# Molecular basis of plasma membrane rupture in lytic cell death and its inhibition by cytoprotective agent glycine

> **NIH NIH R35** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $402,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Plasma membrane rupture (PMR) in lytic cell death—including pyroptosis, necroptosis, and post-apoptotic
secondary necrosis—is a cataclysmic event that releases large-size intracellular molecules known as damage-
associated molecular patterns (DAMPs), which in turn propagate the inflammatory response. Lytic cell death
plays an important role in host defense against pathogen infections, but its dysregulation is also implicated in
many inflammatory diseases and pathological conditions. PMR was thought to be a passive event, until a recent
study identified NINJ1 to be responsible for carrying out this process. NINJ1 is a 16-kDa plasma membrane
protein previously identified to be mediating cell adhesion through homotypic binding. It has two transmembrane
helices and one extracellular amphipathic helix. NINJ1 undergoes oligomerization to induce PMR, and the
amphipathic helix seems to play an important role in this process. However, a highly similar protein NINJ2 in the
plasma membrane bearing a similar amphipathic helix does not induce PMR. To understand the molecular basis
of NINJ1-oligomerization mediated PMR, we use cryogenic electron microscopy (cryoEM) to study the structures
of NINJ1 and NINJ2 oligomers. The progress we have made is shedding light on a mechanistic understanding
of this process. However, it also points to more hypotheses that need to be tested in order to fully understand
this fundamentally important process. PMR is also linked to glycine cytoprotection in a very recent study. It was
demonstrated that glycine treatment prevented NINJ1 oligomerization and thus prevented PMR in bone marrow
derived macrophages receiving various forms of lytic cell death stimuli. We will include glycine treatment in our
test of hypotheses for the search of signal that triggers NINJ1 oligomerization. This further elucidation of the
molecular basis of glycine cytoprotection would inform the development of better cell preservation strategies or
agents.

## Key facts

- **NIH application ID:** 10930843
- **Project number:** 5R35GM151043-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Xinghong Dai
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2023-09-25 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930843

## Citation

> US National Institutes of Health, RePORTER application 10930843, Molecular basis of plasma membrane rupture in lytic cell death and its inhibition by cytoprotective agent glycine (5R35GM151043-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10930843. Licensed CC0.

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