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A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells

Author

Listed:
  • Xue Li

    (VA Connecticut Healthcare System
    Yale University School of Medicine
    Shengjing Hospital of China Medical University)

  • Quan Jiang

    (VA Connecticut Healthcare System
    Yale University School of Medicine)

  • Guiyu Song

    (VA Connecticut Healthcare System
    Yale University School of Medicine
    Shengjing Hospital of China Medical University)

  • Mahsa Nouri Barkestani

    (VA Connecticut Healthcare System
    Yale University School of Medicine)

  • Qianxun Wang

    (VA Connecticut Healthcare System
    Yale University School of Medicine)

  • Shaoxun Wang

    (VA Connecticut Healthcare System
    Yale University School of Medicine)

  • Matthew Fan

    (Yale University)

  • Caodi Fang

    (VA Connecticut Healthcare System
    Yale University School of Medicine)

  • Bo Jiang

    (Yale University School of Medicine
    Yale University School of Medicine
    The First Hospital of China Medical University)

  • Justin Johnson

    (Yale University School of Medicine)

  • Arnar Geirsson

    (Yale University School of Medicine)

  • George Tellides

    (Yale University School of Medicine)

  • Jordan S. Pober

    (Yale University School of Medicine)

  • Dan Jane-wit

    (VA Connecticut Healthcare System
    Yale University School of Medicine
    Yale University School of Medicine)

Abstract

Internalization of complement membrane attack complexes (MACs) assembles NLRP3 inflammasomes in endothelial cells (EC) and promotes IL-β-mediated tissue inflammation. Informed by proteomics analyses of FACS-sorted inflammasomes, we identify a protein complex modulating inflammasome activity on endosomes. ZFVYE21, a Rab5 effector, partners with Rubicon and RNF34, forming a “ZRR” complex that is stabilized in a Rab5- and ZFYVE21-dependent manner on early endosomes. There, Rubicon competitively disrupts inhibitory associations between caspase-1 and its pseudosubstrate, Flightless I (FliI), while RNF34 ubiquitinylates and degradatively removes FliI from the signaling endosome. The concerted actions of the ZRR complex increase pools of endosome-associated caspase-1 available for activation. The ZRR complex is assembled in human tissues, its associated signaling responses occur in three mouse models in vivo, and the ZRR complex promotes inflammation in a skin model of chronic rejection. The ZRR signaling complex reflects a potential therapeutic target for attenuating inflammasome-mediated tissue injury.

Suggested Citation

  • Xue Li & Quan Jiang & Guiyu Song & Mahsa Nouri Barkestani & Qianxun Wang & Shaoxun Wang & Matthew Fan & Caodi Fang & Bo Jiang & Justin Johnson & Arnar Geirsson & George Tellides & Jordan S. Pober & Da, 2023. "A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38684-2
    DOI: 10.1038/s41467-023-38684-2
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    References listed on IDEAS

    as
    1. Caodi Fang & Thomas D. Manes & Lufang Liu & Kevin Liu & Lingfeng Qin & Guangxin Li & Zuzana Tobiasova & Nancy C. Kirkiles-Smith & Manal Patel & Jonathan Merola & Whitney Fu & Rebecca Liu & Catherine X, 2019. "ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Joseph S. Bednash & Nathaniel Weathington & James Londino & Mauricio Rojas & Dexter L. Gulick & Robert Fort & SeungHye Han & Alison C. McKelvey & Bill B. Chen & Rama K. Mallampalli, 2017. "Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
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