期刊
EMBO JOURNAL
卷 38, 期 16, 页码 -出版社
WILEY
DOI: 10.15252/embj.2018100727
关键词
Argonaute; let-7a; miRNA; translational readthrough
资金
- Wellcome Trust/DBT India Alliance Fellowship [IA/I/15/1/501833]
- Department of Science and Technology (DST)-Science and Engineering Research Board (SERB), India [YSS/2015/000989]
- Council of Scientific and Industrial Research (CSIR)-UGC, India
- KVPY (Kishore Vaigyanik Protsahan Yojana) fellowship from DST, India
- Women Scientist Scheme from DST, India [SR/WOS-A/LS-1204/2015 (G)]
- Indian Institute of Science (Part (2A) XII Plan (506/BC)), Department of Biotechnology (DBT) - Indian Institute of Science (IISc) Partnership Program for Advanced Research in Biological Sciences
- UGC (University Grants Commission), India
Translational readthrough generates proteins with extended C-termini, which often possess distinct properties. Here, we have used various reporter assays to demonstrate translational readthrough of AGO1 mRNA. Analysis of ribosome profiling data and mass spectrometry data provided additional evidence for translational readthrough of AGO1. The endogenous readthrough product, Ago1x, could be detected by a specific antibody both in vitro and in vivo. This readthrough process is directed by a cis sequence downstream of the canonical AGO1 stop codon, which is sufficient to drive readthrough even in a heterologous context. This cis sequence has a let-7a miRNA-binding site, and readthrough is promoted by let-7a miRNA. Interestingly, Ago1x can load miRNAs on target mRNAs without causing post-transcriptional gene silencing, due to its inability to interact with GW182. Because of these properties, Ago1x can serve as a competitive inhibitor of miRNA pathway. In support of this, we observed increased global translation in cells overexpressing Ago1x. Overall, our results reveal a negative feedback loop in the miRNA pathway mediated by the translational readthrough product of AGO1.
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