disease in mice. Our study thus uncovers novel drug targets for TNF-driven diseases.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

-Generation of caspase-3-uncleavable GSDMD mouse model
-Demonstration that caspase-3-uncleavable GSDMD mouse do not suffer from auto-inflammatory disease
-Validated that GSDMD activation promotes anti-microbial defence
-Validated that GSDMD activation promotes TNF-driven lethality

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

TNF-mediated diseases were traditionally believed to be solely driven by necroptosis, a form of necrotic death. Multi labs and biotech companies are developing such inhibitors to block these pathways, however, there are limited success.
Our work has now uncovered GSDMD, as a novel player in TNF-driven disease, therefore providing a new drug target.

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