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First published online March 30, 2007
doi: 10.1242/10.1242/jcs.03429

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The role of GW/P-bodies in RNA processing and silencing

¹ Department of Oral Biology, University of Florida, Gainesville, FL 32610, USA
² Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada
³ Division of Rheumatology and Clinical Immunology, Department of Medicine, and Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA

^* Author for correspondence (e-mail: echan{at}ufl.edu)

Accepted 21 February 2007

	Summary

Top Summary Introduction GWBs uncovered GW body function GW body formation and... Conclusions and perspectives References

 
GW bodies, also known as mammalian P-bodies, are cytoplasmic foci involved in the post-transcriptional regulation of eukaryotic gene expression. Recently, GW bodies have been linked to RNA interference and demonstrated to be important for short-interfering-RNA- and microRNA-mediated mRNA decay and translational repression. Evidence indicates that both passenger and guide strands of short-interfering RNA duplexes can localize to GW bodies, thereby indicating that RNA-induced silencing complexes may be activated within these cytoplasmic centers. Formation of GW bodies appears to depend on both specific protein factors and RNA, in particular, microRNA. Work over the past few years has significantly increased our understanding of the biology of GW bodies, revealing that they are specialized cell components that spatially regulate mRNA turnover in various biological processes. The formation of GW bodies appears to depend on both specific protein factors and RNA, in particular, microRNA. Here, we propose a working model for GW body assembly in terms of its relationship to RNA interference. In this process, one or more heteromeric protein complexes accumulate in successive steps into larger ribonucleoprotein structures.

Key words: GW bodies, P-bodies, RNA interference, mRNA degradation, microRNA, short-interfering RNA

	Introduction

Top Summary Introduction GWBs uncovered GW body function GW body formation and... Conclusions and perspectives References

 
The control of mRNA stability plays key roles in both the post-transcriptional regulation of eukaryotic gene expression (Keene and Lager, 2005; Wilusz and Wilusz, 2004) and mRNA quality control (Fasken and Corbett, 2005). The latter involves the recognition and rapid degradation of aberrant mRNAs and takes place when translation termination occurs too early (nonsense-mediated decay) or fails to occur (non-stop decay) (Fasken and Corbett, 2005) or when translation elongation stalls (no-go decay) (Doma and Parker, 2006). In eukaryotes, mRNA turnover is regulated by two major mechanisms. One involves the multisubunit exosome, where transcripts are degraded by 3'-to-5' exonucleases (for a review, see van Hoof and Parker, 1999). The second mechanism involves cytoplasmic compartments termed GW bodies (GWBs), which spatially control mRNA turnover by the 5'-to-3' mRNA decay machinery. These discrete cytoplasmic foci, also called Dcp-containing bodies or processing (P)-bodies, constitute sites of mRNA degradation, storage and translational repression (Brengues et al., 2005; Coller and Parker, 2005; Cougot et al., 2004; Eystathioy et al., 2002; Eystathioy et al., 2003; Sheth and Parker, 2003; Van Dijk et al., 2002). Recently, they have also been shown to function in RNA interference (RNAi) (Jakymiw et al., 2005; Liu et al., 2005a; Liu et al., 2005b; Meister et al., 2005; Pillai et al., 2005; Sen and Blau, 2005).

RNAi is a post-transcriptional silencing mechanism in which small double-stranded RNA molecules induce sequence-specific degradation and/or translational repression of homologous mRNAs (for reviews, see Filipowicz et al., 2005; Meister and Tuschl, 2004; Rana, 2007; Sen and Blau, 2006; Valencia-Sanchez et al., 2006). The discovery that RNAi effector proteins (Jakymiw et al., 2005; Liu et al., 2005a; Liu et al., 2005b; Sen and Blau, 2005) and small RNAs localize to GWBs (Jakymiw et al., 2005; Pauley et al., 2006; Pillai et al., 2005), and that GWB assembly appears to be required for the proper functioning of the RNAi pathway (Jakymiw et al., 2005; Liu et al., 2005a; Meister et al., 2005), suggests that these foci are specifically involved in short-interfering RNA (siRNA)- and microRNA (miRNA)-mediated mRNA degradation and/or translational repression.

