Nature Immunology
- 7, 1182 - 1190 (2006)
Published online: 8 October 2006; | doi:10.1038/ni1396
RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte developmentYi Gu1, 3, Hee-Don Chae1, 3, Jamie E Siefring1, Aparna C Jasti1, David A Hildeman2 & David A Williams11
Division of Experimental Hematology, Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. 2
Division of Immunobiology, Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. 3
These authors contributed equally to this work.
Correspondence should be addressed to David A Williams david.williams@cchmc.org or Yi Gu yi.gu@cchmc.org RhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family with unknown physiological function. Here we demonstrate that Rhoh-/- mice have impaired T cell receptor (TCR)–mediated thymocyte selection and maturation, resulting in T cell deficiency. RhoH deficiency resulted in defective CD3 phosphorylation, impaired translocation of the signaling molecule Zap70 to the immunological synapse and reduced activation of Zap70-mediated signaling in thymic and peripheral T cells. Proteomic analyses demonstrated that RhoH is a component of TCR signaling and is required for recruitment of Zap70 to the TCR through interaction with RhoH noncanonical immunoreceptor tyrosine-based activation motifs (ITAMs). In vivo reconstitution studies also demonstrated that RhoH function depends on phosphorylation of the RhoH ITAMs. These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70.
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