IFN-g induces multiple gene regulatory pathways to combat pathogens and tumors. The death-associated protein kinase 1 (DAPK1) is an important IFN-induced regulator of cell death and autophagy. Recently we have identified that ATF6, an ER resident transcription factor, in association with the transcription factor CEBP-b regulates the IFN-g-induced expression of Dapk1 though a novel enhancer element. ATF6 migrates to Golgi in response to IFN-g, where it undergoes proteolysis to yield  the transcriptionally active form that enters nucleus and induces gene expression.  IFN-g-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-b were essential for the formation of a novel transcriptional complex that regulates Dapk1. ASK1 (MAP3K5) is activated by various stress stimuli. Although originally identified as a kinase that stimulates apoptosis, ASK1 also contributes to cytokine responses, cell differentiation and immunity. However, the exact targets of this kinase are unclear. Here, we report that IFN-γ activates ASK1-MKK3/MKK6-p38MAP kinase pathway for controlling the activity of ATF6. The terminal enzyme in this pathway, p38MAP kinase, phosphorylates a critical threonine residue in ATF6, upstream of its DNA binding domain, which is required for its proteolytic processing. ATF6 mutants lacking the p38 MAPK phosphorylation site fail to undergo proteolytic processing in the Golgi, drive IFN-g induced gene expression and autophagy. We also show that mice lacking Ask1 are highly susceptible to lethal bacterial infection owing to defective autophagy. Together, these results identify a novel host-defense pathway controlled by IFN-g.