Regulation of the Death-Associated Protein Kinase 1 Expression and Autophagy via ATF6 Requires Apoptosis Signal-Regulating Kinase 1

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 exp...

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Bibliographic Details
Published in:	Molecular and cellular biology Vol. 34; no. 21; pp. 4033 - 4048
Main Authors:	Gade, Padmaja, Manjegowda, Srikanta B., Nallar, Shreeram C., Maachani, Uday B., Cross, Alan S., Kalvakolanu, Dhananjaya V.
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 01-11-2014 American Society for Microbiology
Subjects:	Activating Transcription Factor 6 - genetics Activating Transcription Factor 6 - metabolism Animals Autophagy Bacillus anthracis - pathogenicity Binding Sites Cell Line Death-Associated Protein Kinases - genetics Death-Associated Protein Kinases - metabolism Gene Knockdown Techniques Humans Interferon-gamma - metabolism Liver - immunology Liver - microbiology MAP Kinase Kinase Kinase 5 - metabolism MAP Kinase Signaling System Mice Mutation Phosphorylation Sf9 Cells Spleen - immunology Spleen - microbiology
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1098-5549 0270-7306 1098-5549
DOI:	10.1128/MCB.00397-14