# Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release

> **NIH NIH P01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $1,886,706

## Abstract

OVERALL PROGRAM PROJECT: ABSTRACT
Cell death pathways have historically been characterized by the proteases that become
activated during cell fate decisions. Apoptosis has been defined by initiator and effector caspase
activation and, largely due to the reagents available; cell death decisions were initially thought to
be binary – caspase-dependent (apoptosis) or caspase-independent (all others). Much like
other binary distinctions – like Th1 versus Th2 T cells or M1 versus M2 macrophages, which
have undergone substantial expansion in the past decade, cell death decisions and their
consequences are now recognized to be much more variables. In fact, even the mechanisms of
cell death have been refined. They are no longer categorized by the proteases which activate
the cascades but rather, by the effector mechanism. Necroptotic cell death is caused by
activation of the pore-forming protein, MLKL. Secondary necrosis is caused by activation of the
pore-forming protein, DFNA5 (Gasdermin E/GSDME), and pyroptosis is caused by activation of
the pore-forming protein, Gasdermin D (GSDMD) This last category of cell death - pyroptosis -
is one of the most immunologically important forms of cell death. Not only does pyroptosis kill
the cell, but also GSDMD activation allows the release of IL-1β. This cytokine is among the most
important in acute and chronic inflammation. Its secretion is implicated in rare genetic
inflammatory diseases such as Familial Mediterranean Fever as well as more common diseases
such as myocardial infarction, Alzheimer's disease, Crohn's disease and Ulcerative Colitis,
Multiple Sclerosis and many others. With the discovery of the inflammasome in 2002 and its
subsequent study, it became clear that the amyloid-like activation of these inflammasome
complexes drove pro-IL-1β cleavage and IL-1β release from the cell, but also pyroptosis.
Missing from this biochemistry, though, was the cell biology underlying IL-1β release. How is IL-
1β recognized by caspases and other proteases? If IL-1β is not released through a secretory
ER-Golgi mechanism, how is trafficked out of the cell? How is this release coordinated with
pyroptosis and other regulated cell death pathways that are operative in different populations of
immune effector cells. This Program Project aims to utilize cell physiology, biochemistry,
structural biology, and mouse and human disease models to unravel these important questions.

## Key facts

- **NIH application ID:** 10024450
- **Project number:** 1P01AI141350-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** GEORGE R DUBYAK
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,886,706
- **Award type:** 1
- **Project period:** 2020-07-24 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024450

## Citation

> US National Institutes of Health, RePORTER application 10024450, Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release (1P01AI141350-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10024450. Licensed CC0.

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