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 () and Tadashi Yamamoto ()
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Taku Ito-Kureha: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University
Takahisa Miyao: Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences
Saori Nishijima: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University
Toru Suzuki: Laboratory for Immunogenetics, RIKEN Center for Integrative Medical Sciences
Shin-ichi Koizumi: Immune Signal Unit, Okinawa Institute of Science and Technology Graduate University
Alejandro Villar-Briones: Instrumental Analysis Section, Research Support Division, Okinawa Institute of Science and Technology Graduate University
Akinori Takahashi: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University
Nobuko Akiyama: Laboratory for Immunogenetics, RIKEN Center for Integrative Medical Sciences
Masahiro Morita: Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio
Isao Naguro: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Hiroki Ishikawa: Immune Signal Unit, Okinawa Institute of Science and Technology Graduate University
Hidenori Ichijo: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Taishin Akiyama: Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences
Tadashi Yamamoto: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19975-4

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