Summary: New research reveals how the body clears dying cells under stress, uncovering an unexpected role for classic stress-response genes. Using the model organism C. elegans, scientists visualized a stress-activated pathway that promotes removal of cellular debris—a process fundamental to immune health, development and tissue maintenance.
By combining live imaging with CRISPR/Cas9 gene editing, the team observed this cellular cleanup machinery in real time and identified a conserved gene linked to human immune disorders. Their results offer fresh insight into conditions such as Chediak-Higashi Syndrome, where defective debris clearance undermines immune function.
Key facts
- Stress-response genes trigger cleanup: Classical stress-response factors activate a pathway that enhances phagocytic removal of dying cells.
- Real-time visualization: State-of-the-art live imaging in C. elegans allowed researchers to watch phagocytic machinery at work during stress.
- Human relevance: The identified gene corresponds to human LYST, mutations of which are associated with immune disorders.
Source: UT Arlington
Overview
A study from The University of Texas at Arlington describes a newly discovered mechanism by which organisms maintain efficient clearance of dying cells when exposed to stress. The research highlights unexpected functions for well-known stress-response genes and explains how they support phagocytosis—the process by which dead cells and debris are engulfed and removed.
“The body continually produces new cells and must remove the old or damaged ones,” said Aladin Elkhalil, lead author and doctoral student in the lab of Piya Ghose, assistant professor of biology at UT Arlington. “Efficient removal of dead cells is as critical as producing new ones—failure to clear cellular debris can cause a range of health problems.”
Published in the open-access journal PLoS Genetics, the study was led by Dr. Ghose with graduate students Elkhalil and Alec Whited. They used the transparent roundworm C. elegans, a widely used genetic model, because its clear body enables direct observation of live cell behavior, including cell death and phagocytosis.
The team focused on stress-response genes that have conserved counterparts in humans and tested how these genes influence the removal of dying cells. Using CRISPR/Cas9 and classical genetic approaches, they identified a stress-responsive pathway that becomes active during heat stress and other insults to facilitate cellular cleanup.
Advanced fluorescence microscopy allowed the researchers to capture the timing and localization of key components in the cell-clearance machinery. This live imaging revealed how stress-related transcription factors and phagocytic genes are switched on and coordinate during the clearance process.
A central finding is the involvement of a gene whose human equivalent is LYST, known for its role in vesicle trafficking and linked to Chediak-Higashi Syndrome—a rare disorder characterized by impaired cellular debris clearance and compromised immune responses.
“We discovered that the worm version of this gene is regulated by classical stress-response factors, a connection that had not been shown before,” Elkhalil said. “Understanding why this pathway is engaged under stress opens an important avenue for future research into adaptive mechanisms that preserve tissue health.”
Methods and experimental approach
The researchers combined forward and reverse genetics, CRISPR/Cas9 gene editing, stress-response assays and high-resolution live imaging. They leveraged a developmental program in C. elegans called Compartmentalized Cell Elimination (CCE), where distinct segments of polarized embryonic cells are removed by different mechanisms. This system enabled the team to dissect compartment-specific and stress-adaptive features of phagocytic clearance.
Under heat stress, the selective autophagy receptor SQST-1/p62 was shown to promote nuclear localization of the oxidative stress transcription factor SKN-1/Nrf by negatively regulating WDR-23. SKN-1/Nrf then activates transcription of the lysosomal trafficking gene lyst-1 (the worm homolog of human LYST), which supports phagocytic resolution of developmentally killed cells even during stress.
Implications
These findings reveal an adaptive, transcriptionally regulated stress response that directly supports phagocytosis. By linking stress-sensing pathways to genes that control lysosomal trafficking and corpse removal, the work suggests mechanisms that preserve tissue integrity under adverse conditions. The conservation of key components between worms and humans highlights potential relevance to immune disorders and diseases where defective clearance contributes to pathology.
Funding: This work was supported by The Cancer Prevention Research Institute of Texas (CPRIT) (RR100091) and the National Institutes of Health–National Institute of General Medical Sciences (R35GM142489).
About this research and contact information
Author: Katherine Bennett
Source: UT Arlington
Contact: Katherine Bennett – UT Arlington
Image credit: Neuroscience News
Original research (open access): “SQST-1/p62-regulated SKN-1/Nrf mediates a phagocytic stress response via transcriptional activation of lyst-1/LYST” by Piya Ghose et al., published in PLOS Genetics.
Abstract (condensed)
Cells die as part of normal development or in response to stress, injury or disease. Rapid and efficient clearance of dead cells prevents secondary damage and autoimmunity. The study explores whether stress alters developmental cell elimination and whether adaptive stress responses facilitate clearance, especially in polarized cells with compartment-specific vulnerabilities.
Using the Compartmentalized Cell Elimination model in C. elegans, the authors combine genetic screens, CRISPR editing, stress assays and live imaging to identify an adaptive phagocytic stress response. Under heat stress, SQST-1/p62 promotes nuclear translocation of SKN-1/Nrf by negatively regulating WDR-23. SKN-1/Nrf then drives transcription of lyst-1/LYST, enhancing lysosomal trafficking and phagocytic resolution of internalized, developmentally killed cells during stress.