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An IFN-?-stimulated ATF6-C/EBP-?-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy.

ABSTRACT: The IFN family of cytokines operates a frontline defense against pathogens and neoplastic cells in vivo by controlling the expression of several genes. The death-associated protein kinase 1 (DAPK1), an IFN-?-induced enzyme, controls cell cycle, apoptosis, autophagy, and tumor metastasis, and its expression is frequently down-regulated in a number of human tumors. Although the biochemical action of DAPK1 is well understood, mechanisms that regulate its expression are unclear. Previously, we have shown that transcription factor C/EBP-? is required for the basal and IFN-?-induced expression of DAPK1. Here, we show that ATF6, an ER stress-induced transcription factor, interacts with C/EBP-? in an IFN-stimulated manner and is obligatory for Dapk1 expression. IFN-stimulated proteolytic processing of ATF6 and ERK1/2-mediated phosphorylation of C/EBP-? are necessary for these interactions. More importantly, IFN-? failed to activate autophagic response in cells lacking either ATF6 or C/EBP-?. Consistent with these observations, the Atf6(-/-) mice were highly susceptible to lethal bacterial infections compared with the wild-type mice. These studies not only unravel an IFN signaling pathway that controls cell growth and antibacterial defense, but also expand the role of ATF6 beyond ER stress.

SUBMITTER: Gade P

PROVIDER: S-EPMC3387052 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy.

Gade Padmaja P Ramachandran Girish G Maachani Uday B UB Rizzo Mark A MA Okada Tetsuya T Prywes Ron R Cross Alan S AS Mori Kazutoshi K Kalvakolanu Dhananjaya V DV

Proceedings of the National Academy of Sciences of the United States of America 20120613 26

The IFN family of cytokines operates a frontline defense against pathogens and neoplastic cells in vivo by controlling the expression of several genes. The death-associated protein kinase 1 (DAPK1), an IFN-γ-induced enzyme, controls cell cycle, apoptosis, autophagy, and tumor metastasis, and its expression is frequently down-regulated in a number of human tumors. Although the biochemical action of DAPK1 is well understood, mechanisms that regulate its expression are unclear. Previously, we have ...[more]

PMID: 22699507

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Project description:Transcription factor C/EBP-beta regulates a number of physiological responses. During an investigation of the growth-suppressive effects of interferons (IFNs), we noticed that cebpb(-/-) cells fail to undergo apoptosis upon gamma IFN (IFN-gamma) treatment, compared to wild-type controls. To examine the basis for this response, we have performed gene expression profiling of isogenic wild-type and cebpb(-/-) bone marrow macrophages and identified a number of IFN-gamma-regulated genes that are dependent on C/EBP-beta for their expression. These genes are distinct from those regulated by the JAK-STAT pathways. Genes identified in this screen appear to participate in various cellular pathways. Thus, we identify a new pathway through which the IFNs exert their effects on cellular genes through C/EBP-beta. One of these genes is death-associated protein kinase 1 (dapk1). DAPK1 is critical for regulating the cell cycle, apoptosis, and metastasis. Using site-directed mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we show that C/EBP-beta binds to the promoter of dapk1 and is required for the regulation of dapk1. Both mouse dapk1 and human dapk1 exhibited similar dependences on C/EBP-beta for their expression. The expression of the other members of the DAPK family occurred independently of C/EBP-beta. Members of the C/EBP family of transcription factors other than C/EBP-beta did not significantly affect dapk1 expression. We identified two elements in this promoter that respond to C/EBP-beta. One of these is a consensus C/EBP-beta-binding site that constitutively binds to C/EBP-beta. The other element exhibits homology to the cyclic AMP response element/activating transcription factor binding sites. C/EBP-beta binds to this site in an IFN-gamma-dependent manner. Inhibition of ERK1/2 or mutation of an ERK1/2 site in the C/EBP-beta protein suppressed the IFN-gamma-induced response of this promoter. Together, our data show a critical role for C/EBP-beta in a novel IFN-induced cell growth-suppressive pathway via DAPK1.

Dataset Information

An IFN-?-stimulated ATF6-C/EBP-?-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy.

Publications

An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy.

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