title: Growth-regulating Mycobacterium tuberculosis VapC-mt4 toxin is an isoacceptor-specific tRNase.
abstract: Toxin-antitoxin (TA) systems are implicated in the downregulation of bacterial cell growth associated with stress survival and latent tuberculosis infection, yet the activities and intracellular targets of these TA toxins are largely uncharacterized. Here, we use a specialized RNA-seq approach to identify targets of a Mycobacterium tuberculosis VapC TA toxin, VapC-mt4 (also known as VapC4), which have eluded detection using conventional approaches. Distinct from the one other characterized VapC toxin in M. tuberculosis that cuts 23S rRNA at the sarcin-ricin loop, VapC-mt4 selectively targets three of the 45 M. tuberculosis tRNAs (tRNA(Ala2), tRNA(Ser26) and tRNA(Ser24)) for cleavage at, or adjacent to, their anticodons, resulting in the generation of tRNA halves. While tRNA cleavage is sometimes enlisted as a bacterial host defense mechanism, VapC-mt4 instead alters specific tRNAs to inhibit translation and modulate growth. This stress-linked activity of VapC-mt4 mirrors basic features of eukaryotic tRNases that also generate tRNA halves and inhibit translation in response to stress.
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Cruz
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jared D
authors.initials: JD
authors.lastname: Sharp
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hoffer
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Maehigashi
authors.affiliation: 1] Waksman Institute, Rutgers University, Piscataway, New Jersey 08854, USA [2] Department of Genetics, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Irina O
authors.initials: IO
authors.lastname: Vvedenskaya
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Konkimalla
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Husson
authors.affiliation: 1] Waksman Institute, Rutgers University, Piscataway, New Jersey 08854, USA [2] Department of Genetics, Rutgers University, Piscataway, New Jersey 08854, USA [3] Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA.
authors.forename: Bryce E
authors.initials: BE
authors.lastname: Nickels
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Dunham
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA [2] Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Woychik
mesh_terms: D000926:Anticodon / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics* / Q000378:metabolism; D015152:Blotting, Northern; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D004926:Escherichia coli; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D012338:RNA, Ribosomal, 23S / Q000378:metabolism*; D012343:RNA, Transfer / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D000926:Anticodon; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D012338:RNA, Ribosomal, 23S; C000606753:Rv0595c protein, Mycobacterium tuberculosis; D012343:RNA, Transfer; D004722:Endoribonucleases