气候变化领域集成服务门户(CCPortal): Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response

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DOI	10.1073/pnas.2022136118
	Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response
	Barth V.C.; Chauhan U.; Zeng J.; Su X.; Zheng H.; Husson R.N.; Woychik N.A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:32
英文摘要	The Mycobacterium tuberculosis (Mtb) VapBC4 toxin-antitoxin system is essential for the establishment of Mtb infection. Using a multitier, systems-level approach, we uncovered the sequential molecular events triggered by the VapC4 toxin that activate a circumscribed set of critical stress survival pathways which undoubtedly underlie Mtb virulence. VapC4 exclusively inactivated the sole transfer RNACys(tRNACys) through cleavage at a single site within the anticodon sequence. Depletion of the pool of tRNACysled to ribosome stalling at Cys codons within actively translating messenger RNAs. Genome mapping of these Cys-stalled ribosomes unexpectedly uncovered several unannotated Cys-containing open reading frames (ORFs). Four of these are small ORFs (sORFs) encoding Cys-rich proteins of fewer than 50 amino acids that function as Cys-responsive attenuators that engage ribosome stalling at tracts of Cys codons to control translation of downstream genes. Thus, VapC4 mimics a state of Cys starvation, which then activates Cys attenuation at sORFs to globally redirect metabolism toward the synthesis of free Cys. The resulting newly enriched pool of Cys feeds into the synthesis of mycothiol, the glutathione counterpart in this pathogen that is responsible for maintaining cellular redox homeostasis during oxidative stress, as well as into a circumscribed subset of cellular pathways that enable cells to defend against oxidative and copper stresses characteristically endured by Mtb within macrophages. Our ability to pinpoint activation or down-regulation of pathways that collectively align with Mtb virulence-associated stress responses and the nonreplicating persistent state brings to light a direct and vital role for the VapC4 toxin in mediating these critical pathways. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Mass spectrometry; Mycothiol; Protein translation; RNA-seq; Sulfur assimilation
语种	英语
scopus关键词	bacterial toxin; copper; cysteine; cysteine rich protein; glutathione; messenger RNA; mycothiol; thiol; transfer RNA; unclassified drug; VapC4 toxin; bacterial protein; bacterial RNA; bacterial toxin; copper; cysteine transfer RNA; enzyme; Rv0595c protein, Mycobacterium tuberculosis; sulfur; amino acid metabolism; amino acid synthesis; Article; bacterial survival; bacterial virulence; cell activation; cellular stress response; codon; controlled study; detoxification; down regulation; downstream processing; gene activation; gene mapping; innate immunity; macrophage; Mycobacterium smegmatis; Mycobacterium tuberculosis; nonhuman; open reading frame; oxidation reduction state; oxidative stress; ribosome; RNA cleavage; RNA sequence; RNA translation; signal transduction; starvation; codon usage; drug effect; gene expression regulation; genetics; host pathogen interaction; metabolism; Mycobacterium tuberculosis; open reading frame; oxidative stress; pathogenicity; physiology; protein synthesis; Bacterial Proteins; Bacterial Toxins; Codon Usage; Copper; Cysteine; Enzymes; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions; Mycobacterium tuberculosis; Open Reading Frames; Oxidative Stress; Protein Biosynthesis; Ribosomes; RNA, Bacterial; RNA, Transfer, Cys; Sulfur
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/251079
作者单位	Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States; Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08904, United States; Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08904, United States; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08904, United States; Center for Integrative Proteomics Research, Rutgers University, Piscataway, NJ 08854, United States
推荐引用方式 GB/T 7714	Barth V.C.,Chauhan U.,Zeng J.,et al. Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response[J],2021,118(32).
APA	Barth V.C..,Chauhan U..,Zeng J..,Su X..,Zheng H..,...&Woychik N.A..(2021).Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response.Proceedings of the National Academy of Sciences of the United States of America,118(32).
MLA	Barth V.C.,et al."Mycobacterium tuberculosis VapC4 toxin engages small ORFs to initiate an integrated oxidative and copper stress response".Proceedings of the National Academy of Sciences of the United States of America 118.32(2021).