tRNA-mediated codon-biased translation in mycobacterial hypoxic persistence.
Microbial pathogens adapt to the stress of infection by regulating transcription, translation and protein modification. We report that changes in gene expression in hypoxia-induced non-replicating persistence in mycobacteria-which models tuberculous granulomas-are partly determined by a mechanism of tRNA reprogramming and codon-biased translation. Mycobacterium bovis BCG responded to each stage of hypoxia and aerobic resuscitation by uniquely reprogramming 40 modified ribonucleosides in tRNA, which correlate with selective translation of mRNAs from families of codon-biased persistence genes. For example, early hypoxia increases wobble cmo5U in tRNAThr(UGU), which parallels translation of transcripts enriched in its cognate codon, ACG, including the DosR master regulator of hypoxic bacteriostasis. Codon re-engineering of dosR exaggerates hypoxia-induced changes in codon-biased DosR translation, with altered dosR expression revealing unanticipated effects on bacterial survival during hypoxia. These results reveal a coordinated system of tRNA modifications and translation of codon-biased transcripts that enhance expression of stress response proteins in mycobacteria.
Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-14 Enterprise Wing, Singapore 138602, Singapore.|Department of Microbiology and Immunology Programme, Yong Loo Lin School of Medicine, 28 Medical Drive, Centre for Life Sciences, Level 3, National University of Singapore, Singapore 117456, Singapore.
Yok Hian
http://orcid.org/0000-0002-4909-8382
YH
Chionh
Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-14 Enterprise Wing, Singapore 138602, Singapore.|Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Megan
M
McBee
Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
I Ramesh
IR
Babu
Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-14 Enterprise Wing, Singapore 138602, Singapore.
Fabian
F
Hia
Department of Microbiology and Immunology Programme, Yong Loo Lin School of Medicine, 28 Medical Drive, Centre for Life Sciences, Level 3, National University of Singapore, Singapore 117456, Singapore.
Wenwei
W
Lin
Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-14 Enterprise Wing, Singapore 138602, Singapore.
Wei
W
Zhao
Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-14 Enterprise Wing, Singapore 138602, Singapore.|Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Jianshu
J
Cao
Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego street 116, 90-924 Lodz, Poland.
Agnieszka
A
Dziergowska
Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego street 116, 90-924 Lodz, Poland.
Andrzej
A
Malkiewicz
College of Nanoscale Science and Engineering, State University of New York, 257 Fuller Road, Albany, New York 12203, USA.
Thomas J
TJ
Begley
Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-14 Enterprise Wing, Singapore 138602, Singapore.|Department of Microbiology and Immunology Programme, Yong Loo Lin School of Medicine, 28 Medical Drive, Centre for Life Sciences, Level 3, National University of Singapore, Singapore 117456, Singapore.
Sylvie
S
Alonso
Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, #03-14 Enterprise Wing, Singapore 138602, Singapore.|Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Peter C
PC
Dedon
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003062:Codon; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D009163:Mycobacterium bovis / Q000378:metabolism*; D010101:Oxygen Consumption; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D012329:RNA, Bacterial / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
D001426:Bacterial Proteins; D003062:Codon; D012329:RNA, Bacterial; D012333:RNA, Messenger; D012343:RNA, Transfer