Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ATP-sensitive potassium channels mediate survival during infection in mammals and insects

Nature Genetics volume 39, pages 1453–1460 (2007)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Responses of mayday mice to MCMV infection and to TLR stimuli ex vivo.
Figure 2: Genetic mapping and identification of mayday and slumber.
Figure 3: Progressive and sustained changes in heart gene expression in Kcnj8mydy/mydy mice after LPS injection.
Figure 4: dSUR is protective against FHV infection in Drosophila.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Gene Expression Omnibus

References

  1. Beutler, B. et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24, 353–389 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nat. Immunol. 7, 131–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Inohara, N., Chamaillard, M., McDonald, C. & Nunez, G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu. Rev. Biochem. 74, 355–383 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Hart, P.H. et al. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor α, interleukin 1, and prostaglandin E2. Proc. Natl. Acad. Sci. USA 86, 3803–3807 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Berg, D.J. et al. Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J. Clin. Invest. 96, 2339–2347 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Muchamuel, T., Menon, S., Pisacane, P., Howard, M.C. & Cockayne, D.A. IL-13 protects mice from lipopolysaccharide-induced lethal endotoxemia: correlation with down-modulation of TNF-α, IFN-γ, and IL-12 production. J. Immunol. 158, 2898–2903 (1997).

    CAS  PubMed  Google Scholar 

  7. Hausmann, E.H., Hao, S.Y., Pace, J.L. & Parmely, M.J. Transforming growth factor β1 and γ interferon provide opposing signals to lipopolysaccharide-activated mouse macrophages. Infect. Immun. 62, 3625–3632 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kinjyo, I. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583–591 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Nakagawa, R. et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677–687 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Croker, B.A. et al. SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity 20, 153–165 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Kano, A. et al. Endothelial cells require STAT3 for protection against endotoxin-induced inflammation. J. Exp. Med. 198, 1517–1525 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sly, L.M., Rauh, M.J., Kalesnikoff, J., Song, C.H. & Krystal, G. LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 21, 227–239 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Boone, D.L. et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Kobayashi, K. et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Crozat, K. et al. Analysis of the MCMV resistome by ENU mutagenesis. Mamm. Genome 17, 398–406 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Dokun, A.O. et al. Specific and nonspecific NK cell activation during virus infection. Nat. Immunol. 2, 951–956 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Brown, M.G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Lee, S.H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28, 42–45 (2001).

    CAS  PubMed  Google Scholar 

  19. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signaling. Nature 424, 743–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Tabeta, K. et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl. Acad. Sci. USA 101, 3516–3521 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Krug, A. et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21, 107–119 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Presti, R.M., Pollock, J.L., Dal Canto, A.J., O'Guin, A.K. & Virgin, H.W. Interferon γ regulates acute and latent murine cytomegalovirus infection and chronic disease of the great vessels 1. J. Exp. Med. 188, 577–588 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Salazar-Mather, T.P., Lewis, C.A. & Biron, C.A. Type I interferons regulate inflammatory cell trafficking and macrophage inflammatory protein 1α delivery to the liver. J. Clin. Invest. 110, 321–330 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van Dommelen, S.L. et al. Perforin and granzymes have distinct roles in defensive immunity and immunopathology. Immunity 25, 835–848 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Pao, L.I. et al. Functional analysis of granzyme M and its role in immunity to infection. J. Immunol. 175, 3235–3243 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Crozat, K. et al. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J. Exp. Med. 204, 853–863 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Miki, T. et al. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat. Med. 8, 466–472 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Chutkow, W.A. et al. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 KATP channels. J. Clin. Invest. 110, 203–208 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kane, G.C. et al. Gene knockout of the KCNJ8-encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia. FASEB J. 20, 2271–2280 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Lehmann, V., Freudenberg, M.A. & Galanos, C. Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and d-galactosamine-treated mice. J. Exp. Med. 165, 657–663 (1987).

