# Elucidating the structural mechanism of pore formation by the (GSDM) Gasdermin family

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $514,489

## Abstract

Gasdermins (GSDMs) represent a family of related proteins that caught the attention of the field
recently with fascinating biology. The GSDM family comprises six members in human (GSDMA,
GSMDB, GSDMC, GSDMD, GSDME/DFNA5, and DFNB59), and in mouse, three forms of GSDMA are
present, GSDMA1-3. Recently, GSDMD was identified as a downstream effector of inflammasomes,
which are supramolecular complexes that activate inflammatory caspases (-1, -4 and -5 in human and -
1 and -11 in mouse). GSDMD gets cleaved by caspases to generate an N-terminal fragment (GSDMD-
NT) and a C-terminal fragment (GSDMD-CT). GSDMD-NT mediates pyroptosis, a lytic cell death
involving spillage of cellular contents, as well as secretion of the IL-1β cytokine, which is processed by
caspase-1 to the mature form.
We and others found that upon cleavage by inflammatory caspases, GSDMD-NT specifically binds to
phosphatidylinositol phosphates (PIPs), phosphatidic acid (PA), phosphatidylserine (PS) and cardiolipin,
and exhibits strong membrane-disrupting cytotoxicity in mammalian cells by forming pores on
membranes during pyroptosis and in vitro. Other GSDMs are insensitive to inflammatory caspases.
GSDME (also known as DFNA5) was shown to be activated by apoptotic caspases (-3 and -7), which
also specifically block pyroptosis by cleaving GSDMD at a distinct site from the inflammatory caspases
to inactivate the protein. Similar to apoptotic caspases, Enterovirus 71 (EV71) viral protease 3C cleaves
GSDMD at a distinct site to inactivate it and to inhibit virus-induced pyroptosis. The activating enzymes
for the remaining GSDMs remain to be discovered.
Importantly, GSDMs, which are expressed in a variety of tissues, appear to exhibit a universal pore
formation activity in vitro, suggesting that they each mediate lytic cell death under different physiological
and pathological contexts. Here we propose to elucidate the structural mechanism of pore formation by
the GSDM family; understanding how GSDMD and other gasdermin proteins are regulated and exert
their pore forming activity will not only provide new insights on gasdermin-mediated cell death including
pyroptosis, but also afford new therapeutic strategies for treating inflammasome-related and
gasdermin-related diseases.

## Key facts

- **NIH application ID:** 10417119
- **Project number:** 5R01AI139914-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Hao Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $514,489
- **Award type:** 5
- **Project period:** 2018-06-12 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417119

## Citation

> US National Institutes of Health, RePORTER application 10417119, Elucidating the structural mechanism of pore formation by the (GSDM) Gasdermin family (5R01AI139914-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10417119. Licensed CC0.

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