CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin.

Article Details

Citation

Saini V, Marchese A, Majetschak M

CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin.

J Biol Chem. 2010 May 14;285(20):15566-76. doi: 10.1074/jbc.M110.103408. Epub 2010 Mar 12.

PubMed ID
20228059 [ View in PubMed
]
Abstract

Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier. Ubiquitin is also a natural constituent of plasma, and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties. In addition, ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo. However, its mechanism of action is unknown. Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 (CXCR4 and CD184) agonist. Extracellular ubiquitin promotes intracellular Ca(2+) flux and reduces cAMP levels through a G protein-coupled receptor that signals via a Galpha(i/o) protein in THP1 cells. Toll-like receptor 4 stimulation reduces ubiquitin-binding sites, which enabled identification of four Galpha(i/o) PCRs as ubiquitin receptor candidates. Overexpression of candidate genes in HEK293 cells, gene silencing in THP1 cells, competition binding, and signaling studies with the CXCR4 agonist stromal cell-derived factor-1alpha (chemokine (CXC motif) ligand 12) and inhibitor AMD3100 identify CXCR4 as a functional ubiquitin receptor. Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology, has implications for the understanding of CXCR4-mediated events, and is expected to facilitate development of new therapeutic avenues for a variety of diseases.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
C-X-C chemokine receptor type 4P61073Details