86 : IFN-γ, ER-stress, autophagy and antimicrobial defense: A novel ATF6/C/EBP-β centric signaling pathway

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-g induced enzyme, controls cell cycle, apoptosis, autophagy, and tumor metastasis; and its expression is frequently down regulated in a number of human tumors. Previously, we have shown that transcription factor C/EBP-b is required for the basal and IFN-g-induced expression of DAPK1. Here, we show that ATF6, an ER stress-induced transcription factor, interacts with C/EBP-b in an IFN-stimulated manner and is obligatory for Dapk1 expression. IFN-stimulated proteolytic processing and p38 MAPK dependent phosphorylation of ATF6; and ERK1/2-mediated phosphorylation of C/EBP-b are necessary for these interactions. The activation of this pathway is independent from the IFN-induced JAK-STAT pathways. More importantly, IFN-g-failed to activate autophagy in cells lacking either ATF6 or C/EBP-b. Consistent with these observations, the Atf6-/- mice were highly susceptible to lethal bacterial infections compared to the wildtype mice. These studies, for the first time, not only unravel a novel IFN signaling pathway that controls cell growth, autophagy and antibacterial defense but also expand the role of ATF6 beyond ER-stress.