Selective inhibition of IFNG-induced autophagy by <i>Mir155</i>- and <i>Mir31</i>-responsive WNT5A and SHH signaling

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 <i>Mycobacteria</i>, <i>Shigella,</i> and <i>Listeria</i> but not <i>Klebsiella</i>, <i>Staphylococcus,</i> and <i>Escherichia</i> 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 <i>mir155</i>-null macrophages emphasized the role of MTOR-responsive epigenetic modifications in the induction of <i>Mir155</i> and <i>Mir31</i>. Importantly, cellular levels of PP2A, a phosphatase, were regulated by <i>Mir155</i> and <i>Mir31</i> 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.