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Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone

Author

Listed:
  • Bei Liu

    (Hollings Cancer Center, Medical University of South Carolina)

  • Yi Yang

    (University of Connecticut School of Medicine)

  • Zhijuan Qiu

    (University of Connecticut School of Medicine)

  • Matthew Staron

    (University of Connecticut School of Medicine)

  • Feng Hong

    (University of Connecticut School of Medicine
    Lea's Foundation Center for Hematologic Disorders and Neag Comprehensive Cancer Center, University of Connecticut School of Medicine)

  • Yi Li

    (University of Connecticut School of Medicine)

  • Shuang Wu

    (Hollings Cancer Center, Medical University of South Carolina
    University of Connecticut School of Medicine)

  • Yunfeng Li

    (Molecular and Structural Biology, University of Connecticut School of Medicine)

  • Bing Hao

    (Molecular and Structural Biology, University of Connecticut School of Medicine)

  • Robert Bona

    (Lea's Foundation Center for Hematologic Disorders and Neag Comprehensive Cancer Center, University of Connecticut School of Medicine)

  • David Han

    (University of Connecticut School of Medicine)

  • Zihai Li

    (Hollings Cancer Center, Medical University of South Carolina
    University of Connecticut School of Medicine)

Abstract

Cytosolic HSP90 requires multiple cochaperones in folding client proteins. However, the function of gp96 (HSP90b1, grp94), an HSP90 paralogue in the endoplasmic reticulum (ER), is believed to be independent of cochaperones. Here, we demonstrate that gp96 chaperones multiple Toll-like receptors (TLRs), but not TLR3, in a manner that is dependent on another ER luminal protein, CNPY3. gp96 directly interacts with CNPY3, and the complex dissociates in the presence of adenosine triphosphate (ATP). Genetic disruption of gp96–CNPY3 interaction completely abolishes their TLR chaperone function. Moreover, we demonstrate that TLR9 forms a multimolecular complex with gp96 and CNPY3, and the binding of TLR9 to either molecule requires the presence of the other. We suggest that CNPY3 interacts with the ATP-sensitive conformation of gp96 to promote substrate loading. Our study has thus established CNPY3 as a TLR-specific cochaperone for gp96.

Suggested Citation

  • Bei Liu & Yi Yang & Zhijuan Qiu & Matthew Staron & Feng Hong & Yi Li & Shuang Wu & Yunfeng Li & Bing Hao & Robert Bona & David Han & Zihai Li, 2010. "Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone," Nature Communications, Nature, vol. 1(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1070
    DOI: 10.1038/ncomms1070
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    Cited by:

    1. Pei Zhao & Chao Wang & Shuhong Sun & Xi Wang & William E. Balch, 2024. "Tracing genetic diversity captures the molecular basis of misfolding disease," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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