    Article  CAS  PubMed  Google Scholar 

  31. Cherry, S. & Silverman, N. Host-pathogen interactions in Drosophila: new tricks from an old friend. Nat. Immunol. 7, 911–917 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Akasaka, T. et al. The ATP-sensitive potassium (KATP) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by tinman. Proc. Natl. Acad. Sci. USA 103, 11999–12004 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gitlin, L. et al. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103, 8459–8464 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Georgel, P. et al. Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4–dependent pathway. Virology 362, 304–313 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Takahashi, K. et al. Roles of caspase-8 and caspase-10 in innate immune responses to double-stranded RNA. J. Immunol. 176, 4520–4524 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Galanos, C., Freudenberg, M.A. & Reutter, W. Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc. Natl. Acad. Sci. USA 76, 5939–5943 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Keppler, D.O., Schulz-Holstege, C., Fauler, J., Reiffen, K.A. & Schneider, F. Uridylate trapping, induction of UTP deficiency, and stimulation of pyrimidine synthesis de novo by D-galactosone. Biochem. J. 206, 139–146 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Leist, M. et al. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-α requires transcriptional arrest. J. Immunol. 153, 1778–1788 (1994).

    CAS  PubMed  Google Scholar 

  42. Alekseev, A.E., Brady, P.A. & Terzic, A. Ligand-insensitive state of cardiac ATP-sensitive K+ channels. Basis for channel opening. J. Gen. Physiol. 111, 381–394 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zambon, R.A., Vakharia, V.N. & Wu, L.P. RNAi is an antiviral immune response against a dsRNA virus in Drosophila melanogaster. Cell. Microbiol. 8, 880–889 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Dostert, C. et al. The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of Drosophila. Nat. Immunol. 6, 946–953 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Galiana-Arnoux, D., Dostert, C., Schneemann, A., Hoffmann, J.A. & Imler, J.L. Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. Nat. Immunol. 7, 590–597 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Rutschmann, S. et al. PanR1, a dominant negative missense allele of the gene encoding TNF-α (Tnf), does not impair lymphoid development. J. Immunol. 176, 7525–7532 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Hoebe, K., Du, X., Goode, J., Mann, N. & Beutler, B. Lps2: a new locus required for responses to lipopolysaccharide, revealed by germline mutagenesis and phenotypic screening. J. Endotoxin Res. 9, 250–255 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Smyth, G.K. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article 3 (2004).

    Article  Google Scholar 

  49. Eisen, M.B., Spellman, P.T., Brown, P.O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95, 14863–14868 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank For M.B.A. Oldstone and J.L. Whitton (TSRI) for IFN-β– and IFN-γ–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.

Author information

Author notes

  1. Ben Croker

    Present address: Present Address: Cancer and Haematology Division, The Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3050, Australia.,

Authors and Affiliations

  1. Department of Genetics, IMM-31, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Ben Croker, Karine Crozat, Michael Berger, Yu Xia, Sosathya Sovath & Bruce Beutler

  2. DNA Array Core Facility, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Lana Schaffer

  3. UPR 9022 – CNRS, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084, Strasbourg cedex, France

    Ioannis Eleftherianos & Jean-Luc Imler

Authors
  1. Ben Croker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karine Crozat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sosathya Sovath
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lana Schaffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ioannis Eleftherianos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Luc Imler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bruce Beutler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B. Croker identified the mayday mutant, positionally cloned the mutation, carried out much of the phenotypic analysis presented, and contributed to the writing of the paper. K. Crozat identified the slumber, solitaire and goodnight mutations, positionally identified slumber, and contributed to the phenotypic characterization of these mutants and the writing of the paper. M. Berger analyzed the TLF-mediated macrophage responses in mayday mutant mice. Y. Xia and S. Sovath contributed to the mapping and sequencing work and microarray analysis. L. Schaffer assisted with interpretation of microarray data. J. Imler and I. Eleftherianos studied the role of dSUR during viral infection in Drosophila and contributed to the writing of the paper. B. Beutler contributed to the mutagenesis effort and to the design of experiments and their written presentation.

Corresponding author

Correspondence to Bruce Beutler.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1, Supplementary Table 1 (PDF 45 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Croker, B., Crozat, K., Berger, M. et al. ATP-sensitive potassium channels mediate survival during infection in mammals and insects. Nat Genet 39, 1453–1460 (2007). https://doi.org/10.1038/ng.2007.25

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2007.25

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing