The Wag31 protein interacts with AccA3 and coordinates cell wall lipid permeability and lipophilic drug resistance in Mycobacterium smegmatis
The Wag31 protein interacts with AccA3 and coordinates cell wall lipid permeability and lipophilic drug resistance in Mycobacterium smegmatis
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DOI：
10.1016/j.bbrc.2014.04.116
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发表时间：
2014-06-06
影响因子：
3.1
通讯作者：
Wang, Hong-hai
中科院分区：
文献类型：
--
作者：
Xu, Wen-xi;Zhang, Lu;Wang, Hong-hai
结核分枝杆菌，特别是耐药结核，是对全球人类健康的严重威胁。与其他细菌病原体相比，结核分枝杆菌通过其异常富含脂质的细胞壁获得更强的天然耐药性。作为DivIVA的同源物，Wag31已被证明与肽聚糖合成、细胞生长和细胞分裂密切相关。以往的研究很少探讨Wag31在耐药中的作用。在本研究中，我们发现耻垢分枝杆菌中Wag31的敲除导致对四种亲脂药物（利福平、新生物素、红霉素和氯法齐明）的耐药性共同降低，并增加细胞对亲脂分子的通透性。通过共免疫沉淀在Wag31相互作用组中鉴定了6个参与脂肪酸和霉菌酸合成的蛋白（AccA3、AccD4和AccD5、Fas、InhA和MmpL3）。下拉实验证实Wag31-AccA3相互作用。AccA3过表达导致脂质通透性降低，利福平和新生物霉素耐药增加。证实了亲脂性耐药、脂质通透性与Wag31-AccA3相互作用密切相关。这些结果表明Wag31保持了对亲脂性药物的抗性，并且Wag31可能通过Wag31- acca3相互作用在控制细胞壁脂质通透性方面发挥作用。(C) 2014爱思唯尔公司版权所有。
Mycobacterium tuberculosis, especially drug resistant tuberculosis, is a serious threat to global human health. Compared with other bacterial pathogens, M. tuberculosis gains stronger natural drug resistance from its unusually lipid-rich cell wall. As a DivIVA homolog, Wag31 has been demonstrated to be closely involved in peptidoglycan synthesis, cell growth and cell division. Previous research rarely investigated the role of Wag31 in drug resistance. In this study, we found Wag31 knock-down in Mycobacterium smegmatis resulted in a co-decrease of the resistance to four lipophilic drugs (rifampicin, novobiocin, erythromycin and clofazimine) and an increase in the cell permeability to lipophilic molecules. Six proteins (AccA3, AccD4 and AccD5, Fas, InhA and MmpL3) that are involved in fatty acid and mycolic acid synthesis were identified in the Wag31 interactome through Co-Immunoprecipitation. The Wag31-AccA3 interaction was confirmed by the pull-down assay. AccA3 overexpression resulted in a decrease in lipid permeability and an increase in the resistance of rifampicin and novobiocin. It confirmed the close relationship of lipophilic drug resistance, lipid permeability and the Wag31-AccA3 interaction. These results demonstrated that Wag31 maintained the resistance to lipophilic drugs and that Wag31 could play a role in controlling the lipid permeability of the cell wall through the Wag31-AccA3 interaction. (C) 2014 Elsevier Inc. All rights reserved.