Cargando…
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking
Mycobacterium tuberculosis (Mtb) disrupts anti-microbial pathways of macrophages, cells that normally kill bacteria. Over 40 years ago, D'Arcy Hart showed that Mtb avoids delivery to lysosomes, but the molecular mechanisms that allow Mtb to elude lysosomal degradation are poorly understood. Spe...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814348/ https://www.ncbi.nlm.nih.gov/pubmed/24204276 http://dx.doi.org/10.1371/journal.ppat.1003734 |
_version_ | 1782289242139918336 |
---|---|
author | Mehra, Alka Zahra, Aleena Thompson, Victor Sirisaengtaksin, Natalie Wells, Ashley Porto, Maura Köster, Stefan Penberthy, Kristen Kubota, Yoshihisha Dricot, Amelie Rogan, Daniel Vidal, Marc Hill, David E. Bean, Andrew J. Philips, Jennifer A. |
author_facet | Mehra, Alka Zahra, Aleena Thompson, Victor Sirisaengtaksin, Natalie Wells, Ashley Porto, Maura Köster, Stefan Penberthy, Kristen Kubota, Yoshihisha Dricot, Amelie Rogan, Daniel Vidal, Marc Hill, David E. Bean, Andrew J. Philips, Jennifer A. |
author_sort | Mehra, Alka |
collection | PubMed |
description | Mycobacterium tuberculosis (Mtb) disrupts anti-microbial pathways of macrophages, cells that normally kill bacteria. Over 40 years ago, D'Arcy Hart showed that Mtb avoids delivery to lysosomes, but the molecular mechanisms that allow Mtb to elude lysosomal degradation are poorly understood. Specialized secretion systems are often used by bacterial pathogens to translocate effectors that target the host, and Mtb encodes type VII secretion systems (TSSSs) that enable mycobacteria to secrete proteins across their complex cell envelope; however, their cellular targets are unknown. Here, we describe a systematic strategy to identify bacterial virulence factors by looking for interactions between the Mtb secretome and host proteins using a high throughput, high stringency, yeast two-hybrid (Y2H) platform. Using this approach we identified an interaction between EsxH, which is secreted by the Esx-3 TSSS, and human hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). ESCRT has a well-described role in directing proteins destined for lysosomal degradation into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs), ensuring degradation of the sorted cargo upon MVB-lysosome fusion. Here, we show that ESCRT is required to deliver Mtb to the lysosome and to restrict intracellular bacterial growth. Further, EsxH, in complex with EsxG, disrupts ESCRT function and impairs phagosome maturation. Thus, we demonstrate a role for a TSSS and the host ESCRT machinery in one of the central features of tuberculosis pathogenesis. |
format | Online Article Text |
id | pubmed-3814348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38143482013-11-07 Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking Mehra, Alka Zahra, Aleena Thompson, Victor Sirisaengtaksin, Natalie Wells, Ashley Porto, Maura Köster, Stefan Penberthy, Kristen Kubota, Yoshihisha Dricot, Amelie Rogan, Daniel Vidal, Marc Hill, David E. Bean, Andrew J. Philips, Jennifer A. PLoS Pathog Research Article Mycobacterium tuberculosis (Mtb) disrupts anti-microbial pathways of macrophages, cells that normally kill bacteria. Over 40 years ago, D'Arcy Hart showed that Mtb avoids delivery to lysosomes, but the molecular mechanisms that allow Mtb to elude lysosomal degradation are poorly understood. Specialized secretion systems are often used by bacterial pathogens to translocate effectors that target the host, and Mtb encodes type VII secretion systems (TSSSs) that enable mycobacteria to secrete proteins across their complex cell envelope; however, their cellular targets are unknown. Here, we describe a systematic strategy to identify bacterial virulence factors by looking for interactions between the Mtb secretome and host proteins using a high throughput, high stringency, yeast two-hybrid (Y2H) platform. Using this approach we identified an interaction between EsxH, which is secreted by the Esx-3 TSSS, and human hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). ESCRT has a well-described role in directing proteins destined for lysosomal degradation into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs), ensuring degradation of the sorted cargo upon MVB-lysosome fusion. Here, we show that ESCRT is required to deliver Mtb to the lysosome and to restrict intracellular bacterial growth. Further, EsxH, in complex with EsxG, disrupts ESCRT function and impairs phagosome maturation. Thus, we demonstrate a role for a TSSS and the host ESCRT machinery in one of the central features of tuberculosis pathogenesis. Public Library of Science 2013-10-31 /pmc/articles/PMC3814348/ /pubmed/24204276 http://dx.doi.org/10.1371/journal.ppat.1003734 Text en © 2013 Mehra et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Mehra, Alka Zahra, Aleena Thompson, Victor Sirisaengtaksin, Natalie Wells, Ashley Porto, Maura Köster, Stefan Penberthy, Kristen Kubota, Yoshihisha Dricot, Amelie Rogan, Daniel Vidal, Marc Hill, David E. Bean, Andrew J. Philips, Jennifer A. Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking |
title |
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking |
title_full |
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking |
title_fullStr |
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking |
title_full_unstemmed |
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking |
title_short |
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking |
title_sort | mycobacterium tuberculosis type vii secreted effector esxh targets host escrt to impair trafficking |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814348/ https://www.ncbi.nlm.nih.gov/pubmed/24204276 http://dx.doi.org/10.1371/journal.ppat.1003734 |
work_keys_str_mv | AT mehraalka mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT zahraaleena mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT thompsonvictor mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT sirisaengtaksinnatalie mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT wellsashley mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT portomaura mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT kosterstefan mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT penberthykristen mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT kubotayoshihisha mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT dricotamelie mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT rogandaniel mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT vidalmarc mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT hilldavide mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT beanandrewj mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking AT philipsjennifera mycobacteriumtuberculosistypeviisecretedeffectoresxhtargetshostescrttoimpairtrafficking |