| First Author | Gade P | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 26 | Pages | 10316-21 |
| PubMed ID | 22699507 | Mgi Jnum | J:185579 |
| Mgi Id | MGI:5429447 | Doi | 10.1073/pnas.1119273109 |
| Citation | Gade P, et al. (2012) An IFN-gamma-stimulated ATF6-C/EBP-beta-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy. Proc Natl Acad Sci U S A 109(26):10316-21 |
| abstractText | 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-gamma-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-beta is required for the basal and IFN-gamma-induced expression of DAPK1. Here, we show that ATF6, an ER stress-induced transcription factor, interacts with C/EBP-beta 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-beta are necessary for these interactions. More importantly, IFN-gamma failed to activate autophagic response in cells lacking either ATF6 or C/EBP-beta. 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. |
