Abstract
CASP2/caspase 2 plays a role in aging, neurodegeneration, and cancer. The contributions of CASP2 have been attributed to its regulatory role in apoptotic and nonapoptotic processes including the cell cycle, DNA repair, lipid biosynthesis, and regulation of oxidant levels in the cells. Previously, our lab demonstrated CASP2-mediated modulation of autophagy during oxidative stress. Here we report the novel finding that CASP2 is an endogenous repressor of autophagy. Knockout or knockdown of CASP2 resulted in upregulation of autophagy in a variety of cell types and tissues. Reinsertion of Caspase-2 gene (Casp2) in mouse embryonic fibroblast (MEFs) lacking Casp2 (casp2-/-) suppresses autophagy, suggesting its role as a negative regulator of autophagy. Loss of CASP2-mediated autophagy involved AMP-activated protein kinase, mechanistic target of rapamycin, mitogen-activated protein kinase, and autophagy-related proteins, indicating the involvement of the canonical pathway of autophagy. The present study also demonstrates an important role for loss of CASP2-induced enhanced reactive oxygen species production as an upstream event in autophagy induction. Additionally, in response to a variety of stressors that induce CASP2-mediated apoptosis, casp2-/- cells demonstrate a further upregulation of autophagy compared with wild-type MEFs, and upregulated autophagy provides a survival advantage. In conclusion, we document a novel role for CASP2 as a negative regulator of autophagy, which may provide important insight into the role of CASP2 in various processes including aging, neurodegeneration, and cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1054-1070 |
| Number of pages | 17 |
| Journal | Autophagy |
| Volume | 10 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2014 |
Bibliographical note
Funding Information:The authors wish to thank Dr Junying Yuan of Harvard University and Dr Carol Troy of Columbia University for providing the casp2−/− mice. The authors thank Dr Noboru Mizushima (Mizushima N et al., 2003)81 and RIKEN BioResource center for kindly providing GFP-LC3 Mice. The authors thank Dr Shengkan Jin from UMDNJ-Robert Wood Johnson Medical School (NJ USA) for kindly providing atg5−/− and Atg5+/+ MEFs and Dr Toren Finkel from the National Heart, Blood, and Lung institute (NIH, Bethesda, USA) for kindly providing atg7−/− and Atg7+/+ MEFs. The authors also thank Dr Victoria Centonze-Frohlich for her contributions and guidance in microscopy experiments. Images were generated in the Core Optical Imaging Facility, which is supported by UTHSCSA, NIH-NCI P30 CA54174 (San Antonio Cancer Institute), NIH-NIA P30 AG013319 (Nathan Shock Center) and NIH-NIA P01AG19316. The authors also thank Michelle E Bendele for assistance in mouse breeding and Sonya Karbch for her help in the experiments. This work has been supported by NIH grant 5 R37 AG007218-21.
Keywords
- Apoptosis
- Autophagy
- Autophagy regulators
- Caspase 2
- Caspases
- Reactive oxygen species
