title: The proneurotrophin receptor sortilin is required for Mycobacterium tuberculosis control by macrophages.
abstract: Sorting of luminal and membrane proteins into phagosomes is critical for the immune function of this organelle. However, little is known about the mechanisms that contribute to the spatiotemporal regulation of this process. Here, we investigated the role of the proneurotrophin receptor sortilin during phagosome maturation and mycobacterial killing. We show that this receptor is acquired by mycobacteria-containing phagosomes via interactions with the adaptor proteins AP-1 and GGAs. Interestingly, the phagosomal association of sortilin is critical for the delivery of acid sphingomyelinase (ASMase) and required for efficient phagosome maturation. Macrophages from Sort1(-/-) mice are less efficient in restricting the growth of Mycobacterium bovis BCG and M. tuberculosis. In vivo, Sort1(-/-) mice showed a substantial increase in cellular infiltration of neutrophils in their lungs and higher bacterial burden after infection with M. tuberculosis. Altogether, sortilin defines a pathway required for optimal intracellular mycobacteria control and lung inflammation in vivo.
authors.affiliation: Research Group Phagosome Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Vázquez
authors.affiliation: Host-pathogen interactions in tuberculosis laboratory, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Rodgers
authors.affiliation: Host-pathogen interactions in tuberculosis laboratory, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herbst
authors.affiliation: Host-pathogen interactions in tuberculosis laboratory, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Coade
authors.affiliation: Research Group Phagosome Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Gronow
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzman
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
authors.affiliation: Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kanzaki
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Medical Biochemistry, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.affiliation: Host-pathogen interactions in tuberculosis laboratory, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London, NW7 1AA, UK.
authors.forename: Maximiliano G
authors.initials: MG
authors.lastname: Gutierrez
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D058491:Bacterial Load; D004195:Disease Models, Animal; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D050296:Microbial Viability; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010588:Phagosomes / Q000378:metabolism* / Q000382:microbiology*; D014397:Tuberculosis, Pulmonary / Q000382:microbiology / Q000473:pathology; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000099183:Sortilin