title: Mycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair trafficking.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Department of Pathology and Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Alka
authors.initials: A
authors.lastname: Mehra
authors.forename: Aleena
authors.initials: A
authors.lastname: Zahra
authors.forename: Victor
authors.initials: V
authors.lastname: Thompson
authors.forename: Natalie
authors.initials: N
authors.lastname: Sirisaengtaksin
authors.forename: Ashley
authors.initials: A
authors.lastname: Wells
authors.forename: Maura
authors.initials: M
authors.lastname: Porto
authors.forename: Stefan
authors.initials: S
authors.lastname: Köster
authors.forename: Kristen
authors.initials: K
authors.lastname: Penberthy
authors.forename: Yoshihisha
authors.initials: Y
authors.lastname: Kubota
authors.forename: Amelie
authors.initials: A
authors.lastname: Dricot
authors.forename: Daniel
authors.initials: D
authors.lastname: Rogan
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bean
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Philips
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D058947:Bacterial Secretion Systems; D002473:Cell Wall / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011992:Endosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000276:immunology / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008561:Membrane Fusion / Q000235:genetics / Q000276:immunology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate