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Ezrin and Moesin Function Together to Promote T Cell Activation¹

Meredith H. Shaffer^*, Renell S. Dupree^*, Peimin Zhu, Ichiko Saotome, Richard F. Schmidt^*, Andrea I. McClatchey, Bruce D. Freedman and Janis K. Burkhardt^2,*

^* Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104; and Massachusetts General Hospital Cancer Center and Harvard Medical School, Department of Pathology, Charlestown, MA 02129

The highly homologous proteins ezrin, radixin, and moesin link proteins to the actin cytoskeleton. The two family members expressed in T cells, ezrin and moesin, are implicated in promoting T cell activation and polarity. To elucidate the contributions of ezrin and moesin, we conducted a systematic analysis of their function during T cell activation. In response to TCR engagement, ezrin and moesin were phosphorylated in parallel at the regulatory threonine, and both proteins ultimately localized to the distal pole complex (DPC). However, ezrin exhibited unique behaviors, including tyrosine phosphorylation and transient localization to the immunological synapse before movement to the DPC. To ask whether these differences reflect unique requirements for ezrin vs moesin in T cell signaling, we generated mice with conditional deletion of ezrin in mature T cells. Ezrin^–/– T cells exhibited normal immunological synapse organization based upon localization of protein kinase C-, talin, and phospho-ZAP70. DPC localization of CD43 and RhoGDP dissociation inhibitor, as well as the novel DPC protein Src homology region 2 domain-containing phosphatase-1, was also unaffected. However, recruitment of three novel DPC proteins, ezrin binding protein of 50 kDa, Csk binding protein, and the p85 subunit of PI3K was partially perturbed. Biochemical analysis of ezrin^–/– T cells or T cells suppressed for moesin using small interfering RNA showed intact early TCR signaling, but diminished levels of IL-2. The defects in IL-2 production were more pronounced in T cells deficient for both ezrin and moesin. These cells also exhibited diminished phospholipase C-1 phosphorylation and calcium flux. We conclude that despite their unique movement and phosphorylation patterns, ezrin and moesin function together to promote T cell activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI50098 and P01 CA093615 (to J.K.B.) and by National Institutes of Health Training Grants T32-HD07516-09 and T32-GM7229-29 (to M.H.S.).

² Address correspondence and reprint requests to Dr. Janis K. Burkhardt, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, 816D Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: jburkhar{at}mail.med.upenn.edu

³ Abbreviations used in this paper: IS, immunological synapse; DPC, distal pole complex; ERM, ezrin, radixin, and moesin; MCC, moth cytochrome c; PKC, protein kinase C; PLC, phospholipase C; SH2, Src homology 2; SHP-1, Src homology region 2 domain-containing phosphatase-1; shRNA, short hairpin RNA; siRNA, small interfering RNA; Tg, transgenic; CBP/PAG, Csk binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomain.

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