4.8 Article

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

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NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -

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NATURE RESEARCH
DOI: 10.1038/s41467-020-19975-4

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  1. JSPS KAKENHI [15K19140]
  2. Institute of Medical Science at the University of Tokyo
  3. JSPS [17H04038, 20H03441]
  4. Okinawa Institute of Science and Technology Graduate University
  5. Grants-in-Aid for Scientific Research [15K19140, 20H03441, 17H04038] Funding Source: KAKEN

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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. The CCR4-NOT complex catalyzes mRNA deadenylation and hence regulates protein translation. Here the authors show that CNOT3 regulation of this complex is needed for positive selection of thymocytes via a mechanism involving inhibition of pro-apoptotic gene expression.

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