GWBs are enriched in mRNA decay factors and pools of stored messenger ribonucleoproteins (mRNPs) (Bruno and Wilkinson, 2006; Sheth and Parker, 2006). Moreover, they are dynamic structures, whose size and number appear to depend on specific intracellular processes. For instance, GWBs vary in size and number throughout the cell cycle, the largest of which are observed in late S and G2 phase (Yang et al., 2004). Furthermore, stress (Kedersha et al., 2005; Teixeira et al., 2005), cell proliferation (Yang et al., 2004), blocking mRNA decay (Andrei et al., 2005; Cougot et al., 2004; Sheth and Parker, 2003) and inhibition of translational initiation (Brengues et al., 2005; Sheth and Parker, 2003; Teixeira et al., 2005) all increase the size and number of GWBs. Conversely, blocking transcription, deadenylation of mRNAs or translational elongation decreases the size and number of GWBs (Cougot et al., 2004; Sheth and Parker, 2003). Recent studies have highlighted the importance of these structures in the regulation of mRNA turnover and provided insights into their involvement in RNA silencing. Here, we review the current understanding of GWB function, focusing on its recent links to RNAi, and discuss the role of these cytoplasmic foci in RNA-induced silencing complex (RISC) activation. We also examine the requirements for GWB formation and disassembly and propose a working model for their genesis.

	GWBs uncovered

Top Summary Introduction GWBs uncovered GW body function GW body formation and... Conclusions and perspectives References

 
GWBs were first identified and characterized in studies using an autoimmune serum from a human patient with motor and sensory neuropathy (Eystathioy et al., 2002). They were named as such because they harbor the mRNA-binding protein GW182. GW182 is characterized by glycine (G) and tryptophan (W) repeat-rich domains and a canonical RNA-recognition motif and has been demonstrated to associate with a specific subset of transcripts in HeLa cells (Eystathioy et al., 2002). The finding that a set of mammalian proteins involved in mRNA degradation – Dcp1/2, Xrn1 and LSm1-7 – localize to similar prominent cytoplasmic foci (Bashkirov et al., 1997; Eystathioy et al., 2003; Ingelfinger et al., 2002; Van Dijk et al., 2002), and that GWBs are active sites of mRNA decay in human cells (Cougot et al., 2004), indicated that GWBs are involved in the spatial regulation of mRNA turnover, and more specifically, a selective 5'-to-3' mRNA degradation pathway. Concurrent studies identified GWB-related structures referred to as P-bodies in budding yeast, and these were found to play a role in mRNA decapping and 5'-to-3' decay (Sheth and Parker, 2003). In particular, Sheth and Parker demonstrated that insertion of a poly(G) tract into mRNAs, which blocks 5'-to-3' exonuclease activity, causes accumulation of decay intermediates within P-bodies, suggesting that the mRNA decay process is associated with them (Sheth and Parker, 2003).

These bodies are thought to be conserved in budding yeast and mammals because both the yeast P-bodies and mammalian GWBs contain activators of decapping and decapping enzymes (Cougot et al., 2004; Eystathioy et al., 2003; Ingelfinger et al., 2002; Lykke-Andersen, 2002; Segal et al., 2006; Sheth and Parker, 2003; Van Dijk et al., 2002). Note, however, that GWBs differ from yeast P-bodies in that they contain translation initiation factors and other proteins that have no yeast counterparts, such as factors involved in RNAi [e.g. GW182 and Argonaute (Ago) proteins] (Anderson and Kedersha, 2006; Segal et al., 2006). Furthermore, there are functional differences between GWBs and yeast P-bodies in terms of their responses to stress and cell growth (Schneider et al., 2006). For example, P-bodies increase in size and number during growth limitation, increased cell density, and stress (Teixeira et al., 2005), whereas GWBs increase in size and number in proliferating cells (Yang et al., 2004) and dynamically interact with stress granules in stressed mammalian cells (Kedersha et al., 2005). Therefore, one needs to be cautious when generalizing about these structures because differences do exist, not only between species but even within a population of GWBs in a single mammalian cell (Fig. 1). Interestingly, a recent report similarly found that some GW/P-bodies that contain Mex-3B, a newly described class of human RNA-binding protein that localizes to GW/P-bodies, are also devoid of Dcp1 (Buchet-Poyau et al., 2007). The function of a particular GW/P-body may therefore depend on its organization or composition.

View larger version (54K): [in this window] [in a new window]   Fig. 1. GW bodies (GWBs) are heterogeneous structures with obvious differences in protein composition. (Top) HEp-2 cells stained with human anti-GWB serum (a prototype serum often used as a GWB marker and known to contain antibodies to GW182, hAgo2 and Ge-1, but not Dcp1; green) and rabbit anti-Dcp1 antibody (often used as a marker for P-bodies; red) demonstrate that not all GWBs contain Dcp1. (Bottom) HEp-2 cells stained with mouse anti-hAgo2 monoclonal (green) and rabbit anti-RCK/p54 (red) polyclonal antibodies demonstrate that not all foci containing RCK/p54 contain hAgo2. Conversely, not all foci that stain for hAgo2 contain RCK/p54. Arrows, GWBs that do not contain both protein factors. Arrowheads, GWBs that do contain both protein factors. Nuclei (blue) were counterstained with DAPI. Bar, 10 µm.

