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Dev Cell. 2016 May 23;37(4):337-349. doi: 10.1016/j.devcel.2016.04.018.

The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis.

Author information

1
Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA.
2
Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
3
Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA; Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: andrew.thorburn@ucdenver.edu.

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.

PMID:
27219062
PMCID:
PMC4886731
DOI:
10.1016/j.devcel.2016.04.018
[Indexed for MEDLINE]
Free PMC Article

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