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

Autor: Li X; VA Connecticut Healthcare System, West Haven, CT, USA.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA.; Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China., Jiang Q; VA Connecticut Healthcare System, West Haven, CT, USA.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA., Song G; VA Connecticut Healthcare System, West Haven, CT, USA. guiyu.song@yale.edu.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA. guiyu.song@yale.edu.; Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China. guiyu.song@yale.edu., Barkestani MN; VA Connecticut Healthcare System, West Haven, CT, USA.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA., Wang Q; VA Connecticut Healthcare System, West Haven, CT, USA.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA., Wang S; VA Connecticut Healthcare System, West Haven, CT, USA.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA., Fan M; Yale College, Yale University, New Haven, CT, USA., Fang C; VA Connecticut Healthcare System, West Haven, CT, USA.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA., Jiang B; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA.; Dept of Surgery, Yale University School of Medicine, New Haven, CT, USA.; Dept of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China., Johnson J; Dept of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Geirsson A; Dept of Surgery, Yale University School of Medicine, New Haven, CT, USA., Tellides G; Dept of Surgery, Yale University School of Medicine, New Haven, CT, USA., Pober JS; Dept of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Jane-Wit D; VA Connecticut Healthcare System, West Haven, CT, USA. dan.jane-wit@yale.edu.; Department of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA. dan.jane-wit@yale.edu.; Dept of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. dan.jane-wit@yale.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 May 24; Vol. 14 (1), pp. 3002. Date of Electronic Publication: 2023 May 24.
DOI: 10.1038/s41467-023-38684-2
Abstrakt: 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.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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