Differential Function of Themis CABIT Domains during T Cell Development

作者：Okada Toshiyuki; Nitta Takeshi; Kaji Kentaro; Takashima Akiko; Oda Hiroyo; Tamehiro Norimasa; Goto Motohito; Okamura Tadashi; Patrick Michael S; Suzuki Harumi^*

来源：PLos One, 2014, 9(2): e89115.

DOI：10.1371/journal.pone.0089115

Themis (also named Gasp) is a newly identified Grb2-binding protein that is essential for thymocyte positive selection. Despite the possible involvement of Themis in TCR-mediated signal transduction, its function remains unresolved and controversial. Themis contains two functionally uncharacterized regions called CABIT (cysteine-containing, all-beta in Themis) domains, a nuclear localization signal (NLS), and a proline-rich sequence (PRS). To elucidate the role of these motifs in Themis's function in vivo, we established a series of mutant Themis transgenic mice on a Themis(-/-) background. Deletion of the highly conserved Core motif of CABIT1 or CABIT2 (Core1 or Core2, respectively), the NLS, or the PRS abolished Grb2-association, as well as TCR-dependent tyrosine-phosphorylation and the ability to induce positive selection in the thymus. The NLS and Core1 motifs were required for the nuclear localization of Themis, whereas Core2 and PRS were not. Furthermore, expression of Delta Core1- but not Delta Core2-Themis conferred dominant negative-type inhibition on T cell development. Collectively, our current results indicate that PRS, NLS, CABIT1, and CABIT2 are all required for positive selection, and that each of the CABIT domains exerts distinct functions during positive selection.

• 出版日期2014-2-21