气候变化领域集成服务门户(CCPortal): HflX is a GTPase that controls hypoxia-induced replication arrest in slow-growing mycobacteria

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DOI	10.1073/pnas.2006717118
	HflX is a GTPase that controls hypoxia-induced replication arrest in slow-growing mycobacteria
	Ngan J.Y.G.; Pasunooti S.; Tse W.; Meng W.; Ngan S.F.C.; Jia H.; Lin J.Q.; Ng S.W.; Jaafa M.T.; Cho S.L.S.; Lim J.; Koh H.Q.V.; Ghani N.A.; Pethe K.; Sze S.K.; Lescar J.; Alonso S.
发表日期	2021
ISSN	00278424
卷号	118 期号:12
英文摘要	GTPase high frequency of lysogenization X (HflX) is highly conserved in prokaryotes and acts as a ribosome-splitting factor as part of the heat shock response in Escherichia coli. Here we report that HflX produced by slow-growing Mycobacterium bovis bacillus Calmette–Guérin (BCG) is a GTPase that plays a critical role in the pathogen’s transition to a nonreplicating, drug-tolerant state in response to hypoxia. Indeed, HflX-deficient M. bovis BCG (KO) replicated markedly faster in the microaerophilic phase of a hypoxia model that resulted in premature entry into dormancy. The KO mutant displayed hallmarks of nonreplicating mycobacteria, including phenotypic drug resistance, altered morphology, low intracellular ATP levels, and overexpression of Dormancy (Dos) regulon proteins. Mice nasally infected with HflX KO mutant displayed increased bacterial burden in the lungs, spleen, and lymph nodes during the chronic phase of infection, consistent with the higher replication rate observed in vitro in microaerophilic conditions. Unlike fast growing mycobacteria, M. bovis BCG HlfX was not involved in antibiotic resistance under aerobic growth. Proteomics, pull-down, and ribo-sequencing approaches supported that mycobacterial HflX is a ribosome-binding protein that controls translational activity of the cell. With HflX fully conserved between M. bovis BCG and M. tuberculosis, our work provides further insights into the molecular mechanisms deployed by pathogenic mycobacteria to adapt to their hypoxic microenvironment. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Mycobacteria \| tuberculosis \| HflX \| ribosome-splitting factor \| hypoxia
语种	英语
scopus关键词	adenosine triphosphate; antibiotic agent; guanosine triphosphatase; protein high frequency of lysogenization X; ribosome protein; unclassified drug; anaerobic growth; animal experiment; animal model; animal tissue; antibiotic resistance; Article; bacterial growth; bacterial load; bacterial virulence; cell activity; controlled study; dormancy; drug tolerance; enzyme mechanism; hypoxia; in vitro study; infection; lung parenchyma; lymph node; microaerophilic phase; mouse; Mycobacterium bovis BCG; Mycobacterium tuberculosis; nonhuman; priority journal; protein expression; proteomics; spleen tissue; tuberculosis
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180179
作者单位	Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore117456, Singapore; Life Sciences Institute, Immunology Programme, National University of Singapore117456, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University636921, Singapore
推荐引用方式 GB/T 7714	Ngan J.Y.G.,Pasunooti S.,Tse W.,et al. HflX is a GTPase that controls hypoxia-induced replication arrest in slow-growing mycobacteria[J],2021,118(12).
APA	Ngan J.Y.G..,Pasunooti S..,Tse W..,Meng W..,Ngan S.F.C..,...&Alonso S..(2021).HflX is a GTPase that controls hypoxia-induced replication arrest in slow-growing mycobacteria.Proceedings of the National Academy of Sciences of the United States of America,118(12).
MLA	Ngan J.Y.G.,et al."HflX is a GTPase that controls hypoxia-induced replication arrest in slow-growing mycobacteria".Proceedings of the National Academy of Sciences of the United States of America 118.12(2021).