An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy.
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-γ-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-β is required for the basal and IFN-γ-induced expression of DAPK1. Here, we show that ATF6, an ER stress-induced transcription factor, interacts with C/EBP-β 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-β are necessary for these interactions. More importantly, IFN-γ failed to activate autophagic response in cells lacking either ATF6 or C/EBP-β. 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.
Department of Microbiology and Immunology, Center for Vaccine Development, and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Padmaja
P
Gade
Girish
G
Ramachandran
Uday B
UB
Maachani
Mark A
MA
Rizzo
Tetsuya
T
Okada
Ron
R
Prywes
Alan S
AS
Cross
Kazutoshi
K
Mori
Dhananjaya V
DV
Kalvakolanu
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D064550:Death-Associated Protein Kinases; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D014157:Transcription Factors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D014157:Transcription Factors; D007371:Interferon-gamma; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases