Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection

Claire B. Peán, Mark Schiebler, Sharon W S Tan, Jessica A. Sharrock, Katrin Kierdorf, Karen P. Brown, M. Charlotte Maserumule, Shinelle Menezes, Martina Pilátová, Kévin Bronda, Pierre Guermonprez, Brian M. Stramer, R. Andres Floto, Marc S. Dionne*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via ATG2 repression. In Drosophila infected with Mycobacterium marinum, mycobacterium-induced STAT activity triggered by unpaired-family cytokines reduces Atg2 expression, permitting deregulation of lipid droplets. Increased Atg2 expression or reduced macrophage triglyceride biosynthesis, normalizes lipid deposition in infected phagocytes and reduces numbers of viable intracellular mycobacteria. In human macrophages, addition of IL-6 promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2 regulation as a mechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infection in Drosophila.

Original languageEnglish
Article number14642
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 6 Mar 2017

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