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...
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Public Library of Science (PLoS)
2013
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oai:doaj.org-article:8cf2ec156ac647b2b5f8f2e3b35e59d32021-11-18T06:07:23ZMycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair trafficking.1553-73661553-737410.1371/journal.ppat.1003734https://doaj.org/article/8cf2ec156ac647b2b5f8f2e3b35e59d32013-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24204276/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Mycobacterium 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.Alka MehraAleena ZahraVictor ThompsonNatalie SirisaengtaksinAshley WellsMaura PortoStefan KösterKristen PenberthyYoshihisha KubotaAmelie DricotDaniel RoganMarc VidalDavid E HillAndrew J BeanJennifer A PhilipsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 10, p e1003734 (2013) |
| institution |
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| collection |
DOAJ |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Alka Mehra Aleena Zahra Victor Thompson Natalie Sirisaengtaksin Ashley Wells Maura Porto Stefan Köster Kristen Penberthy Yoshihisha Kubota Amelie Dricot Daniel Rogan Marc Vidal David E Hill Andrew J Bean Jennifer A Philips Mycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair trafficking. |
| 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 |
article |
| author |
Alka Mehra Aleena Zahra Victor Thompson Natalie Sirisaengtaksin Ashley Wells Maura Porto Stefan Köster Kristen Penberthy Yoshihisha Kubota Amelie Dricot Daniel Rogan Marc Vidal David E Hill Andrew J Bean Jennifer A Philips |
| author_facet |
Alka Mehra Aleena Zahra Victor Thompson Natalie Sirisaengtaksin Ashley Wells Maura Porto Stefan Köster Kristen Penberthy Yoshihisha Kubota Amelie Dricot Daniel Rogan Marc Vidal David E Hill Andrew J Bean Jennifer A Philips |
| author_sort |
Alka Mehra |
| title |
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_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_sort |
mycobacterium tuberculosis type vii secreted effector esxh targets host escrt to impair trafficking. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/8cf2ec156ac647b2b5f8f2e3b35e59d3 |
| work_keys_str_mv |
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| _version_ |
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