Control of CXCR2 activity through its ubiquitination on K327 residue

BMC Cell Biology

Research Article

Julie Dwyer¹  Nicolas Bidère¹  Sonia M Dubois¹  Sandy Azzi¹  Héloise M Leclair¹  Julie Gavard² 

[1] CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France;INSERM, U1016, 22 rue Mechain, 75014, Paris, France;Universite Paris Descartes, Sorbonne Paris Cite, 12 rue de l’Ecole de Medecine, 75006, Paris, France;CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France;INSERM, U1016, 22 rue Mechain, 75014, Paris, France;Universite Paris Descartes, Sorbonne Paris Cite, 12 rue de l’Ecole de Medecine, 75006, Paris, France;Institut Cochin, 22 rue Mechain, Rm. 306, 75014, Paris, France;

关键词: Chemokine receptor;    Ubiquitination;    Arrestin;    Internalization;    Signaling;   

DOI  :  10.1186/s12860-014-0038-0

 received in 2014-06-26, accepted in 2014-10-09,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundThe interleukin-8 chemokine (IL-8) G-protein coupled receptor CXCR2 governs pro-inflammatory and pro-angiogenic responses in leukocytes and endothelial cells. At a molecular standpoint, CXCR2 is widely reported to operate through calcium flux, phosphoinoisitide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK). While CXCR2 trafficking is suspected to be intertwined with its signaling, the exact mechanism is not fully elucidated.ResultsHere, we identified the lysine 327 within the CXCR2 C-terminal tail as a key residue for ubiquitination, internalization, and signaling. First, the substitution to an arginine of K327 mutation was associated with a reduction in CXCR2 poly-ubiquitination. While WT CXCR2 was rapidly internalized following IL-8 administration, K327R mutant remained at the plasma membrane. Finally, K327R mutant failed to promote the recruitment of β-arrestin2, as estimated by imagery and bioluminescence resonance transfer. As a consequence, the activation of intracellular signaling, including both early events such as ERK phosphorylation and the increase in calcium flux, and the latter activation of the AP1 and NF-κB transcription factors, was blunted.ConclusionsOverall, our results demonstrate that CXCR2 ubiquitination on K327 residue modulates agonist-activated CXCR2 cell sorting and intracellular signaling. Thus, the inhibition of K327 ubiquitination might emerge as an effective mean to curb exacerbated CXCR2 signaling in several pathological conditions, such as inflammatory diseases and cancer.

【 授权许可】

Unknown   
© Leclair et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.