An IFN-γ–stimulated ATF6–C/EBP-β–signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy

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-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.

ER-stress mobilization of death-associated protein kinase-1–dependent xenophagy counteracts mitochondria stress–induced epithelial barrier dysfunction

“…Molecular knockout and use of PERK, IRE1 and JNK selective inhibitors indicated that tunicamycin abrogation of the DNP-induced epithelial barrier defect was dependent on the ATF6 arm of the UPR. Other studies support a beneficial role for ATF6 in limiting enteric inflammation: mutation in a protease resulting in reduced ATF6 activation increased susceptibility to DSS-induced colitis (data on bacterial translocation were not presented) (40); and, ATF6 -/-mice display increased susceptibility to bacteria correlating with decreased autophagy in macrophages (41). Further, IL-10 can exert an anti-inflammatory effect via inhibition of TNFa-induced nuclear translocation of ATF6 (20).…”

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

“…Furthermore, LL-37 induced autophagy in human macrophages via the purinergic receptor P2RX7, which can activate different downstream signaling pathways such as mitogen-activated protein kinases and enhance the expression of CEBPB (CCAAT/enhancer binding protein [C/EBP], b), pathways, which contribute to transcriptional activation of both BECN1 and ATG5. 18,29 Notably, these pathways are involved in enhanced expression of LL-37. 30,31 Here, we have demonstrated that LL-37-mediated autophagy requires intracellular calcium influx together with the signaling pathways AMPK and PtdIns3K downstream of the P2RX7 receptor.…”

Epidermal growth factor-induced C/EBPbeta participates in EMT by dampening miR-203 in esophageal squamous cell carcinoma

“…However, sporadic evidence suggests that C/ EBPb LIP can also be a transcriptional activator, as is demonstrated in breast cancer lines MCF-7 and SKBR3 in which C/EBPb LIP upregulated the expression of the chemokine receptor CXCR4 . The varying roles of C/EBPb LIP are likely dependent on requisite partners for target specificity and combinatorial control of gene regulation (Gade et al, 2012) in different cellular contexts.…”