期刊
EMBO JOURNAL
卷 36, 期 14, 页码 2088-2106出版社
WILEY
DOI: 10.15252/embj.201696386
关键词
Argonaute proteins; gene silencing; microRNA; phosphorylation; RISC
资金
- NIH National Center for Research Resources (NCRR)
- Fonds de Recherche du Quebec-Sante scholarship
- Canadian Institutes of Health Research
- Deutsche Forschungsgemeinschaft (DFG) [SFB 960]
- Bavarian Genome Research Network (BayGene)
- Bavarian Systems-Biology Network (BioSysNet)
- Deutsche Forschungsgemeinschaft [SFB 960]
Argonaute proteins associate with microRNAs and are key components of gene silencing pathways. With such a pivotal role, these proteins represent ideal targets for regulatory post-translational modifications. Using quantitative mass spectrometry, we find that a C-terminal serine/threonine cluster is phosphorylated at five different residues in human and Caenorhabditis elegans. In human, hyper-phosphorylation does not affect microRNA binding, localization, or cleavage activity of Ago2. However, mRNA binding is strongly affected. Strikingly, on Ago2 mutants that cannot bind microRNAs or mRNAs, the cluster remains unphosphorylated indicating a role at late stages of gene silencing. In C. elegans, the phosphorylation of the conserved cluster of ALG-1 is essential for microRNA function in vivo. Furthermore, a single point mutation within the cluster is sufficient to phenocopy the loss of its complete phosphorylation. Interestingly, this mutant retains its capacity to produce and bind microRNAs and represses expression when artificially tethered to an mRNA. Altogether, our data suggest that the phosphorylation state of the serine/threonine cluster is important for Argonaute-mRNA interactions.
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