Selective inhibition of IFNG-induced autophagy by Mir155- and Mir31-responsive WNT5A and SHH signaling
Selective inhibition of IFNG-induced autophagy by Mir155- and Mir31-responsive WNT5A and SHH signaling
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DOI：
10.4161/auto.27225
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发表时间：
2014-02-01
期刊：
影响因子：
13.3
通讯作者：
Balaji, Kithiganahalli Narayanaswamy
中科院分区：
文献类型：
--
作者：
Holla, Sahana;Kurowska-Stolarska, Mariola;Balaji, Kithiganahalli Narayanaswamy
自噬是清除细胞内感染物的主要免疫机制之一。然而，几种病原体已经进化出逃避自噬的策略。在这里，我们证明了分枝杆菌、志贺氏菌和李斯特菌而不是克雷伯氏菌、葡萄球菌和埃希氏菌通过MTOR激活WNT和SHH通路来抑制IFNG诱导的巨噬细胞自噬。利用获得或丧失功能的分析以及Mir155缺失的巨噬细胞强调了MTOR反应的表观遗传修饰在Mir155和Mir31的诱导中的作用。重要的是，磷酸酶PP2A的细胞水平受到Mir155和Mir31的调节，以微调自噬。PP2A的表达减弱导致GSK3B的抑制，从而促进WNT和SHH信号通路的长时间激活。持续的WNT和SHH信号影响抗炎脂氧合酶的表达，从而抑制IFNG诱导的JAK-STAT信号，并有助于逃避自噬。总之，这些结果确立了新的宿主因素和病原体所使用的抑制机制的作用，以限制自噬，这可能是治疗干预的目标。
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.