TY - JOUR
T1 - The CCR4–NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression
AU - Ito-Kureha, Taku
AU - Miyao, Takahisa
AU - Nishijima, Saori
AU - Suzuki, Toru
AU - Koizumi, Shin ichi
AU - Villar-Briones, Alejandro
AU - Takahashi, Akinori
AU - Akiyama, Nobuko
AU - Morita, Masahiro
AU - Naguro, Isao
AU - Ishikawa, Hiroki
AU - Ichijo, Hidenori
AU - Akiyama, Taishin
AU - Yamamoto, Tadashi
N1 - Funding Information:
This study was partially supported by JSPS KAKENHI Grant Number15K19140 (T.Y.), a Grant for a Joint Research Project of the Institute of Medical Science at the University of Tokyo (T.K. and T.A.), Grants-in-Aid for Scientific Research from JSPS (17H04038 and 20H03441) (T.A.), and by support from the Okinawa Institute of Science and Technology Graduate University.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-19975-4
DO - 10.1038/s41467-020-19975-4
M3 - Article
C2 - 33268794
AN - SCOPUS:85097023120
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6169
ER -