Activator of G-protein signaling 3-induced lysosomal biogenesis limits macrophage intracellular bacterial infection

Ali Vural, Souhaila M. Al Khodor, Gordon Y C Cheung, Chong Shan Shi, Lalitha Srinivasan, Travis J. McQuiston, Il Young Hwang, Anthony J. Yeh, Joe B. Blumer, Volker Briken, Peter R. Williamson, Michael Otto, Iain D C Fraser, John H. Kehrl

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12 Citations (Scopus)

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 ofG-protein signaling 3 (AGS3), an LPS-inducible protein inmacrophages, affects both lysosomal biogenesis and activity. AGS3 binds the Gi family of G proteins via its G-protein regulatory (GoLoco) motif, stabilizing the Ga 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.

Original languageEnglish
Pages (from-to)846-856
Number of pages11
JournalJournal of Immunology
Volume196
Issue number2
DOIs
Publication statusPublished - 15 Jan 2016

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ASJC Scopus subject areas

  • Immunology

Cite this

Vural, A., Al Khodor, S. M., Cheung, G. Y. C., Shi, C. S., Srinivasan, L., McQuiston, T. J., Hwang, I. Y., Yeh, A. J., Blumer, J. B., Briken, V., Williamson, P. R., Otto, M., Fraser, I. D. C., & Kehrl, J. H. (2016). Activator of G-protein signaling 3-induced lysosomal biogenesis limits macrophage intracellular bacterial infection. Journal of Immunology, 196(2), 846-856. https://doi.org/10.4049/jimmunol.1501595