Engagement of S1P1-degradative mechanisms leads to vascular leak in mice
Open Access
- 1 June 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (6), 2290-2300
- https://doi.org/10.1172/jci45403
Abstract
GPCR inhibitors are highly prevalent in modern therapeutics. However, interference with complex GPCR regulatory mechanisms leads to both therapeutic efficacy and adverse effects. Recently, the sphingosine-1-phosphate (S1P) receptor inhibitor FTY720 (also known as Fingolimod), which induces lymphopenia and prevents neuroinflammation, was adopted as a disease-modifying therapeutic in multiple sclerosis. Although highly efficacious, dose-dependent increases in adverse events have tempered its utility. We show here that FTY720P induces phosphorylation of the C-terminal domain of S1P receptor 1 (S1P1) at multiple sites, resulting in GPCR internalization, polyubiquitinylation, and degradation. We also identified the ubiquitin E3 ligase WWP2 in the GPCR complex and demonstrated its requirement in FTY720-induced receptor degradation. GPCR degradation was not essential for the induction of lymphopenia, but was critical for pulmonary vascular leak in vivo. Prevention of receptor phosphorylation, internalization, and degradation inhibited vascular leak, which suggests that discrete mechanisms of S1P receptor regulation are responsible for the efficacy and adverse events associated with this class of therapeutics.Keywords
This publication has 51 references indexed in Scilit:
- FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P 1 ) modulationProceedings of the National Academy of Sciences of the United States of America, 2010
- CD69 Suppresses Sphingosine 1-Phosophate Receptor-1 (S1P1) Function through Interaction with Membrane Helix 4Journal of Biological Chemistry, 2010
- Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kineticsThe Journal of Experimental Medicine, 2010
- FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous systemBritish Journal of Pharmacology, 2009
- The vascular S1P gradient—Cellular sources and biological significanceBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2008
- Full Pharmacological Efficacy of a Novel S1P1 Agonist That Does Not Require S1P-Like Headgroup InteractionsMolecular Pharmacology, 2008
- Principles of bioactive lipid signalling: lessons from sphingolipidsNature Reviews Molecular Cell Biology, 2008
- S1P1 Receptor Signaling Overrides Retention Mediated by Gαi-Coupled Receptors to Promote T Cell EgressImmunity, 2008
- Immunosurveillance by Hematopoietic Progenitor Cells Trafficking through Blood, Lymph, and Peripheral TissuesCell, 2007
- CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organsNature, 2006