title: IFNG and autophagy: a critical role for the ER-stress mediator ATF6 in controlling bacterial infections.
abstract: IFNG/IFNγ plays a critical role in driving innate and acquired defenses against infectious pathogens. The death-associated protein kinase 1 (DAPK1), originally identified as an activator of IFNG-induced cell death, controls autophagy. Previously, we have shown that transcription factor CEBPB (C/EBP-β) regulates IFNG-induced expression of Dapk1 through a CRE/ATF motif in its enhancer. In this paper we have shown that ATF6, an ER-resident transcription factor regulates IFNG-induced Dapk1 expression through the CRE/ATF site, in association with CEBPB. IFNG-stimulated proteolytic cleavage of ATF6, and MAPK1/3 (ERK2/1)-dependent phosphorylation of CEBPB together control the expression of Dapk1. Consistent with their requirement for DAPK1 expression, IFNG fails to induce autophagy in cells lacking either Atf6 or Cebpb. More importantly, the Atf6(-/-) mice are highly susceptible to lethal bacterial infections due to a loss of autophagy. This study reported a connection between ER stress and autophagy in mediating antibacterial defenses.
authors.affiliation: Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. dkalvako@umaryland.edu
authors.forename: Dhananjaya V
authors.initials: DV
authors.lastname: Kalvakolanu
authors.forename: Padmaja
authors.initials: P
authors.lastname: Gade
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D001424:Bacterial Infections / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological
chemical_list: D051702:Activating Transcription Factor 6; D051017:Apoptosis Regulatory Proteins; D007371:Interferon-gamma; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases