Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis

Autores
Martini, María Carla; Hicks, Nathan D.; Xiao, Junpei; Alonso, Maria Natalia; Barbier, Thibault; Sixsmith, Jaimie; Fortune, Sarah M.; Shell, Scarlet S.
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Despite the existence of well-characterized, canonical mutations that confer high-level drug resistance to Mycobacterium tuberculosis (Mtb), there is evidence that drug resistance mechanisms are more complex than simple acquisition of such mutations. Recent studies have shown that Mtb can acquire non-canonical resistance-associated mutations that confer survival advantages in the presence of certain drugs, likely acting as stepping-stones for acquisition of high-level resistance. Rv2752c/rnj, encoding RNase J, is disproportionately mutated in drug-resistant clinical Mtb isolates. Here we show that deletion of rnj confers increased tolerance to lethal concentrations of several drugs. RNAseq revealed that RNase J affects expression of a subset of genes enriched for PE/PPE genes and stable RNAs and is key for proper 23S rRNA maturation. Gene expression differences implicated two sRNAs and ppe50-ppe51 as important contributors to the drug tolerance phenotype. In addition, we found that in the absence of RNase J, many short RNA fragments accumulate because they are degraded at slower rates. We show that the accumulated transcript fragments are targets of RNase J and are characterized by strong secondary structure and high G+C content, indicating that RNase J has a rate-limiting role in degradation of highly structured RNAs. Taken together, our results demonstrate that RNase J indirectly affects drug tolerance, as well as reveal the endogenous roles of RNase J in mycobacterial RNA metabolism.
Fil: Martini, María Carla. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Hicks, Nathan D.. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Xiao, Junpei. Worcester Polytechnic Institute; Estados Unidos
Fil: Alonso, Maria Natalia. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barbier, Thibault. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Sixsmith, Jaimie. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Fortune, Sarah M.. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Shell, Scarlet S.. Worcester Polytechnic Institute; Estados Unidos
Materia
MYCOBACTERIUM TUBERCULOSIS
RNASE J
ANTIBIOTIC RESISTANCE
RNA METABOLISM
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/212976
Acceder
id CONICETDig_685e953910665dd39169234678f862e6
oai_identifier_str oai:ri.conicet.gov.ar:11336/212976
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosisMartini, María CarlaHicks, Nathan D.Xiao, JunpeiAlonso, Maria NataliaBarbier, ThibaultSixsmith, JaimieFortune, Sarah M.Shell, Scarlet S.MYCOBACTERIUM TUBERCULOSISRNASE JANTIBIOTIC RESISTANCERNA METABOLISMhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Despite the existence of well-characterized, canonical mutations that confer high-level drug resistance to Mycobacterium tuberculosis (Mtb), there is evidence that drug resistance mechanisms are more complex than simple acquisition of such mutations. Recent studies have shown that Mtb can acquire non-canonical resistance-associated mutations that confer survival advantages in the presence of certain drugs, likely acting as stepping-stones for acquisition of high-level resistance. Rv2752c/rnj, encoding RNase J, is disproportionately mutated in drug-resistant clinical Mtb isolates. Here we show that deletion of rnj confers increased tolerance to lethal concentrations of several drugs. RNAseq revealed that RNase J affects expression of a subset of genes enriched for PE/PPE genes and stable RNAs and is key for proper 23S rRNA maturation. Gene expression differences implicated two sRNAs and ppe50-ppe51 as important contributors to the drug tolerance phenotype. In addition, we found that in the absence of RNase J, many short RNA fragments accumulate because they are degraded at slower rates. We show that the accumulated transcript fragments are targets of RNase J and are characterized by strong secondary structure and high G+C content, indicating that RNase J has a rate-limiting role in degradation of highly structured RNAs. Taken together, our results demonstrate that RNase J indirectly affects drug tolerance, as well as reveal the endogenous roles of RNase J in mycobacterial RNA metabolism.Fil: Martini, María Carla. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hicks, Nathan D.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Xiao, Junpei. Worcester Polytechnic Institute; Estados UnidosFil: Alonso, Maria Natalia. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barbier, Thibault. Harvard University. Harvard School of Public Health; Estados UnidosFil: Sixsmith, Jaimie. Harvard University. Harvard School of Public Health; Estados UnidosFil: Fortune, Sarah M.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Shell, Scarlet S.. Worcester Polytechnic Institute; Estados UnidosPublic Library of Science2022-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/212976Martini, María Carla; Hicks, Nathan D.; Xiao, Junpei; Alonso, Maria Natalia; Barbier, Thibault; et al.; Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis; Public Library of Science; Plos Pathogens; 18; 7; 7-2022; 1-221553-7366CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1010705info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010705info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:18:09Zoai:ri.conicet.gov.ar:11336/212976instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 12:18:09.612CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
title Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
spellingShingle Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
Martini, María Carla
MYCOBACTERIUM TUBERCULOSIS
RNASE J
ANTIBIOTIC RESISTANCE
RNA METABOLISM
title_short Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
title_full Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
title_fullStr Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
title_full_unstemmed Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
title_sort Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis
dc.creator.none.fl_str_mv Martini, María Carla
Hicks, Nathan D.
Xiao, Junpei
Alonso, Maria Natalia
Barbier, Thibault
Sixsmith, Jaimie
Fortune, Sarah M.
Shell, Scarlet S.
author Martini, María Carla
author_facet Martini, María Carla
Hicks, Nathan D.
Xiao, Junpei
Alonso, Maria Natalia
Barbier, Thibault
Sixsmith, Jaimie
Fortune, Sarah M.
Shell, Scarlet S.
author_role author
author2 Hicks, Nathan D.
Xiao, Junpei
Alonso, Maria Natalia
Barbier, Thibault
Sixsmith, Jaimie
Fortune, Sarah M.
Shell, Scarlet S.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MYCOBACTERIUM TUBERCULOSIS
RNASE J
ANTIBIOTIC RESISTANCE
RNA METABOLISM
topic MYCOBACTERIUM TUBERCULOSIS
RNASE J
ANTIBIOTIC RESISTANCE
RNA METABOLISM
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Despite the existence of well-characterized, canonical mutations that confer high-level drug resistance to Mycobacterium tuberculosis (Mtb), there is evidence that drug resistance mechanisms are more complex than simple acquisition of such mutations. Recent studies have shown that Mtb can acquire non-canonical resistance-associated mutations that confer survival advantages in the presence of certain drugs, likely acting as stepping-stones for acquisition of high-level resistance. Rv2752c/rnj, encoding RNase J, is disproportionately mutated in drug-resistant clinical Mtb isolates. Here we show that deletion of rnj confers increased tolerance to lethal concentrations of several drugs. RNAseq revealed that RNase J affects expression of a subset of genes enriched for PE/PPE genes and stable RNAs and is key for proper 23S rRNA maturation. Gene expression differences implicated two sRNAs and ppe50-ppe51 as important contributors to the drug tolerance phenotype. In addition, we found that in the absence of RNase J, many short RNA fragments accumulate because they are degraded at slower rates. We show that the accumulated transcript fragments are targets of RNase J and are characterized by strong secondary structure and high G+C content, indicating that RNase J has a rate-limiting role in degradation of highly structured RNAs. Taken together, our results demonstrate that RNase J indirectly affects drug tolerance, as well as reveal the endogenous roles of RNase J in mycobacterial RNA metabolism.
Fil: Martini, María Carla. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Hicks, Nathan D.. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Xiao, Junpei. Worcester Polytechnic Institute; Estados Unidos
Fil: Alonso, Maria Natalia. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barbier, Thibault. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Sixsmith, Jaimie. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Fortune, Sarah M.. Harvard University. Harvard School of Public Health; Estados Unidos
Fil: Shell, Scarlet S.. Worcester Polytechnic Institute; Estados Unidos
description Despite the existence of well-characterized, canonical mutations that confer high-level drug resistance to Mycobacterium tuberculosis (Mtb), there is evidence that drug resistance mechanisms are more complex than simple acquisition of such mutations. Recent studies have shown that Mtb can acquire non-canonical resistance-associated mutations that confer survival advantages in the presence of certain drugs, likely acting as stepping-stones for acquisition of high-level resistance. Rv2752c/rnj, encoding RNase J, is disproportionately mutated in drug-resistant clinical Mtb isolates. Here we show that deletion of rnj confers increased tolerance to lethal concentrations of several drugs. RNAseq revealed that RNase J affects expression of a subset of genes enriched for PE/PPE genes and stable RNAs and is key for proper 23S rRNA maturation. Gene expression differences implicated two sRNAs and ppe50-ppe51 as important contributors to the drug tolerance phenotype. In addition, we found that in the absence of RNase J, many short RNA fragments accumulate because they are degraded at slower rates. We show that the accumulated transcript fragments are targets of RNase J and are characterized by strong secondary structure and high G+C content, indicating that RNase J has a rate-limiting role in degradation of highly structured RNAs. Taken together, our results demonstrate that RNase J indirectly affects drug tolerance, as well as reveal the endogenous roles of RNase J in mycobacterial RNA metabolism.
publishDate 2022
dc.date.none.fl_str_mv 2022-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/212976
Martini, María Carla; Hicks, Nathan D.; Xiao, Junpei; Alonso, Maria Natalia; Barbier, Thibault; et al.; Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis; Public Library of Science; Plos Pathogens; 18; 7; 7-2022; 1-22
1553-7366
CONICET Digital
CONICET
url http://hdl.handle.net/11336/212976
identifier_str_mv Martini, María Carla; Hicks, Nathan D.; Xiao, Junpei; Alonso, Maria Natalia; Barbier, Thibault; et al.; Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis; Public Library of Science; Plos Pathogens; 18; 7; 7-2022; 1-22
1553-7366
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1010705
info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010705
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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