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A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses

Nature Immunology volume 8, pages 497–503 (2007)Cite this article

Abstract

The family of mammalian Nod-like receptors (NLRs) consists of critical intracellular immune proteins structurally related to plant resistance proteins. The NLRs NALP3 and IPAF, for example, can each form a multiprotein proinflammatory complex called the 'inflammasome', and mutations in the gene encoding Nod2, another NLR, are positively associated with Crohn disease. Here we show that many NLRs interacted with the ubiquitin ligase–associated protein SGT1 and heat-shock protein 90 (HSP90), both of which have plant orthologs essential for R-protein responses. 'Knockdown' of SGT1 by small interfering RNA or chemical inhibition of HSP90 abrogated inflammasome activity, and inhibition of HSP90 blocked Nod2-mediated activation of the transcription factor NF-κB and reduced NALP3-mediated gout-like inflammation in mice. Our data demonstrate a similarity in one type of innate immunity in plants and mammals that is consistent with convergent evolution of a shared mechanism.

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Figure 1: SGT1 and HSP90 are conserved NLR-interacting partners.
Figure 2: SGT1 and HSP90 are needed for the formation of a functional complex on the LRR domain of NALP3.
Figure 3: SGT1 is essential for inflammasome activity.
Figure 4: Active HSP90 is essential for inflammasome activity.
Figure 5: HSP90 is required for Nod2 and IPAF activity.
Figure 6: The HSP90 inhibitor geldanamycin suppresses MSU-induced peritonitis in mice.

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Acknowledgements

We thank H. Everett for critical reading of the manuscript. Supported by the Swiss National Science Foundation (J.T.) and the Commission of Technology and Innovation (J.T.) and by a Marie Curie Intra-European Fellowship (V.P.).

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Author notes

  1. Fabio Martinon

    Present address: Present address: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.,

  2. Annick Mayor and Fabio Martinon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, University of Lausanne, Epalinges, CH-1066, Switzerland

    Annick Mayor, Fabio Martinon, Virginie Pétrilli & Jürg Tschopp

  2. Apoxis, Lausanne, CH-1004, Switzerland

    Thibaut De Smedt

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  1. Annick Mayor
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  2. Fabio Martinon
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Contributions

A.M. and F.M. designed and did most of the work; T.D.S. and V.P. did the in vivo studies; J.T. conceived and codesigned the study.

Corresponding author

Correspondence to Jürg Tschopp.

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Competing interests

J.T. is a cofounder of and T.D.S, is an employee of Apoxis.

Supplementary information

Supplementary Fig. 1

Geldanamycin does not affect IL-6 production and secretion in THP1 cells. (PDF 18 kb)

Supplementary Fig. 2

NALP3 degradation is a proteasome dependent process. (PDF 41 kb)

Supplementary Fig. 3

SGT1 is not involved in the degradation of NALP3 upon geldanamycin treatment. (PDF 67 kb)

Supplementary Fig. 4

Hypothetical model for the potential role of SGT1 and HSP90 in the inflammasome activity. (PDF 58 kb)

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Mayor, A., Martinon, F., De Smedt, T. et al. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat Immunol 8, 497–503 (2007). https://doi.org/10.1038/ni1459

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