[HTML][HTML] Moesin controls clathrin-mediated S1PR1 internalization in T cells

A Nomachi, M Yoshinaga, J Liu, P Kanchanawong… - PLoS …, 2013 - journals.plos.org
A Nomachi, M Yoshinaga, J Liu, P Kanchanawong, K Tohyama, D Thumkeo, T Watanabe…
PLoS One, 2013journals.plos.org
The lipid mediator sphingosine 1-phosphate (S1P) regulates a wide range of cellular
activities, including vascular maturation, angiogenesis, and immune-cell trafficking. Among
the five known receptors for S1P (S1PR1-S1PR5), S1PR1 is a critical regulator of
lymphocyte trafficking: its signaling is required for lymphocyte egress from lymphoid organs,
while its down-modulation by agonist-induced internalization is a prerequisite for
lymphocyte entry into lymphoid organs from the bloodstream. Despite the importance of …
The lipid mediator sphingosine 1-phosphate (S1P) regulates a wide range of cellular activities, including vascular maturation, angiogenesis, and immune-cell trafficking. Among the five known receptors for S1P (S1PR1-S1PR5), S1PR1 is a critical regulator of lymphocyte trafficking: its signaling is required for lymphocyte egress from lymphoid organs, while its down-modulation by agonist-induced internalization is a prerequisite for lymphocyte entry into lymphoid organs from the bloodstream. Despite the importance of S1PR1 down-regulation in determining lymphocyte behavior, the molecular mechanism of its internalization in lymphocytes has not been defined. Here we show that agonist-induced S1PR1 internalization in T cells occurs via clathrin-mediated endocytosis and is regulated by moesin, an ezrin-radixin-moesin (ERM) family member. In S1P-stimulated T cells, S1PR1 relocalized within clathrin-coated vesicles (CCVs) and early endosomes, and S1PR1 internalization was blocked when clathrin was pharmacologically inhibited. Stimulating moesin-deficient T cells with S1P failed to induce S1PR1 internalization and CCV formation. Furthermore, treating moesin-deficient mice with FTY720, an S1P receptor agonist known to internalize S1PR1, caused delayed lymphopenia, and lymphocytes isolated from FTY720-treated moesin-deficient mice still responded to S1P ex vivo in chemotaxis assays. These results reveal a novel role for moesin in regulating clathrin-dependent S1PR1 internalization through CCV formation.
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