Cumulative effects of weakly repressive regulatory regions in the 3' UTR maintain PD-1 expression homeostasis in mammals.
Cumulative effects of weakly repressive regulatory regions in the 3' UTR maintain PD-1 expression homeostasis in mammals.
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DOI：
10.1038/s42003-023-04922-y
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发表时间：
2023-05-18
影响因子：
5.9
通讯作者：
Zhao, Wenxue
中科院分区：
文献类型：
--
作者：
Lai, Xiaoqian;Li, Rong;Wang, Panpan;Li, Meng;Xiao, Chenxi;Cao, Qiang;Li, Xin;Zhao, Wenxue
PD-1已成为癌症治疗的常见靶标。然而，PD-1表达稳态的分子调控仍不清楚。在这里，我们报告PD-1 3' UTR可以通过促进mRNA降解来显著抑制基因表达。PD-1 3' UTR的缺失抑制T细胞活性并促进T-ALL细胞增殖。有趣的是，强大的抑制可归因于许多弱调控区域的累积效应，我们表明这些区域能够更好地维持PD-1表达稳态。我们进一步鉴定了通过3' UTR调节PD-1表达的几种RNA结合蛋白（RBP），包括IGF 2BP 2、RBM 38、SRSF 7和SRSF 4。此外，尽管快速进化，PD-1 3'UTR在功能上是保守的，并通过许多常见的RBP结合位点强烈抑制基因表达。这些发现揭示了一种以前未被认识到的维持PD-1表达稳态的机制，并可能代表了一种一般模型，说明小的调控效应如何在基因表达和生物学调控中发挥重要作用。证明程序性细胞死亡-1（PD-1）3' UTR通过促进mRNA衰变和各种RNA结合蛋白（包括IGF 2BP 2、RBM 38、SRSF 7和SRSF 4）通过3' UTR调节PD-1表达来调节基因表达。
PD-1 has become a common target for cancer treatment. However, the molecular regulation of PD-1 expression homeostasis remains unclear. Here we report the PD-1 3’ UTR can dramatically repress gene expression via promoting mRNA decay. Deletion of the PD-1 3’ UTR inhibits T cell activity and promotes T-ALL cell proliferation. Interestingly, the robust repression is attributable to cumulative effects of many weak regulatory regions, which we show together are better able to maintain PD-1 expression homeostasis. We further identify several RNA binding proteins (RBPs) that modulate PD-1 expression via the 3’ UTR, including IGF2BP2, RBM38, SRSF7, and SRSF4. Moreover, despite rapid evolution, PD-1 3’ UTRs are functionally conserved and strongly repress gene expression through many common RBP binding sites. These findings reveal a previously unrecognized mechanism of maintaining PD-1 expression homeostasis and might represent a general model for how small regulatory effects play big roles in regulation of gene expression and biology. Demonstration that the programmed cell death-1 (PD-1) 3’ UTR plays a crucial role regulating gene expression by promoting mRNA decay and various RNA binding proteins, including IGF2BP2, RBM38, SRSF7, and SRSF4, regulate PD-1 expression via the 3’ UTR.
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肌肉闪烁的丧失1导致心脏病理和胚胎剪接同工型的持久性。
影响因子：
4.6
作者：
Dixon DM;Choi J;El-Ghazali A;Park SY;Roos KP;Jordan MC;Fishbein MC;Comai L;Reddy S
通讯作者：
Reddy S
DOI：
10.1073/pnas.82.15.4987
发表时间：
1985-01-01
影响因子：
11.1
作者：
MEIJLINK, F;CURRAN, T;VERMA, IM
通讯作者：
VERMA, IM
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B
DOI：
10.4049/jimmunol.1402550
发表时间：
2015-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bally AP;Lu P;Tang Y;Austin JW;Scharer CD;Ahmed R;Boss JM
通讯作者：
Boss JM
DOI：
10.1084/jem.20130208
发表时间：
2014-03-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lu P;Youngblood BA;Austin JW;Mohammed AU;Butler R;Ahmed R;Boss JM
通讯作者：
Boss JM