Summary: New research has uncovered how the body clears dying cells during times of stress, shedding light on the unexpected role of classic stress-response genes. Using the model organism C. elegans, scientists tracked how these genes activate a pathway that helps remove cellular debris, a process essential for immune health and development.
Live imaging and CRISPR techniques allowed researchers to observe this stress-cell clearance machinery in real time. These findings could provide new insight into diseases like Chediak-Higashi Syndrome, where the body fails to clean up dead cells effectively.
Key Facts:
- Stress-Cleanup Link: Classic stress-response genes activate a pathway that clears dying cells.
- Live Imaging Used: Researchers used real-time imaging in C. elegans to visualize cellular cleanup during stress.
- Human Relevance: The key gene identified is related to a human gene (LYST) involved in immune disorders.
Source: UT Arlington
A new study from The University of Texas at Arlington details a novel strategy for how the body clears out dead cells during stress, revealing unexpected roles for well-known stress-response genes—a discovery that could help scientists better understand diseases affecting the immune system, brain and metabolism.
“The body is constantly creating new cells and removing old cells once they die,” said Aladin Elkhalil, lead author of the study and a third-year doctoral student in the lab of Piya Ghose, assistant professor of biology at UT Arlington.
“This removal of dead cells is just as important as creating new ones, because if the body is unable to rid itself of dead cells, it can lead to various health problems”
Published in the peer-reviewed, open-access journal PLoS Genetics, the study was conducted on the roundworm C. elegans by Dr. Ghose, Elkhalil and Alec Whited, another graduate student in the Ghose lab.
This tiny, transparent organism is a widely used tool in genetic research because its see-through body allows scientists to observe live cell behavior, including how cells die. The research team took advantage of these unique features in several innovative ways.
“This has been an exciting study, where stress meets cell behavior,” said Ghose. “It’s fascinating to see how our cells adapt to changes in their surroundings and still perform their normal functions. Understanding that process is essential to our normal physiology and development.”
The team examined stress-response genes—many of which have human counterparts—in a new context: how they help remove dying cells. Using tools like CRISPR/Cas9 gene-editing technology, they manipulated these genes to identify a specific stress-response pathway that activates to help in the removal of dying cells.
Using state-of-the-art live imaging, the researchers were able to characterize this stress-response pathway by observing key components of the cell clearance machinery in action. This allowed them to see when and how stress-related and clearance genes are switched on during the removal process.
A key gene was identified: The human version, known as lyst, is linked to Chediak-Higashi Syndrome, a rare disorder in which cells struggle clearing out debris, leading to immune system problems.
“One of the novel findings in our study is that the worm version of this gene is controlled by classical stress-response genes, which was previously unknown,” Elkhalil said.
“An intriguing question is why this pathway needs to be in place at all. That leaves us with an exciting avenue for future research.”
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 genetics and neuroscience research news
Author: Katherine Bennett
Source: UT Arlington
Contact: Katherine Bennett – UT Arlington
Image: The image is credited to 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. PLOS Genetics
Abstract
SQST-1/p62-regulated SKN-1/Nrf mediates a phagocytic stress response via transcriptional activation of lyst-1/LYST
Cells may be intrinsically fated to die to sculpt tissues during development or to maintain homeostasis. Cells can also die in response to various stressors, injury or pathological conditions.
Additionally, cells of the metazoan body are often highly specialized with distinct domains that differ both structurally and with respect to their neighbors. Specialized cells can also die, as in normal brain development or pathological states and their different regions may be eliminated via different programs.
Clearance of different types of cell debris must be performed quickly and efficiently to prevent autoimmunity and secondary necrosis of neighboring cells. Moreover, all cells, including those programmed to die, may be subject to various stressors.
Some largely unexplored questions include whether predestined cell elimination during development could be altered by stress, if adaptive stress responses exist and if polarized cells may need compartment-specific stress-adaptive programs.
We leveraged Compartmentalized Cell Elimination (CCE) in the nematode C. elegans to explore these questions. CCE is a developmental cell death program whereby three segments of two embryonic polarized cell types are eliminated differently.
We have previously employed this in vivo genetic system to uncover a cell compartment-specific, cell non-autonomous clearance function of the fusogen EFF-1 in phagosome closure during corpse internalization.
Here, we introduce an adaptive response that serves to aid developmental phagocytosis as a part of CCE during stress.
We employ a combination of forward and reverse genetics, CRISPR/Cas9 gene editing, stress response assays and advanced fluorescence microscopy.
Specifically, we report that, under heat stress, the selective autophagy receptor SQST-1/p62 promotes the nuclear translocation of the oxidative stress-related transcription factor SKN-1/Nrf via negative regulation of WDR-23.
This in turn allows SKN-1/Nrf to transcribe lyst-1/LYST (lysosomal trafficking associated gene) which subsequently promotes the phagocytic resolution of the developmentally-killed internalized cell even under stress conditions.
