title: Regulation of the death-associated protein kinase 1 expression and autophagy via ATF6 requires apoptosis signal-regulating kinase 1.
abstract: The death-associated protein kinase 1 (DAPK1) is an important regulator of cell death and autophagy. Recently, we have identified that ATF6, an endoplasmic reticulum-resident transcription factor, in association with the transcription factor CEBP-β, regulates the gamma interferon (IFN-γ)-induced expression of Dapk1 (P. Gade et al., Proc. Natl. Acad. Sci. U. S. A. 109:10316-10321, 2012, doi.org/10.1073/pnas.1119273109). IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-β were essential for the formation of a novel transcriptional complex that regulates DAPK1. Here, we report that IFN-γ activates the ASK1-MKK3/MKK6-p38 mitogen-activated protein kinase (MAPK) pathway for controlling the activity of ATF6. The terminal enzyme in this pathway, p38 MAPK, phosphorylates a critical threonine residue in ATF6 upstream of its DNA binding domain. ATF6 mutants defective for p38 MAPK phosphorylation fail to undergo proteolytic processing in the Golgi apparatus and drive IFN-γ-induced gene expression and autophagy. We also show that mice lacking Ask1 are highly susceptible to lethal bacterial infection owing to defective autophagy. Together, these results identify a novel host defense pathway controlled by IFN-γ signaling.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, Maryland, USA.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Gade
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, Maryland, USA.
authors.forename: Srikanta B
authors.initials: SB
authors.lastname: Manjegowda
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, Maryland, USA.
authors.forename: Shreeram C
authors.initials: SC
authors.lastname: Nallar
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, Maryland, USA.
authors.forename: Uday B
authors.initials: UB
authors.lastname: Maachani
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, Maryland, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Cross
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Greenebaum Cancer Center, Baltimore, Maryland, USA dkalvako@umaryland.edu.
authors.forename: Dhananjaya V
authors.initials: DV
authors.lastname: Kalvakolanu
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001408:Bacillus anthracis / Q000472:pathogenicity; D001665:Binding Sites; D002460:Cell Line; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000382:microbiology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D061987:Sf9 Cells; D013154:Spleen / Q000276:immunology / Q000382:microbiology
chemical_list: D051702:Activating Transcription Factor 6; D007371:Interferon-gamma; D064550:Death-Associated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5