title: Expression of cFLIPL Determines the Basal Interaction of Bcl-2 With Beclin-1 and Regulates p53 Dependent Ubiquitination of Beclin-1 During Autophagic Stress.
abstract: Autophagy and apoptosis are two different physiological processes, which is required for the maintenance of cellular homeostasis. The apoptosis associated proteins such as Bcl-2 and p53 have a close association with autophagic proteins HMGB1 and Beclin-1 to modulate autophagic signaling. We demonstrate here the involvement of anti-apoptotic protein cFLIPL in the regulation of autophagy during cellular stress. We found that ectopic expression of cFLIPL decreases the sensitivity of HEK 293T cells against rapamycin and H2 O2 induced autophagic stress. Notably, the selective knockdown of cFLIPL augments autophagic stress in the cells accompanied with JNK1 activation and p53 dependent ubiquitination of Beclin-1. However, re-expression of cFLIPL in cFLIP knockdown cells restores autophagic equilibrium collectively with reversible effects on JNK1 and Beclin-1 integrity. The co-immunoprecipitation analysis suggests that cFLIPL is essential to maintain the canonical interaction of Bcl-2 with Beclin-1 to regulate autophagic stress and cell death. Altogether, our findings suggest that expression of cFLIPL regulates the basal interaction of Bcl-2 with Beclin-1 and substantiates p53 dependent ubiquitination of Beclin-1 during autophagic stress to determine the fate of cell death or survival. J. Cell. Biochem. 117: 1757-1768, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382007, India.
authors.forename: Kishu
authors.initials: K
authors.lastname: Ranjan
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382007, India.
authors.forename: Chandramani
authors.initials: C
authors.lastname: Pathak
mesh_terms: D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C000595707:BCL2 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048055:Mitogen-Activated Protein Kinase 8
keywords: APOPTOSIS; AUTOPHAGY; OXIDATIVE STRESS; UBIQUITINATION; cFLIP