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

作者：Gade Padmaja; Ramachandran Girish; Maachani Uday B; Rizzo Mark A; Okada Tetsuya; Prywes Ron; Cross Alan S; Mori Kazutoshi; Kalvakolanu Dhananjaya V^*

来源：Proceedings of the National Academy of Sciences, 2012, 109(26): 10316-10321.

DOI：10.1073/pnas.1119273109

• signal transduction
• tumor suppression
• gene expression
• innate immunity

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.

• 出版日期2012-6-26