	GW body function

Top Summary Introduction GWBs uncovered GW body function GW body formation and... Conclusions and perspectives References

 
mRNA degradation
The decay of mRNA in GW/P-bodies is thought to occur by a 5'-to-3' exonucleolytic process, which first requires the removal of the 3'-poly(adenosine) [poly(A)] tail – deadenylation. Subsequently, the 5' mRNA cap is irreversibly removed by a decapping complex and the body of the mRNA is degraded by the 5'-to-3' exonuclease Xrn1 (for a review, see Coller and Parker, 2004). Evidence also suggests that GW/P-bodies can regulate translation (Bhattacharyya et al., 2006; Coller and Parker, 2005; Ferraiuolo et al., 2005; Pillai et al., 2005) and store mRNAs (Bhattacharyya et al., 2006; Brengues et al., 2005; Pillai et al., 2005). Moreover, GW/P-bodies also appear to be involved in other mRNA decay pathways, such as nonsense mediated decay (NMD), AU-rich element (ARE)-mediated decay (AMD) and stress-induced decay (SID).

NMD is a surveillance mechanism that removes aberrant mRNA transcripts containing premature termination codons. Several factors involved in NMD, including UPF1-3, SMG5 and SMG7, as well as reporter mRNAs harboring nonsense mutations have been found to localize to GW/P-bodies (Fukuhara et al., 2005; Sheth and Parker, 2006; Unterholzner and Izaurralde, 2004), which links these foci and the NMD process. GWBs have also been linked to AMD, a decay process involving messages containing AREs in the 3'-untranslated region (UTR). In particular, depletion of three GWB proteins, Xrn1, LSm1 or 4E-T, has been demonstrated to inhibit AMD (Ferraiuolo et al., 2005; Stoecklin et al., 2006). Moreover, evidence also indicates that the ARE-binding protein TTP, which is known to destabilize ARE-containing mRNAs, localizes to GWBs (Kedersha et al., 2005) and interacts with and activates the decapping complex (Fenger-Gron et al., 2005; Lykke-Andersen and Wagner, 2005). Finally, the observation that the size and number of P-bodies increases during stress in budding yeast cells (Teixeira et al., 2005) and that GWBs can be induced to form and interact with stress granules by specific stresses in mammalian cells demonstrates their importance in SID (Kedersha et al., 2005). However, because budding yeast cells lack stress granules, the mechanism of SID probably differs from that in higher eukaryotes.

In mammalian cells, GWBs and stress granules have been reported to be compositionally and morphologically distinct structures (Cougot et al., 2004; Kedersha et al., 2005); however, evidence indicates that they are functionally and spatially linked (Kedersha et al., 2005). Interestingly, both entities share an assortment of proteins (e.g. CPEB1, Rck/p54, FAST, Xrn1, eIF4 and TTP) and a single class of reporter mRNA has been observed within both GWBs and stress granules (Kedersha et al., 2005; Wilczynska et al., 2005). Moreover, overexpression of TTP and CPEB1, a translational regulator, induces the fusion of stress granules and GWBs, which suggests that these proteins regulate the dynamic interaction between these two structures (Kedersha et al., 2005; Wilczynska et al., 2005). One model is that stress granules serve as mRNA triage sites where transcripts are sorted for storage, re-initiation of translation, or degradation, and that mRNAs targeted for decay are exported from stress granules to GWBs (Kedersha et al., 2005). Regardless of the mechanistic differences between yeast and higher eukaryotes, it is evident that GW/P-bodies have multiple functions, the ultimate goal being mRNA decay and/or storage. It is therefore not surprising that these foci comprise multiple factors and that their specific structural composition and organization probably determines their mode of action.

RNAi
Several groups recently demonstrated a link between GWBs and RNAi (Jakymiw et al., 2005; Liu et al., 2005a; Liu et al., 2005b; Pillai et al., 2005; Sen and Blau, 2005). In particular, the Ago family of proteins, Ago1-4, which are components of RISC, the key effector complex of RNAi, were found to be concentrated in GWBs (Jakymiw et al., 2005; Liu et al., 2005a; Liu et al., 2005b; Sen and Blau, 2005). Moreover, GWBs also appeared to be sites involved in miRNA-mediated repression of targeted mRNAs (Liu et al., 2005b).

