Growth-regulating Mycobacterium tuberculosis VapC-mt4 toxin is an isoacceptor-specific tRNase

• Type of Material: Article
• Authors: Jonathan W. Cruz, Rutgers Robert Wood Johnson Medical School; Jared D. Sharp, Harvard Medical School; Hoffer Hoffer, Emory University; Tatsuya Maehigashi, Emory University; Irina O Vvedenskaya, Rutgers University; Arvind Konkimalla, Rutgers Robert Wood Johnson Medical School; Robert N. Husson, Harvard Medical School; Bryce E. Nickels, Rutgers University; Christine Dunham, Emory University; Nancy A. Woychik, Rutgers Robert Wood Johnson Medical School
• Language: English
• Date: 2015-07-01
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Macmillan Publishers Limited.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms8480
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 6
• Start Page: 7480
• End Page: 7480
• Grant/Funding Information: This work was supported in part by the National Institutes of Health under award numbers R21 AI072399 (to N.A.W. and R.N.H.) and R01 GM095693 (to N.A.W.), R01 GM088343 (to B.E.N.), R21 AI097881 (to R.N.H.) and T32 AI007403 (to J.W.C.); National Science Foundation CAREER award MCB 0953714 (to C.M.D.). C.M.D is a Pew Scholar in the Biomedical Sciences.
• Research Categories: Chemistry, Biochemistry; Biology, Genetics; Health Sciences, Medicine and Surgery

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.