# Regulation of the Cell Death Program by DFNA5

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $521,412

## Abstract

Abstract
Apoptosis and pyroptosis play key physiological roles in growth, survival, homeostasis and innate immunity
of all mammals. Disregulation of these pathways could lead to many diseases including autoimmune,
inflammatory, atherosclerotic and malignant diseases. While apoptosis is an immunologically “silent” form of
programmed cell death executed by activation of the effector caspases 3, 6 and 7, pyroptosis is an
inflammatory form of programmed cell death executed by activation of the inflammatory caspases 1, 4, and
5 in humans. These inflammatory caspases cleave the gasdermin protein, GSDMD, to generate a pore-
forming N-terminal fragment that permeabilizes the plasma membrane leading, to cellular swelling, osmotic
cell lysis and leakage of intracellular contents. If apoptotic cells are not scavenged, such as seen under in
vitro culture conditions or conditions of impaired phagocytosis in vivo, they progress to a lytic and inflammatory
phase called secondary necrosis. Secondary necrosis shares several features with pyroptosis including
plasma membrane permeabilization, swelling, and lysis, and therefore it could represent a form of pyroptosis.
Indeed, we discovered recently that activated caspase-3 cleaves the gasdermin-related protein DFNA5 during
apoptosis to generate a necrotic DFNA5-N fragment that targets the plasma membrane to permeabilize it and
induce secondary necrosis/pyroptosis. Interestingly, unlike WT cells, DFNA5-deficient cells do not roundup
and swell, but extensively fragment into small apoptotic bodies suggesting that DFNA5 is a regulator of cellular
disassembly during apoptosis. As cellular disassembly during apoptosis may impact clearance of dying cells
by phagocytes, we propose to test the hypothesis that DFNA5 cleavage during apoptosis induces pores in
the plasma membrane to release “find me” and other phagocyte activation signals to clear apoptotic cells and
to temper down disassembly of apoptotic cells into small apoptotic bodies. In this application we propose aims
to gain further insight into the physiological function of DFNA5 in vivo, and its role in autoimmunity,
inflammation and innate immunity. We will study the clearance of apoptotic cells in DFNA5-deficient mice
and further assess the pathophysiological consequences of DFNA5 deficiency in the development of
autoimmunity. We will also characterize another novel function of DFNA5 involved in the regulation of the
mitochondrial apoptotic pathway and how this activity might impact cell proliferation and sensitivity to apoptotic
stimuli. Finally, we will investigate the role of DFNA5 in the host innate immunity against viral pathogens,
septic shock and inflammation-induced malignancy. Results from this research should have a high impact on
the field and increase our understanding of the signaling pathways activated during the apoptotic program
leading to cell permeabilization and their impact on tissue homeostasis, and autoimmune and inflammatory
diseases.

## Key facts

- **NIH application ID:** 10085204
- **Project number:** 5R01AR074564-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Emad S Alnemri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $521,412
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085204

## Citation

> US National Institutes of Health, RePORTER application 10085204, Regulation of the Cell Death Program by DFNA5 (5R01AR074564-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085204. Licensed CC0.

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