| First Author | Gade P | Year | 2014 |
| Journal | Mol Cell Biol | Volume | 34 |
| Issue | 21 | Pages | 4033-48 |
| PubMed ID | 25135476 | Mgi Jnum | J:224336 |
| Mgi Id | MGI:5662036 | Doi | 10.1128/MCB.00397-14 |
| Citation | Gade P, et al. (2014) Regulation of the death-associated protein kinase 1 expression and autophagy via ATF6 requires apoptosis signal-regulating kinase 1. Mol Cell Biol 34(21):4033-48 |
| abstractText | 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-beta, regulates the gamma interferon (IFN-gamma)-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-gamma-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-beta were essential for the formation of a novel transcriptional complex that regulates DAPK1. Here, we report that IFN-gamma 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-gamma-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-gamma signaling. |
