6 F, left). region (UTR) of target mRNAs and down-regulate gene expression through a posttranscriptional mechanism that remains poorly understood (Carthew and Sontheimer, 2009; Fabian et al., 2010). Initial studies proposed that miRNAs mediate gene silencing through translational inhibition of the target mRNA (Lee et al., 1993; Wightman et al., 1993; CGP 57380 Olsen and Ambros, 1999). How this translational repression is usually achieved at the molecular level still remains unclear (Humphreys et al., 2005; Pillai et al., 2005; Maroney et al., 2006; Nottrott et al., 2006; Petersen et al., 2006). Recent studies have shown that miRNAs are also capable of promoting deadenylation and subsequent degradation of target mRNAs (Bagga et al., 2005; Lim et al., 2005; Giraldez et al., 2006; Wu et al., 2006). Using large-scale quantitative experiments in mammalian cells, it was demonstrated that the effects of miRNAs on target protein expression are typically mirrored by changes in the levels of their cognate mRNAs (Baek et al., 2008; Selbach et al., 2008). Also, a recent genome-wide ribosome-profiling CGP 57380 study CD80 argued that miRNAs predominantly elicit gene silencing in mammalian cells by regulating the mRNA levels of their endogenous targets (Guo et al., 2010). These results support a model by which miRNAs, in addition to inhibiting translation, are capable of target mRNA destabilization. Both of these processes contribute toward gene silencing. The modest magnitudes of miRNA-mediated repression of endogenous targets in cells make it hard to conclusively determine the molecular mechanisms behind these processes. A recent ribosome-profiling study in zebrafish and a kinetics study in S2 cells suggest that a translational repression event, mostly likely an inhibition of translation initiation, occurs before mRNA deadenylation and decay (Bazzini et al., 2012; Djuranovic et al., 2012). However, how miRNAs coordinate the regulation of translational repression and mRNA stability is still unclear. The miRNA-induced silencing complex (miRISC) is usually a multimeric protein complex, which elicits the posttranscriptional silencing mediated by miRNAs. Two highly conserved families of CGP 57380 proteins, Argonaute (Ago) and GW182/TNRC6 (GW), represent the core components of the miRISC (Eulalio et al., 2009b). Ago proteins directly associate with miRNA and recruit GW proteins to the target mRNA. GW proteins are essential for miRNA-mediated gene silencing (Jakymiw et al., 2005; Liu et al., 2005a; Behm-Ansmant et al., 2006; Eulalio et al., 2008). Recent studies have shown that this N-terminal WG/GW motif of GW proteins interacts with Ago, whereas the C-terminal domain name of GW proteins is essential and sufficient for the gene-silencing function (Chekulaeva et al., 2009; Eulalio et al., 2009a; Lazzaretti et al., 2009; Zipprich et al., 2009). The C-terminal silencing domain name of GW proteins has been shown to associate with poly(A)-binding protein (PABP), PAN2/PAN3, and CNOT1/CCR4/CAF1 cytoplasmic deadenylase complexes (Chen et al., 2009; Fabian et al., 2009, 2011; Zekri et al., 2009; Piao et al., 2010; Braun et al., 2011; Chekulaeva et al., 2011). The recruitment of these proteins activates miRNA-induced mRNA deadenylation and subsequent destabilization. Both GW and Ago CGP 57380 proteins accumulate in specific cytoplasmic foci known as digesting bodies (P physiques or GW physiques) in metazoa (Jakymiw et al., 2005; Liu et al., 2005a,b; Pillai et al., 2005; Blau and Sen, 2005; Behm-Ansmant et al., 2006; Leung.