期刊
AUTOPHAGY
卷 10, 期 2, 页码 311-330出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.27225
关键词
autophagy; IFNG; WNT-SHH signaling; microRNA; lipoxygenase
类别
资金
- Department of Biotechnology (DBT)
- Department of Science and Technology (DST)
- Council for Scientific and Industrial Research (CSIR)
- Indian Council of Medical Research (ICMR)
- Government of India
- Indo-French Center for Promotion of Advanced Research (IFCPAR/CEFIPRA)
- IISc
- Versus Arthritis [19213] Funding Source: researchfish
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.
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