Regulation of the Death-Associated Protein Kinase 1 Expression and Autophagy via ATF6 Requires Apoptosis Signal-Regulating Kinase 1

Abstract

The death-associated protein kinase 1 (DAPK1) is an important regulator of cell death and autophagy. Recently, we have identified that ATF6, an endoplasmic reticulum-resident transcription factor, in association with the transcription factor CEBP-β, regulates the gamma interferon (IFN-γ)-induced expression of Dapk1 (P. Gade et al., Proc. Natl. Acad. Sci. U. S. A. 109:10316–10321, 2012, doi.org/10.1073/pnas.1119273109). IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-β were essential for the formation of a novel transcriptional complex that regulates DAPK1. Here, we report that IFN-γ activates the ASK1-MKK3/MKK6–p38 mitogen-activated protein kinase (MAPK) pathway for controlling the activity of ATF6. The terminal enzyme in this pathway, p38 MAPK, phosphorylates a critical threonine residue in ATF6 upstream of its DNA binding domain. ATF6 mutants defective for p38 MAPK phosphorylation fail to undergo proteolytic processing in the Golgi apparatus and drive IFN-γ-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-γ signaling.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00397-14.

ACKNOWLEDGMENTS

These studies were supported by NIH grant CA78282 to D.V.K.

We thank Hidenori Ichijo for supplying Ask1-deficient mice and ASK1 expression plasmids.

P.G., S.B.M., S.C.N., and U.B.M. performed experiments; P.G., A.S.C., and D.V.K. designed the experiments. P.G. analyzed the data, and P.G. and D.V.K. wrote the manuscript.