Gasdermin D is a novel effector in the extrinsic apoptosis pathway

Project Information

Inflapoptosis

Grant agreement ID: 838252

DOI

10.3030/838252

Project terminated on 30 September 2020

EC signature date 10 April 2019

Start date 1 September 2019

End date 31 August 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 191 149,44

EU contribution

€ 191 149,44

Coordinated by

UNIVERSITE DE LAUSANNE
Switzerland

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

Reporting period: 2019-09-01 to 2021-08-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

-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

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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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