Mycobacterium tuberculosis Acetyltransferase Suppresses Oxidative Stress by Inducing Peroxisome Formation in Macrophages.
Mycobacterium tuberculosis Acetyltransferase Suppresses Oxidative Stress by Inducing Peroxisome Formation in Macrophages.
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DOI：
10.3390/ijms23052584
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发表时间：
2022-02-26
影响因子：
5.6
通讯作者：
Sonawane A
中科院分区：
文献类型：
--
作者：
Behera A;Jain P;Ganguli G;Biswas M;Padhi A;Pattanaik KP;Nayak B;Ergün S;Hagens K;Redinger N;Saqib M;Mishra BB;Schaible UE;Karnati S;Sonawane A
结核分枝杆菌（Mtb）抑制宿主氧化应激反应，促进其在巨噬细胞中的生存，然而，其潜在的分子机制知之甚少。在这里，我们确定了Mtb乙酰转移酶（Rv3034c）作为一种新的对抗巨噬细胞氧化应激反应诱导过氧化物酶体形成。Mtb的可诱导Rv 3034 c缺失突变体未能诱导巨噬细胞中过氧化物酶体生物发生、过氧化物酶体β氧化途径中间体（ACOX 1、ACAA 1、MFP 2）的表达，导致细胞内存活率低于亲代菌株。这种降低的毒力表型通过Rv3034c的补充来挽救。过氧化物酶体诱导依赖于Rv3034c和巨噬细胞甘露糖受体（MR）之间的相互作用。Rv3034c和MR之间的相互作用诱导过氧化物酶体生物合成蛋白PEX5 p、PEX13 p、PEX14 p、PEX11β、PEX19 p、过氧化物酶体膜脂质转运蛋白ABCD 3和过氧化氢酶的表达。PEX14 p和ABCD3的表达也在Mtb气溶胶感染小鼠的肺中增强。这是第一份报告，过氧化物酶体介导的ROS平衡的控制是必不可少的先天性免疫反应结核分枝杆菌，但可以抵消的分枝杆菌乙酰转移酶Rv3034c。因此，过氧化物酶体是结核病宿主导向治疗的重要靶点。
Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis.
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影响因子：
3.4
作者：
Ganguli, Geetanjali;Pattanaik, Kali Prasad;Sonawane, Avinash
通讯作者：
Sonawane, Avinash
影响因子：
5.8
作者：
Makni-Maalej, Karama;Chiandotto, Melanie;El-Benna, Jamel
通讯作者：
El-Benna, Jamel
影响因子：
3.4
作者：
Butler, Rachel E.;Cihlarova, Vera;Stewart, Graham R.
通讯作者：
Stewart, Graham R.
影响因子：
3.4
作者：
Ehrt S;Schnappinger D
通讯作者：
Schnappinger D
影响因子：
32.4
作者：
Di Cara, Francesca;Sheshachalam, Avinash;Simmonds, Andrew J.
通讯作者：
Simmonds, Andrew J.