# Identification of the molecular regulation between cell survival and cell death in response to infection induced inflammasome activation.

> **NIH NIH P20** · SOUTH DAKOTA STATE UNIVERSITY · 2024 · $215,307

## Abstract

The molecular mechanism that defines whether inflammasome activation leads to cell death or survival 
and activation of immune cells, is unknown. Inflammasomes are protein complexes that function as 
cellular pathogen sensors. Upon sensing a pathogen, a member of the caspase cysteine protease family, 
caspase-1 is activated in inflammasomes. Active caspase-1 cleaves gasdermin-D (GSDMD), that 
subsequently forms pores throughout the plasma membrane leading to a form of cell death named 
pyroptosis. Paradoxically, the formation of GSDMD pores on the plasma membrane does not always lead 
to pyroptosis. It has been described that the endosomal sorting complex required for transport (ESCRT) 
results in membrane repair. It is not known what are the upstream signals which determine whether 
damaged membranes are repaired or not. It is an important problem, because without understanding this, 
the beneficial part of inflammasome activation (cytokine maturation) cannot be uncoupled from the 
detrimental and highly inflammatory pyroptosis. Based on our preliminary data, our hypothesis is that the 
ESCRT complex is inactivated via protease cleavage by caspase-2, which promotes pyroptosis. This 
hypothesis is supported by our preliminary work in which bacterial pore forming toxins trigger the 
pathogen detection response and stimulate inflammasomes. In this system, caspase-2 interacts with and 
cleaves the ESCRT associated protein ALIX. The rationale for the research is that, understanding this 
novel regulation of inflammasome driven pyroptosis could lead to new and innovative approaches to the 
prevention and treatment of a variety of infectious diseases. To test our central hypothesis and 
accomplish our overall objective, we formulated two specific aims: 1.) Elucidate the mechanism underlying 
the inflammasome dependent pyroptosis activation via membrane repair inhibition. Based on the 
preliminary data herein, our working hypothesis is that one or more regulatory components of ESCRT 
complex are inactivated by caspase-2 cleavage. 2.) Identify the upstream mechanisms that unleash 
caspase-2 dependent inactivation of membrane repair mechanisms in pyroptosis.

## Key facts

- **NIH application ID:** 10788332
- **Project number:** 5P20GM135008-03
- **Recipient organization:** SOUTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Gergely Imre
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $215,307
- **Award type:** 5
- **Project period:** 2022-03-20 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10788332

## Citation

> US National Institutes of Health, RePORTER application 10788332, Identification of the molecular regulation between cell survival and cell death in response to infection induced inflammasome activation. (5P20GM135008-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10788332. Licensed CC0.

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