Although autophagy controls cell death and survival, underlying mechanisms are poorly understood. The importance of this process was highlighted by the award of the 2016 Nobel Prize in Medicine to Yoshinori Ohsumi. However, it is unknown if autophagy simply affects if 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. This webcast reports that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TNF-related apoptosis inducing ligand (TRAIL). Surprisingly, this death occurs primarily through necroptosis, not apoptosis. Proximity ligation assays (PLAs) were able to show assembly of the necrosome in association with the autophagy machinery and that it is mediated by p62/SQSTM1 recruitment of RIPK1. Furthermore, 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 and inhibition at different stages of autophagy is important for cell death.
In this webcast, you will learn:
- The necrosome associates with autophagy machinery.
- Inhibition of autophagy can promote or inhibit cell death depending on early or late pathway inhibition.
- Autophagy modulates mode of cell death (apoptosis versus necroptosis).
Dr. Megan Goodall
University of Colorado