RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development.
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 CD3zeta 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.
Gu
Yi
Y
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. yi.gu@cchmc.org
Chae
Hee-Don
HD
Siefring
Jamie E
JE
Jasti
Aparna C
AC
Hildeman
David A
DA
Williams
David A
DA
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D019169:Jurkat Cells; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D011948:Receptors, Antigen, T-Cell; C496930:RhoH protein, mouse; D014157:Transcription Factors; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D020741:rho GTP-Binding Proteins