SQST-1/p62-regulated SKN-1/Nrf mediates a phagocytic stress response via transcriptional activation oflyst-1/LYST
Authors: Elkhalil Aladin , Whited Alec , Ghose Piya 
Published: January 2025

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. 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 nematodeC. elegansto 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 thisin vivogenetic 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. This in turn allows SKN-1/Nrf to transcribe the lysosomal trafficking associated genelyst-1/LYST which subsequently promotes the phagocytic resolution of the developmentally-killed internalized cell even under stress conditions.

Author Summary

During development, cells can have many fates, one of which is to deliberately die. If a cell’s inherent ability to die is lost, unwanted cells remain, which can lead to pathologies such as abnormal brain development or cancer. Dead cell remains must also be fully and efficiently cleared away by being ingested and digested by other cells, to avoid autoimmunity. Cells that are destined to die, like any cell, can be subject to stress, which can change cell behavior. Moreover, cells fated to die often have highly intricate shapes, such as nerve cells in the brain, and their removal may entail different strategies for different regions of the cell. In this study, we have used the pre-destined “3-in-1” death of a structurally-complex cell in the roundwormC. elegansas a platform to describe the genetics behind how one cell bolsters its inherent ability to consume an area of another dying cell by mounting a response to environmental stress. Specifically, we report, to our knowledge for the first time, that a well-known stress-protective protein helps turns on a gene that helps ensure that ingested parts of dead cells are fully digested and removed.