Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis.
Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis.
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DosR赖氨酸乙酰化调节结核分枝杆菌的缺氧反应
DOI：
10.1038/s41426-018-0032-2
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发表时间：
2018-03-21
影响因子：
13.2
通讯作者：
Ge B
中科院分区：
文献类型：
--
作者：
Yang H;Sha W;Liu Z;Tang T;Liu H;Qin L;Cui Z;Chen J;Liu F;Zheng R;Huang X;Wang J;Feng Y;Ge B
摘要结核分枝杆菌（Mtb）感染引起的结核病是一个全球性的公共卫生问题。结核分枝杆菌的一个显著特征是它能够适应缺氧并触发随后过渡到持续感染的休眠状态，但如何调节结核分枝杆菌的缺氧反应在很大程度上仍然未知。在这里，我们进行了定量乙酰化组分析比较通气和缺氧下的Mtb的乙酰化概况，并显示377个乙酰化位点的269 Mtb蛋白在缺氧下发生了显着变化。特别是，在K182处的休眠生存调节因子（DosR）的脱乙酰化促进了Mtb的缺氧反应，并增强了DosR靶向基因的转录。从机制上讲，重组DosRK182R蛋白与DosRK182Q蛋白相比表现出增强的DNA结合活性。此外，Rv0998被鉴定为介导DosR在K182处的乙酰化的乙酰转移酶。Rv0998的缺失也促进了Mtb对缺氧的适应和DosR靶基因的转录。与感染野生型菌株的小鼠相比，感染含有乙酰化缺陷型DosRK182R的Mtb菌株的小鼠的细菌计数要低得多，组织病理学损伤也不那么严重。我们的研究结果表明，缺氧诱导DosR的脱乙酰化，这反过来又增加了其DNA结合能力，以促进靶基因的转录，使Mtb在缺氧下转移到休眠状态。
Abstract Tuberculosis caused by Mycobacterium tuberculosis (Mtb) infection remains a large global public health problem. One striking characteristic of Mtb is its ability to adapt to hypoxia and trigger the ensuing transition to a dormant state for persistent infection, but how the hypoxia response of Mtb is regulated remains largely unknown. Here we performed a quantitative acetylome analysis to compare the acetylation profile of Mtb under aeration and hypoxia, and showed that 377 acetylation sites in 269 Mtb proteins were significantly changed under hypoxia. In particular, deacetylation of dormancy survival regulator (DosR) at K182 promoted the hypoxia response in Mtb and enhanced the transcription of DosR-targeted genes. Mechanistically, recombinant DosRK182R protein demonstrated enhanced DNA-binding activity in comparison with DosRK182Q protein. Moreover, Rv0998 was identified as an acetyltransferase that mediates the acetylation of DosR at K182. Deletion of Rv0998 also promoted the adaptation of Mtb to hypoxia and the transcription of DosR-targeted genes. Mice infected with an Mtb strain containing acetylation-defective DosRK182R had much lower bacterial counts and less severe histopathological impairments compared with those infected with the wild-type strain. Our findings suggest that hypoxia induces the deacetylation of DosR, which in turn increases its DNA-binding ability to promote the transcription of target genes, allowing Mtb to shift to dormancy under hypoxia.
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影响因子：
5.2
作者：
Du P;Sohaskey CD;Shi L
通讯作者：
Shi L
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影响因子：
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作者：
Ren J;Sang Y;Tan Y;Tao J;Ni J;Liu S;Fan X;Zhao W;Lu J;Wu W;Yao YF
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Yao YF
DOI：
10.1165/rcmb.2016-0239oc
发表时间：
2017-05-01
影响因子：
6.4
作者：
Hudock, Teresa A.;Foreman, Taylor W.;Kaushal, Deepak
通讯作者：
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影响因子：
3.1
作者：
Parish, T;Smith, DA;Stoker, NG
通讯作者：
Stoker, NG
影响因子：
6.7
作者：
Lyu LD;Tang BK;Fan XY;Ma H;Zhao GP
通讯作者：
Zhao GP