TY - JOUR
T1 - ATP-sensitive potassium channels mediate survival during infection in mammals and insects
AU - Croker, Ben
AU - Crozat, Karine
AU - Berger, Michael
AU - Xia, Yu
AU - Sovath, Sosathya
AU - Schaffer, Lana
AU - Eleftherianos, Ioannis
AU - Imler, Jean Luc
AU - Beutler, Bruce
N1 - Funding Information:
We thank For M.B.A. Oldstone and J.L. Whitton (TSRI) for IFN-b– and IFN-g–deficient mice, respectively; R. Bodmer (The Burnham Institute for Medical Research, La Jolla, California, USA) for the UAS-dSUR RNAi lines and the GMH5-Gal4 driver line; and C. Galanos and M.A. Freudenberg (Max Planck Institut für Immunbiologie, Freiburg, Germany) for LPS-free poly(I·C). This work was supported by a grant from the National Institutes of Health (AI070167). M.B. was supported by an European Molecular Biology Organization Long-Term Fellowship. This is TSRI manuscript no. 18948.
PY - 2007/12
Y1 - 2007/12
N2 - Specific homeostatic mechanisms confer stability in innate immune responses, preventing injury or death from infection. Here we identify, from a screen of N-ethyl-N-nitrosourea-mutagenized mice, a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and ∼20,000-fold sensitization to lipopolysaccharide (LPS), poly(I·C) and immunostimulatory (CpG) DNA. The LPS hypersensitivity phenotype is not suppressed by mutations in Myd88, Trif, Tnf, Tnfrsf1a, Ifnb, Ifng or Stat1, genes contributing to LPS responses, and results from an abnormality extrinsic to hematopoietic cells. The phenotype is due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 to form an ATP-sensitive potassium channel (KATP) expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. Thus, KATP evolved to serve a homeostatic function during infection, and in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on TLR and/or MDA5 immunoreceptors.
AB - Specific homeostatic mechanisms confer stability in innate immune responses, preventing injury or death from infection. Here we identify, from a screen of N-ethyl-N-nitrosourea-mutagenized mice, a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and ∼20,000-fold sensitization to lipopolysaccharide (LPS), poly(I·C) and immunostimulatory (CpG) DNA. The LPS hypersensitivity phenotype is not suppressed by mutations in Myd88, Trif, Tnf, Tnfrsf1a, Ifnb, Ifng or Stat1, genes contributing to LPS responses, and results from an abnormality extrinsic to hematopoietic cells. The phenotype is due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 to form an ATP-sensitive potassium channel (KATP) expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. Thus, KATP evolved to serve a homeostatic function during infection, and in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on TLR and/or MDA5 immunoreceptors.
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U2 - 10.1038/ng.2007.25
DO - 10.1038/ng.2007.25
M3 - Article
C2 - 18026101
AN - SCOPUS:36549070630
SN - 1061-4036
VL - 39
SP - 1453
EP - 1460
JO - Nature genetics
JF - Nature genetics
IS - 12
ER -