In addition, we and others demonstrated that hAgo2, the catalytic engine of RNA silencing, associates with several components of GWBs, including GW182 (Jakymiw et al., 2005; Liu et al., 2005a; Liu et al., 2005b). Moreover, depletion of GW182, which disrupts GWBs (Yang et al., 2004), perturbs both siRNA- and miRNA-mediated repression (Jakymiw et al., 2005; Liu et al., 2005a). Dominant interfering GW182 and hAgo2 mutants also disrupt GWB formation and similarly inhibit RNA silencing (Jakymiw et al., 2005). The impairment in RNAi appears to depend on blocking the localization of hAgo2 to GWBs (Jakymiw et al., 2005). Indeed, hAgo2 constructs containing point mutations that prevent siRNA binding and localization to GWBs do not repress target reporter mRNA, despite being tethered to the target (Liu et al., 2005a). Additional evidence for the involvement of GW182 and GWB in RNAi comes from studies of the Drosophila melanogaster ortholog and Caenorhabditis elegans functional analog (Ding et al., 2005; Rehwinkel et al., 2005; Schneider et al., 2006). In particular, studies in Drosophila indicate that GW182 interacts with Ago1 and promotes degradation of a subset of miRNA-mediated-decay mRNA targets (Behm-Ansmant et al., 2006). GW182 may thus function as a molecular scaffold that bridges components of the miRNA pathway with mRNA decay enzymes (Behm-Ansmant et al., 2006).

A point of contention is whether GW182 and GWBs are important for both slicer-dependent mechanisms (i.e. siRNA-mediated RNAi) and miRNA-mediated repression or only the latter. Work from our laboratory has demonstrated that transfected fluorophore-labeled siRNAs associate with GW182 protein complexes and localize to GWBs and that GW182 and GWBs play an important role in slicer-mediated functions (Jakymiw et al., 2005). Moreover, Liu et al. found that suppression of GW182 similarly impairs, albeit not as effectively, the ability of an siRNA to silence its target by mRNA cleavage (Liu et al., 2005a). In addition, silencing of the GWB protein TNRC6B, a GW182 paralog, inhibits cleavage of an mRNA reporter gene containing a target site perfectly complementary to an endogenous miRNA (Meister et al., 2005). TNRC6B thus appears to be important for slicer-dependent mechanisms and subsequent mRNA degradation.

Other work has indicated a greater role for GW182 and GWBs in miRNA-mediated translational repression by demonstrating, using various reporter systems, that depletion of GW182 impairs miRNA function (Chu and Rana, 2006; Liu et al., 2005a; Rehwinkel et al., 2005). Furthermore, depletion of GW182 has also been demonstrated to result in alterations of mRNA expression profiles very similar to those seen in cells depleted of the Drosophila miRNA effector Ago1 and not the siRNA effector Ago2, which suggests that GW182 functions in the miRNA pathway (Behm-Ansmant et al., 2006). Whether the above disparities are because of the use of different reporter systems (i.e. exogenously introduced versus endogenous reporter systems), species variations or GW182 redundancy (three paralogs have been identified in humans) will require further study. Interestingly, in the study implicating GW182 in slicer-mediated function, we used siRNAs with a fluorophore conjugated to the 5'-end of the guide strand (Jakymiw et al., 2005). The fluorophore might therefore have interfered with the siRNA activity, making it behave more like an miRNA by producing imperfect base-pairing between siRNA and target. Regardless, the studies collectively demonstrate a role for GW182 and GWBs in RNAi. More work will be needed to determine whether GWBs represent converging sites for siRISC and/or miRISC.

MiRNAs have similarly been identified within GWBs and demonstrated to associate with GW182 protein complexes (Pauley et al., 2006; Pillai et al., 2005). The identification of siRNA and/or miRNA within GWBs suggests that RISC activation, activity and/or recycling may occur within GWBs. Are GWBs sites of RISC activation and activity? Evidence supporting this possibility includes the observation that Ago2, a known GWB component, is directly involved in passenger-strand cleavage of double-stranded siRNAs during RISC assembly (Matranga et al., 2005; Rand et al., 2005). Also, following transient transfection of HeLa cells with a fluorophore-labeled passenger-strand siRNA duplex that has no endogenous mRNA target, the siRNA localizes to GWBs – similarly to a fluorophore-labeled-guide-strand siRNA duplex that has an endogenous mRNA target (Jakymiw et al., 2005). This suggests that the passenger strand and the guide strand localize to GWBs independently of the mRNA target and that passenger-strand cleavage and incorporation of the antisense-strand into RISC may occur within GWBs. Docking of siRNA/miRNA duplexes into RISC and its subsequent activation could therefore be early events in GWB formation. Interestingly, in fission yeast cells, a Dicer ortholog localizes to structures resembling GWBs (Carmichael et al., 2006), which suggests that GWB formation may take place even before RISC activation.

