10.6084/m9.figshare.7992203.v2
Patrick Neubert
Patrick
Neubert
Andrea Weichselbaum
Andrea
Weichselbaum
Carmen Reitinger
Carmen
Reitinger
Valentin Schatz
Valentin
Schatz
Agnes Schröder
Agnes
Schröder
John R. Ferdinand
John R.
Ferdinand
Michaela Simon
Michaela
Simon
Anna-Lorena Bär
Anna-Lorena
Bär
Christoph Brochhausen
Christoph
Brochhausen
Roman G. Gerlach
Roman G.
Gerlach
Stefan Tomiuk
Stefan
Tomiuk
Karin Hammer
Karin
Hammer
Stefan Wagner
Stefan
Wagner
Ger van Zandbergen
Ger
van Zandbergen
Katrina J. Binger
Katrina J.
Binger
Dominik N. Müller
Dominik N.
Müller
Kento Kitada
Kento
Kitada
Menna R. Clatworthy
Menna R.
Clatworthy
Christian Kurts
Christian
Kurts
Jens Titze
Jens
Titze
Zeinab Abdullah
Zeinab
Abdullah
Jonathan Jantsch
Jonathan
Jantsch
HIF1A and NFAT5 coordinate Na<sup>+</sup>-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting
Taylor & Francis Group
2019
Autophagy
cell-autonomous immunity
E. coli
macrophage
salt
sodium
2019-09-16 18:18:45
Journal contribution
https://tandf.figshare.com/articles/journal_contribution/HIF1A_and_NFAT5_coordinate_Na_sup_sup_-boosted_antibacterial_defense_via_enhanced_autophagy_and_autolysosomal_targeting/7992203
<p>Infection and inflammation are able to induce diet-independent Na<sup>+</sup>-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<sup>+</sup>-boosted host defense against the protozoan parasite <i>Leishmania major</i> 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<sup>+</sup> (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against <i>E. coli</i> 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 <i>E. coli</i> to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na<sup>+</sup>-modulated cell autonomous innate immunity.</p> <p><b>Abbreviations</b>: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H<sub>2</sub>DCFDA: 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; <i>E. coli: Escherichia coli</i>; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H<sup>+</sup>-ATPase; WT: wild type</p>