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Published on: May 3, 2024
The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis
Megan L Goodall1, Brent E Fitzwalter1, Shadi Zahedi2
1Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA.
Abstract:
Although autophagy controls cell death and survival, underlying mechanisms are poorly understood, and it is unknown whether autophagy affects only whether or not cells die or also controls other aspects of programmed cell death. MAP3K7 is a tumor suppressor gene associated with poor disease-free survival in prostate cancer. Here, we report that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TRAIL (TNF-related apoptosis-inducing ligand). Surprisingly, this death occurs primarily through necroptosis, not apoptosis, due to assembly of the necrosome in association with the autophagy machinery, mediated by p62/SQSTM1 recruitment of RIPK1. The mechanism of cell death switches to apoptosis if p62-dependent recruitment of the necrosome to the autophagy machinery is blocked. These data show that the autophagy machinery can control the mechanism of programmed cell death by serving as a scaffold rather than by degrading cargo.
Insights
Autophagy machinery controls programmed cell death mechanisms. Blocking p62/SQSTM1 recruitment to autophagy switches cell death from necroptosis to apoptosis, revealing autophagy
Area of Science:
- Cellular biology
- Molecular mechanisms of cell death
- Autophagy research
Background:
- Autophagy's role in cell death and survival is not fully understood.
- The tumor suppressor gene MAP3K7 is linked to poor prostate cancer survival.
- It remains unclear if autophagy influences the type of programmed cell death.
Purpose of the Study:
- To investigate the role of autophagy in regulating programmed cell death mechanisms.
- To explore the function of MAP3K7 in prostate cancer cell death.
- To determine how autophagy machinery influences cell death pathways.
Main Methods:
- Utilizing mouse prostate cell models with Map3k7 deletion.
- Inducing cell death using TNF-related apoptosis-inducing ligand (TRAIL).
- Analyzing the assembly of necrosomes and the involvement of p62/SQSTM1 and RIPK1.
Main Results:
- Map3k7 deletion sensitizes prostate cells to TRAIL-induced cell death.
- This cell death primarily occurs via necroptosis, not apoptosis.
- Necrosome assembly is associated with autophagy machinery via p62/SQSTM1 recruitment of RIPK1.
- Blocking p62-dependent recruitment shifts cell death to apoptosis.
Conclusions:
- Autophagy machinery can act as a scaffold to control programmed cell death mechanisms.
- The recruitment of necrosome components to autophagy influences the cell death pathway.
- These findings reveal a novel role for autophagy in dictating apoptosis versus necroptosis.
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