title: Activator of G-Protein Signaling 3-Induced Lysosomal Biogenesis Limits Macrophage Intracellular Bacterial Infection.
abstract: Many intracellular pathogens cause disease by subverting macrophage innate immune defense mechanisms. Intracellular pathogens actively avoid delivery to or directly target lysosomes, the major intracellular degradative organelle. In this article, we demonstrate that activator of G-protein signaling 3 (AGS3), an LPS-inducible protein in macrophages, affects both lysosomal biogenesis and activity. AGS3 binds the Gi family of G proteins via its G-protein regulatory (GoLoco) motif, stabilizing the Gα subunit in its GDP-bound conformation. Elevated AGS3 levels in macrophages limited the activity of the mammalian target of rapamycin pathway, a sensor of cellular nutritional status. This triggered the nuclear translocation of transcription factor EB, a known activator of lysosomal gene transcription. In contrast, AGS3-deficient macrophages had increased mammalian target of rapamycin activity, reduced transcription factor EB activity, and a lower lysosomal mass. High levels of AGS3 in macrophages enhanced their resistance to infection by Burkholderia cenocepacia J2315, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus, whereas AGS3-deficient macrophages were more susceptible. We conclude that LPS priming increases AGS3 levels, which enhances lysosomal function and increases the capacity of macrophages to eliminate intracellular pathogens.
authors.affiliation: B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ali
authors.initials: A
authors.lastname: Vural
authors.affiliation: Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Souhaila
authors.initials: S
authors.lastname: Al-Khodor
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Gordon Y C
authors.identifier: http://orcid.org/0000-0003-1796-6058
authors.initials: GY
authors.lastname: Cheung
authors.affiliation: B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Chong-Shan
authors.initials: CS
authors.lastname: Shi
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742;
authors.forename: Lalitha
authors.initials: L
authors.lastname: Srinivasan
authors.affiliation: Translational Mycology Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Travis J
authors.identifier: http://orcid.org/0000-0001-7826-8101
authors.initials: TJ
authors.lastname: McQuiston
authors.affiliation: B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Hwang
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Yeh
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Joe B
authors.identifier: http://orcid.org/0000-0002-0020-3815
authors.initials: JB
authors.lastname: Blumer
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742;
authors.forename: Volker
authors.initials: V
authors.lastname: Briken
authors.affiliation: Translational Mycology Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-2222-4115
authors.initials: M
authors.lastname: Otto
authors.affiliation: Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Iain D C
authors.initials: ID
authors.lastname: Fraser
authors.affiliation: B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; jkehrl@niaid.nih.gov.
authors.forename: John H
authors.identifier: http://orcid.org/0000-0002-6526-159X
authors.initials: JH
authors.lastname: Kehrl
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D005434:Flow Cytometry; D020730:Guanine Nucleotide Dissociation Inhibitors; D015151:Immunoblotting; D008247:Lysosomes / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering
chemical_list: D002352:Carrier Proteins; C498915:Gpsm1 protein, mouse; D020730:Guanine Nucleotide Dissociation Inhibitors; D034741:RNA, Small Interfering