Gasdermin D is a novel effector in the extrinsic apoptosis pathway

Informazioni relative al progetto

Inflapoptosis

ID dell’accordo di sovvenzione: 838252

DOI

10.3030/838252

Progetto concluso il 30 Settembre 2020

Data della firma CE 10 Aprile 2019

Data di avvio 1 Settembre 2019

Data di completamento 31 Agosto 2021

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 191 149,44

Contributo UE

€ 191 149,44

Coordinato da

UNIVERSITE DE LAUSANNE
Switzerland

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

Periodo di rendicontazione: 2019-09-01 al 2021-08-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

-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

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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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