Mycobacterium tuberculosisRv3034c regulatesmTORC1andPPAR-γ dependant pexophagy mechanism to control redox levels in macrophages
Mycobacterium tuberculosisRv3034c regulatesmTORC1andPPAR-γ dependant pexophagy mechanism to control redox levels in macrophages
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DOI：
10.1111/cmi.13214
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发表时间：
2020-06-10
影响因子：
3.4
通讯作者：
Sonawane, Avinash
中科院分区：
文献类型：
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作者：
Ganguli, Geetanjali;Pattanaik, Kali Prasad;Sonawane, Avinash
结核分枝杆菌通过几种宿主免疫逃避策略在巨噬细胞内生存。在这里，我们报道了一种新的机制，其中M。结核杆菌糖基转移酶由Rv3034c编码，通过诱导过氧化物体稳态调节宿主氧化应激水平，促进细胞内分枝杆菌感染。我的存在。Rv3034c可诱导Pex3、Pex5、Pex19、Pex11b、Fis-1和DLP-1等过氧化体生物发生和增殖因子的表达，而缺失Rv3034c则降低这些分子的表达，从而选择性地通过吞噬作用降解过氧化体。进一步的研究表明，m。Rv3034c通过下调吞噬相关蛋白(p-AMPKα、p-ULK-1、ATG5、ATG7、Beclin-1、Lc3-II、TFEB和Keap-1)和接头分子(NBR1和p62)的表达来抑制吞噬机制的诱导。抑制作用依赖于mTORC1的磷酸化和过氧化体增殖物激活的受体-γ的激活。结核分枝杆菌Rv3034c可通过激活感染巨噬细胞中的Pex14来诱导功能失调和受损的过氧化物体降解，以维持氧化应激过程中细胞内的动态平衡。总之，这是第一份证明这一点的报告。结核杆菌糖基转移酶调节细胞内氧化还原水平的过氧化物体平衡，有利于巨噬细胞中的分枝杆菌感染。
Mycobacterium tuberculosissurvives inside the macrophages by employing several host immune evasion strategies. Here, we reported a novel mechanism in whichM. tuberculosisacetyltransferase, encoded byRv3034c, induces peroxisome homeostasis to regulate host oxidative stress levels to facilitate intracellular mycobacterial infection. Presence ofM. tuberculosisRv3034c induces the expression of peroxisome biogenesis and proliferation factors such as Pex3, Pex5, Pex19, Pex11b, Fis-1 and DLP-1; while depletion ofRv3034cdecreased the expression of these molecules, thereby selective degradation of peroxisomes via pexophagy. Further studies revealed thatM. tuberculosisRv3034c inhibit induction of pexophagy mechanism by down-regulating the expression of pexophagy associated proteins (p-AMPK alpha, p-ULK-1, Atg5, Atg7, Beclin-1, LC3-II, TFEB and Keap-1) and adaptor molecules (NBR1 and p62). Inhibition was found to be dependent on the phosphorylation of mTORC1 and activation of peroxisome proliferator activated receptor-gamma. In order to maintain intracellular homeostasis during oxidative stress,M. tuberculosisRv3034c was found to induce degradation of dysfunctional and damaged peroxisomes through activation of Pex14 in infected macrophages. In conclusion, this is the first report which demonstrated thatM. tuberculosisacetyltransferase regulate peroxisome homeostasis in response to intracellular redox levels to favour mycobacterial infection in macrophage.