MicroRNAs (miRNAs) are endogenous non-coding small RNAs that post-transcriptionally regulate gene expression primarily through binding to the 3’ untranslated region (3’UTR) of target mRNAs, which results in translation inhibition and/or mRNA degradation. MiRNAs are known to play important roles in various developmental and physiological processes. Staufen is a double-stranded RNA binding protein that has been shown in Drosophila and mammals to regulate mRNA localization, translation and decay. There is only one Staufen homolog identified in C. elegans (stau-1), and the mutants of stau-1 have been shown to exhibit enhanced exogenous RNAi phenotypes and slight germline defects.
Here we demonstrate that loss-of-function mutations of stau-1 increase miRNA activity for several miRNA families. First, both stau-1(tm2266) and stau-1(q798) suppress the developmental timing defects of a let-7 family mutant, mir-48 mir-241(nDf51). In addition, stau-1(tm2266) suppresses the phenotype of a lsy-6 hypomorphic allele (ot150) in a set of bilaterally symmetric gustatory neurons (ASEL/R). Finally, stau-1(tm2266) suppresses the heterochronic phenotype of lin-4(e912); lin-14(n719) animals. Interestingly, stau-1(tm2266) does not suppress the heterochronic phenotype of the 3’UTR deletion mutant lin-14(n355n679), which removes all the predicated binding sites for lin-4 and let-7 family miRNAs. Furthermore, small RNA high-throughput sequencing analysis reveals that there is no dramatic change in most small RNA population between wild type and stau-1(tm2266), except several endogenous siRNAs in the WAGO pathway. The modulation of stau-1 on miRNA activity does not seem to be simply caused by the enhanced exogenous RNAi phenotype of stau-1 mutants since eri-1(mg366) does not suppress, but rather enhances the heterochronic phenotypes of mir-48 mir-241(nDf51) animals. Therefore, our results suggest that STAU-1 negatively modulates miRNA activity downstream of biogenesis, possibly by competing with miRNAs for binding to target mRNA 3’UTRs.
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