# Regulation of Ninj1 oligomerization and cell membrane ruptures during cell death

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $251,250

## Abstract

PROJECT ABSTRACT
Our proposal will examine a central mechanism of cell death pathways—the formation of large membrane
pores during the final stages of cell death. Recent studies have demonstrated that this process involves
Ninjurin1 (Ninj1), a membrane-spanning protein that multimerizes to form large membrane pores that lead to
membrane rupture. These membrane ruptures are essential for advanced signs of cell death and for the
release of larger inflammatory molecules required to mount an effective response to pathogens. The
multimerization of Ninj1 is critical for membrane rupture, but little is known about the specific mechanisms
underlying Ninj1 multimer formation or the direct implications of this oligomerization. This proposal will
determine how Ninj1 is activated by upstream steps of the cell death pathway, including caspase-8 and
caspase-1-driven signaling, and how gasdermin family members regulate this process. We will also examine
the contribution of Ninj1 activation in cell death pathways in the innate immune response to pathogens using
mouse models of Yersinia infection.
Our preliminary experiments demonstrated that Ninj1 expressed in myeloid cells is required for the host
response to Yersinia bacteria. We also showed that Ninj1 controls myeloid-cell driven defenses to Yersinia
infection in mice, underscoring the importance of Ninj1 in the innate immune response to bacterial infections.
Furthermore, our data suggest that GSDMD has a regulatory role in Ninj1 oligomerization initiated via both
caspase-8 and caspase-1. We hypothesize that GSDM proteins are modulating Ninj1 oligomerization and host
responses to caspase-8 and caspase-1 stimulations, and that Ninj1 oligomerization is a critical component in
effector-mediated immunity to Yersinia infections. Using Yersinia infections, cytokines, inhibitors, expression
systems and other tools, we will define the pathway controlling Ninj1 oligomerization during innate immune
signaling to cell death and inflammation to elucidate how this central step in multiple cell death pathways is
regulated.

## Key facts

- **NIH application ID:** 10871496
- **Project number:** 1R21AI182982-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Egil Lien
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $251,250
- **Award type:** 1
- **Project period:** 2024-03-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871496

## Citation

> US National Institutes of Health, RePORTER application 10871496, Regulation of Ninj1 oligomerization and cell membrane ruptures during cell death (1R21AI182982-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10871496. Licensed CC0.

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