An IFN-γ–stimulated ATF6–C/EBP-β–signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy
| Autor: | Tetsuya Okada, Girish Ramachandran, Ron Prywes, Uday Bhanu Maachani, Mark A. Rizzo, Alan S. Cross, Dhananjaya V. Kalvakolanu, Kazutoshi Mori, Padmaja Gade |
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| Rok vydání: | 2012 |
| Předmět: |
Multidisciplinary
ATF6 Autophagy Biological Sciences Biology Cell cycle Cell biology Mice Inbred C57BL Death-Associated Protein Kinases Interferon-gamma Mice Death-Associated Protein Kinase 1 Calcium-Calmodulin-Dependent Protein Kinases Proteolysis Unfolded protein response Animals Signal transduction Apoptosis Regulatory Proteins Promoter Regions Genetic Protein kinase A Transcription factor Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 109:10316-10321 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1119273109 |
| Popis: | 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 shown that transcription factor C/EBP-β is required for the basal and IFN-γ–induced expression of DAPK1 . Here, we show that ATF6, an ER stress-induced transcription factor, interacts with C/EBP-β 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-β are necessary for these interactions. More importantly, IFN-γ failed to activate autophagic response in cells lacking either ATF6 or C/EBP-β. 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. |
| Databáze: | OpenAIRE |
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