title: GA binding protein augments autophagy via transcriptional activation of BECN1-PIK3C3 complex genes.
abstract: Macroautophagy is a vesicular catabolic trafficking pathway that is thought to protect cells from diverse stressors and to promote longevity. Recent studies have revealed that transcription factors play important roles in the regulation of autophagy. In this study, we have identified GA binding protein (GABP) as a transcriptional regulator of the combinatorial expression of BECN1-PIK3C3 complex genes involved in autophagosome initiation. We performed bioinformatics analyses that demonstrated highly conserved putative GABP sites in genes that encode BECN1/Beclin 1, several BECN1 interacting proteins, and downstream autophagy proteins including the ATG12-ATG5-ATG16L1 complex. We demonstrate that GABP binds to the promoter regions of BECN1-PIK3C3 complex genes and activates their transcriptional activities. Knockdown of GABP reduced BECN1-PIK3C3 complex transcripts, BECN1-PIK3C3 complex protein levels and autophagy in cultured cells. Conversely, overexpression of GABP increased autophagy. Nutrient starvation increased GABP-dependent transcriptional activity of BECN1-PIK3C3 complex gene promoters and increased the recruitment of GABP to the BECN1 promoter. Our data reveal a novel function of GABP in the regulation of autophagy via transcriptional activation of the BECN1-PIK3C3 complex.
authors.affiliation: Department of Pathology; Stanford University School of Medicine; Stanford, CA USA.
authors.forename: Wan
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pathology; Stanford University School of Medicine; Stanford, CA USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Swaminathan
authors.affiliation: Department of Pathology; Stanford University School of Medicine; Stanford, CA USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Plowey
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D002460:Cell Line; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D010588:Phagosomes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C512829:Becn1 protein, rat; D051268:GA-Binding Protein Transcription Factor; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases
keywords: BECN1; GA binding protein; PIK3C3; autophagy; transcription