title: A nonapoptotic role for CASP2/caspase 2: modulation of autophagy.
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.
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; South Texas Research Facility; San Antonio, TX USA; Department of Pathology and Laboratory Medicine; All India Institute of Medical Sciences; Patna, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Tiwari
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; South Texas Research Facility; San Antonio, TX USA.
authors.forename: Lokendra K
authors.initials: LK
authors.lastname: Sharma
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; South Texas Research Facility; San Antonio, TX USA.
authors.forename: Difernando
authors.initials: D
authors.lastname: Vanegas
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; South Texas Research Facility; San Antonio, TX USA.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Callaway
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; South Texas Research Facility; San Antonio, TX USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; South Texas Research Facility; San Antonio, TX USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Lechleiter
authors.affiliation: Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; South Texas Research Facility; San Antonio, TX USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Herman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D053143:Caspase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C090208:Casp2 protein, mouse; D053143:Caspase 2; D000071193:Autophagy-Related Protein 7
keywords: apoptosis; autophagy; autophagy regulators; caspase 2; caspases; reactive oxygen species