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- Title
A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells.
- Authors
Li, Xue; Jiang, Quan; Song, Guiyu; Barkestani, Mahsa Nouri; Wang, Qianxun; Wang, Shaoxun; Fan, Matthew; Fang, Caodi; Jiang, Bo; Johnson, Justin; Geirsson, Arnar; Tellides, George; Pober, Jordan S.; Jane-wit, Dan
- 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. NLRP3 inflammasomes trigger release of IL-1 to promote tissue injury. Here, Li et al identify a ZFYVE21-Rubicon-RNF34 (ZRR) signaling complex localizing to endosomes and modulating complement-mediated inflammasome activity in vitro and in vivo.
- Subjects
ENDOTHELIAL cells; INFLAMMASOMES; NLRP3 protein; SKIN inflammation; ENDOSOMES; COMPLEMENT receptors
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-38684-2