| Author |
Shi, Chong-Shan Al-Khodor, Souhaila Williamson, Peter R. Kehrl, John H. Srinivasan, Lalitha Blumer, Joe B. Cheung, Gordon Y. C. Vural, Ali Fraser, Iain D. C. Briken, Volker Otto, Michael Yeh, Anthony J. McQuiston, Travis J. Hwang, Il-Young |
| Description |
Author Affiliation: Vural A ( B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Al-Khodor S ( Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Cheung GY ( Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Shi CS ( B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Srinivasan L ( Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742); McQuiston TJ ( Translational Mycology Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Hwang IY ( B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Yeh AJ ( Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Blumer JB ( Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425.); Briken V ( Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742); Williamson PR ( Translational Mycology Unit, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Otto M ( Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Fraser ID ( Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892); Kehrl JH ( B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892) |
| 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 G 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. |
