HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting
Gerlach, Roman G
van Zandbergen, Ger
Binger, Katrina J
Müller, Dominik N
Taylor & Francis
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Neubert, P., Weichselbaum, A., Reitinger, C., Schatz, V., Schröder, A., Ferdinand, J., Simon, M., et al. (2019). HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting. Autophagy https://doi.org/10.1080/15548627.2019.1596483
Infection and inflammation are able to induce diet-independent Na+-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na+-boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na+ (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na+- modulated cell autonomous innate immunity.
This work was supported by the Deutsche Forschungsgemeinschaft [WA 2539/4-1, 5-1, 7-1]; Deutsche Forschungsgemeinschaft (DE) [JA 1993/ 4-1]; Universitätsklinikum Regensburg [Reform C]; NIHR Cambridge Blood and Transplant Research Unit Organ Donation.
Department of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10027)
External DOI: https://doi.org/10.1080/15548627.2019.1596483
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291847
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Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/