ARE-binding protein ZFP36L1 interacts with CNOT1 to directly repress translation via a deadenylation-independent mechanism

• Hiroshi, Otsuka

• Akira, Fukao

• Takumi, Tomohiro

• Shungo, Adachi

• Toru, Suzuki

• Akinori, Takahashi

• Yoshinori, Funakami

• Toru, Natsume

• Tadashi, Yamamoto

• Kent E., Duncan

• Toshinobu, Fujiwara

抄録

Eukaryotic gene expression can be spatiotemporally tuned at the post-transcriptional level by cis-regulatory elements in mRNA sequences. An important example is the AU-rich element (ARE), which induces mRNA destabilization in a variety of biological contexts in mammals and can also mediate translational control. Regulation is mediated by trans-acting factors that recognize the ARE, such as Tristetraprolin (TTP) and BRF1/ZFP36L1. Although both proteins can destabilize their target mRNAs through the recruitment of the CCR4-NOT deadenylation complex, TTP also directly regulates translation. Whether ZFP36L1 can directly repress translation remains unknown. Here, we used an in vitro translation system derived from mammalian cell lines to address this key mechanistic issue in ARE regulation by ZFP36L1. Functional assays with mutant proteins reveal that ZFP36L1 can repress translation via AU-Rich elements independent of deadenylation. ZFP36L1-mediated translation repression requires interaction between ZFP36L1 and CNOT1, suggesting that it might use a repression mechanism similar to either TPP or miRISC. However, several lines of evidence suggest that the similarity ends there. Unlike, TTP, it does not efficiently interact with either 4E-HP or GIGYF2, suggesting it does not repress translation by recruiting these proteins to the mRNA cap. Moreover, ZFP36L1 could not repress ECMV-IRES driven translation and was resistant to pharmacological eIF4A inhibitor silvestrol, suggesting fundamental differences with miRISC repression via eIF4A. Collectively, our results reveal that ZFP36L1 represses translation directly and suggest that it does so via a novel mechanism distinct from other translational regulators that interact with the CCR4-NOT deadenylase complex.

source:https://www.sciencedirect.com/science/article/pii/S0300908420300808

収録刊行物

• Biochimie

  Biochimie 174 49-56, 2020-04-18

  Elsevier

キーワード

• ZFP36L1
• AU-Rich element
• CCR4-NOT
• Deadenylation
• Translation

詳細情報

• CRID: 1050285700328583296
• NII論文ID: 120006886500
• ISSN: 03009084
• DOI: 10.1016/j.biochi.2020.04.010
• Web Site: http://id.nii.ac.jp/1394/00001380/
• Web Site: https://api.elsevier.com/content/article/PII:S0300908420300808?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S0300908420300808?httpAccept=text/plain
• 本文言語コード: en
• 資料種別: journal article
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