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Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity.

ABSTRACT: Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP, which encodes TAGAP, a guanosine triphosphatase (GTPase)-activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes' adhesion to the cortex through their ?1-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection. Tagap physically interacted with the cytoplasmic domain of plexin-D1 and directly stimulated the activity and signaling of the GTPase RhoA. In addition, Tagap indirectly mediated the activation of Cdc42 in response to the binding of sema3E to plexin-D1. Both RhoA and Cdc42 are key mediators of cytoskeletal and integrin dynamics in thymocytes. Knockdown of Tagap in mice suppressed the sema3E- and plexin-D1-mediated release of thymocytes that adhered within the cortex through ?1-containing integrins. This suppression led to the impaired translocation of thymocytes from the cortex to the medulla and resulted in the formation of ectopic medullary structures within the thymic cortex. Our results suggest that TAGAP variation modulates the risk of autoimmunity by altering thymocyte migration during thymic selection.

SUBMITTER: Duke-Cohan JS

PROVIDER: S-EPMC6393939 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity.

Duke-Cohan Jonathan S JS Ishikawa Yuki Y Yoshizawa Akihiro A Choi Young-Il YI Lee Chin-Nien CN Acuto Oreste O Kissler Stephan S Reinherz Ellis L EL

Science signaling 20180612 534

Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene <i>TAGAP</i>, which encodes TAGAP, a guanosine triphosphatase (GTPase)-activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes' adhesion to the cortex through their β<sub>1</sub>-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their transloca ...[more]

PMID: 29895617

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Dataset Information

Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity.

Publications

Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity.

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