title: Selective inhibition of IFNG-induced autophagy by Mir155- and Mir31-responsive WNT5A and SHH signaling.
abstract: Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents. However, several pathogens have evolved strategies to evade autophagy. Here, we demonstrated that Mycobacteria, Shigella, and Listeria but not Klebsiella, Staphylococcus, and Escherichia inhibit IFNG-induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via MTOR. Utilization of gain- or loss-of-function analyses as well as mir155-null macrophages emphasized the role of MTOR-responsive epigenetic modifications in the induction of Mir155 and Mir31. Importantly, cellular levels of PP2A, a phosphatase, were regulated by Mir155 and Mir31 to fine-tune autophagy. Diminished expression of PP2A led to inhibition of GSK3B, thus facilitating the prolonged activation of WNT and SHH signaling pathways. Sustained WNT and SHH signaling effectuated the expression of anti-inflammatory lipoxygenases, which in tandem inhibited IFNG-induced JAK-STAT signaling and contributed to evasion of autophagy. Altogether, these results established a role for new host factors and inhibitory mechanisms employed by the pathogens to limit autophagy, which could be targeted for therapeutic interventions.
authors.affiliation: Department of Microbiology and Cell Biology; Indian Institute of Science; Bangalore, Karnataka India.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.affiliation: Institute of Infection, Immunity and Inflammation; University of Glasgow; Glasgow, Scotland UK.
authors.forename: Mariola
authors.initials: M
authors.lastname: Kurowska-Stolarska
authors.affiliation: Centre de Recherche des Cordeliers; Institut National de la Santé et de la Recherche Médicale; Paris, France.
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.affiliation: Department of Microbiology and Cell Biology; Indian Institute of Science; Bangalore, Karnataka India.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D053823:Hedgehog Proteins / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051153:Wnt Proteins / Q000276:immunology; D000071818:Wnt-5a Protein
chemical_list: D053823:Hedgehog Proteins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C550417:Mirn33 microRNA, mouse; C465570:Shh protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D007371:Interferon-gamma
keywords: IFNG; WNT-SHH signaling; autophagy; lipoxygenase; microRNA