# Necrotic survivors and plasma membrane integrity signaling

> **NIH NIH DP2** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $1,358,083

## Abstract

PROJECT SUMMARY/ABSTRACT
After decades of cell death study, it is now well accepted that cell death can be highly programmed,
including some lytic forms. For example, the plasma membrane (PM) pore-forming executor for
necroptosis is MLKL, when phosphorylated by RIPK3. For pyroptosis, gasdermin family members
are the PM damaging executors, once processed by caspases or granzymes. Intriguingly, the PM
pore-forming is not the “point of no return” for necroptosis or pyroptosis. This is because ESCRT-
III complex can repair the damaged PM by membrane remodeling. The broken PM fractions can
be shed off. Therefore, for both necroptotic and pyroptotic cells, they can tolerate a limited level
of PM damage and survive for a long time if ESCRT-III repairing capacity is not overwhelmed. In
this grant, we presented our UNPUBLISHED data showing if a necrotic cell can manage to stay
alive, the sub-lethal PM damage is sufficient to initiate a sophisticated signal transduction network.
We named this signaling transduction pathway as Plasma Membrane Integrity signaling (PMI
signaling). PMI signals are efficient in promoting pro-tumor chemokines/cytokines secretions. We
hypothesize that the necrotic “survivors” can stimulate oncogenesis via the PMI signaling pathway
and the consequent chemokines/cytokines paracrine. Our ultimate goal is to mechanistically
understand and further target these “survivors” to improve cancer treatment. To achieve this end,
we will firstly hunt for the sensors for PM integrity loss. We proposed to test a promising ion
channel candidate that is very likely to be one of the sensors for PM damage. We have also
planned an elegant cell culture system to perform both siRNA and sgRNA screen to search for
the PM damage sensors genome-wide. Next, we will use both animal models and human
specimens to probe the necrotic “survivors.” We will further test the roles of the
chemokines/cytokines secreted by these “survivors” in tumorigenesis and metastasis. Third, we
will try to eliminate the necrotic “survivors” directly. Our preliminary data lead us to a candidate
RING E3 ligase. We will test whether targeting this E3 ligase can help us suppress the ESCRT-
III repair action and eradicate necrotic “survivors.” As the necrotic “survivors” were only
discovered not long ago (by us and others), the massive impacts of cell death “survivors” in
contributing to cancers, transplantation, and other illnesses are still fresh and needed to be fully
defined. Innovative research, like this one, will promote the revelation.

## Key facts

- **NIH application ID:** 10241019
- **Project number:** 1DP2GM146320-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yi-Nan Gong
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,358,083
- **Award type:** 1
- **Project period:** 2021-09-22 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241019

## Citation

> US National Institutes of Health, RePORTER application 10241019, Necrotic survivors and plasma membrane integrity signaling (1DP2GM146320-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10241019. Licensed CC0.

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