A nonapoptotic role for CASP2/caspase 2: Modulation of autophagy

Meenakshi Tiwari, Lokendra K. Sharma, Difernando Vanegas, Danielle A. Callaway, Yidong Bai, James D Lechleiter, Brian Herman

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1054-1070
Number of pages17
JournalAutophagy
Volume10
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Caspase 2
Autophagy
Up-Regulation
Fibroblasts
AMP-Activated Protein Kinases
Sirolimus
Mitogen-Activated Protein Kinases
Oxidants
DNA Repair
Genes
Reactive Oxygen Species
Neoplasms
Cell Cycle
Oxidative Stress

Keywords

  • Apoptosis
  • Autophagy
  • Autophagy regulators
  • Caspase 2
  • Caspases
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Tiwari, M., Sharma, L. K., Vanegas, D., Callaway, D. A., Bai, Y., Lechleiter, J. D., & Herman, B. (2014). A nonapoptotic role for CASP2/caspase 2: Modulation of autophagy. Autophagy, 10(6), 1054-1070. https://doi.org/10.4161/auto.28528

A nonapoptotic role for CASP2/caspase 2 : Modulation of autophagy. / Tiwari, Meenakshi; Sharma, Lokendra K.; Vanegas, Difernando; Callaway, Danielle A.; Bai, Yidong; Lechleiter, James D; Herman, Brian.

In: Autophagy, Vol. 10, No. 6, 2014, p. 1054-1070.

Research output: Contribution to journalArticle

Tiwari, M, Sharma, LK, Vanegas, D, Callaway, DA, Bai, Y, Lechleiter, JD & Herman, B 2014, 'A nonapoptotic role for CASP2/caspase 2: Modulation of autophagy', Autophagy, vol. 10, no. 6, pp. 1054-1070. https://doi.org/10.4161/auto.28528
Tiwari, Meenakshi ; Sharma, Lokendra K. ; Vanegas, Difernando ; Callaway, Danielle A. ; Bai, Yidong ; Lechleiter, James D ; Herman, Brian. / A nonapoptotic role for CASP2/caspase 2 : Modulation of autophagy. In: Autophagy. 2014 ; Vol. 10, No. 6. pp. 1054-1070.
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