IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v570y2019i7761d10.1038_s41586-019-1295-z.html
   My bibliography  Save this article

Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome

Author

Listed:
  • Humayun Sharif

    (Harvard Medical School
    Boston Children’s Hospital)

  • Li Wang

    (Harvard Medical School
    Boston Children’s Hospital)

  • Wei Li Wang

    (Harvard Medical School
    Boston Children’s Hospital
    Peking University
    Peking University)

  • Venkat Giri Magupalli

    (Harvard Medical School
    Boston Children’s Hospital)

  • Liudmila Andreeva

    (Harvard Medical School
    Boston Children’s Hospital)

  • Qi Qiao

    (Harvard Medical School
    Boston Children’s Hospital)

  • Arthur V. Hauenstein

    (Harvard Medical School
    Boston Children’s Hospital)

  • Zhaolong Wu

    (Peking University
    Peking University)

  • Gabriel Núñez

    (University of Michigan Medical School)

  • Youdong Mao

    (Peking University
    Peking University
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Hao Wu

    (Harvard Medical School
    Boston Children’s Hospital)

Abstract

The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-β fibrils and extracellular ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 Å. The earring-shaped NLRP3 consists of curved leucine-rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3–NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.

Suggested Citation

  • Humayun Sharif & Li Wang & Wei Li Wang & Venkat Giri Magupalli & Liudmila Andreeva & Qi Qiao & Arthur V. Hauenstein & Zhaolong Wu & Gabriel Núñez & Youdong Mao & Hao Wu, 2019. "Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome," Nature, Nature, vol. 570(7761), pages 338-343, June.
    • Handle: RePEc:nat:nature:v:570:y:2019:i:7761:d:10.1038_s41586-019-1295-z
    DOI: 10.1038/s41586-019-1295-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-019-1295-z
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/s41586-019-1295-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:570:y:2019:i:7761:d:10.1038_s41586-019-1295-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.