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

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 and Dan Jane-wit ()
Additional contact information
Xue Li: VA Connecticut Healthcare System
Quan Jiang: VA Connecticut Healthcare System
Guiyu Song: VA Connecticut Healthcare System
Mahsa Nouri Barkestani: VA Connecticut Healthcare System
Qianxun Wang: VA Connecticut Healthcare System
Shaoxun Wang: VA Connecticut Healthcare System
Matthew Fan: Yale University
Caodi Fang: VA Connecticut Healthcare System
Bo Jiang: Yale University School of Medicine
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

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38684-2

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