The CCR4–NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression

Taku Ito-Kureha, Takahisa Miyao, Saori Nishijima, Toru Suzuki, Shin ichi Koizumi, Alejandro Villar-Briones, Akinori Takahashi, Nobuko Akiyama, Masahiro Morita, Isao Naguro, Hiroki Ishikawa, Hidenori Ichijo, Taishin Akiyama, Tadashi Yamamoto

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1 Citation (Scopus)

Abstract

A repertoire of T cells with diverse antigen receptors is selected in the thymus. However, detailed mechanisms underlying this thymic positive selection are not clear. Here we show that the CCR4-NOT complex limits expression of specific genes through deadenylation of mRNA poly(A) tails, enabling positive selection. Specifically, the CCR4-NOT complex is up-regulated in thymocytes before initiation of positive selection, where in turn, it inhibits up-regulation of pro-apoptotic Bbc3 and Dab2ip. Elimination of the CCR4-NOT complex permits up-regulation of Bbc3 during a later stage of positive selection, inducing thymocyte apoptosis. In addition, CCR4-NOT elimination up-regulates Dab2ip at an early stage of positive selection. Thus, CCR4-NOT might control thymocyte survival during two-distinct stages of positive selection by suppressing expression levels of pro-apoptotic molecules. Taken together, we propose a link between CCR4-NOT-mediated mRNA decay and T cell selection in the thymus.

Original languageEnglish
Article number6169
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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