	GW body formation and structure

Top Summary Introduction GWBs uncovered GW body function GW body formation and... Conclusions and perspectives References

 
Immunogold electron microscopy of GWBs identifies cytoplasmic electron-dense structures that are 100-300 nm in diameter and which lack a membrane (Eystathioy et al., 2002; Yang et al., 2004). Closer inspection reveals that they comprise 8-10 nm strands or fibrils (Yang et al., 2004). Currently, the mechanism of GWB formation is not well understood. It remains unclear whether GWBs form de novo or whether mRNAs and their associated proteins are targeted to pre-existing structures. Furthermore, we do not know whether GWB components are targeted to GWBs independently or as part of larger complexes that form higher-order structures that can be visualized by conventional light microscopy. RNAi-mediated depletion of specific GWB factors in human cells has demonstrated an interdependence of each of the proteins for their accumulation in GWBs (see Table 1). GWBs may thus form by the assembly of one or more heteromeric protein complexes on mRNAs that can amass into larger mRNP structures. The finding that specific enzymes involved in decapping and subsequent 5'-to-3' degradation are dispensable for GWB formation (Andrei et al., 2005) – unlike factors involved at earlier stages of mRNA decay (e.g. mRNA 3'-end trimming) – indicates that earlier stages are more crucial for GWB assembly.

Fig. 2 shows our working model, in which several factors, including RISC, initially interact with the target mRNA to form a specific RNP structure dependent on the type of decay or storage process that will occur (e.g. siRNA-mediated decay versus miRNA-mediated translational repression). This results in the recruitment of other protein complexes, which depend on the composition of the initial RNP; so their final composition or structural organization promotes the proper decay mechanism and/or storage of the mRNA. Such a model would explain why disruption of GWBs by depletion of other GWB components, such as LSm1 or RCK/p54, does not necessarily translate into impaired RISC activity (Chu and Rana, 2006), whereas silencing of GW182 does (Jakymiw et al., 2005). One possibility is that GW182 exists in a smaller RNP complex with RISC components (e.g. hAgo2) that is undetectable by fluorescence microscopy and supersedes the requirement of LSm1 and RCK/p54 for initial target recognition and endonucleolytic cleavage or translation repression. Moreover, not all silencing of GWB factors impairs formation of GWBs equivalently. Interestingly, Andrei et al. have demonstrated that silencing of RCK/p54 has a less pronounced effect on the disassembly of GWBs compared with other factors (Andrei et al., 2005).

View larger version (75K): [in this window] [in a new window]   Fig. 2. A model linking RNAi and GW body (GWB) assembly and function. RNAi activity is triggered by siRNA/miRNA duplexes, which are first processed from either double-stranded RNA (dsRNA) or precursor microRNA (pre-miRNA), respectively, by the RNase-III-type endonuclease Dicer. These duplexes are then incorporated into RISC, where the passenger strand (black) is either cleaved and degraded or removed by the bypass mechanism (Matranga et al., 2005). This activation process and assembly of the guide strand (red) into RISC is thought to initiate early stages of GWB formation. Subsequent targeting by RISC results in further recruitment of one or more heteromeric protein complexes (which could include GW182 and RCK/p54) on the mRNA, which forms a specific RNP structure that causes post-transcriptional inhibition of gene expression (through siRNA-mediated cleavage or miRNA-mediated translational repression, depending on the degree of complementarity between the guide-strand RNA and its target mRNA). The targeted mRNA is eventually degraded by further recruitment of 5'-to-3' mRNA decay factors, which include the deadenylase Ccr4, decapping factors (LSm1-7 ring, Dcp complex) and the 5'-to-3' exonuclease Xrn1. The accumulation of RNA decay factors during degradation could be responsible for the size increases in GWBs, which makes them visible by conventional light microscopy. ORF, open reading frame.

The integrity of GWBs also appears to depend on RNA. Studies in yeast and mammals indicate that mRNA is an integral component of GW/P-bodies (Andrei et al., 2005; Cougot et al., 2004; Eystathioy et al., 2002; Teixeira et al., 2005). Furthermore, silencing of Drosha or its required partner protein, DGCR8, which together comprise the microprocessor complex and are responsible for processing long nuclear primary miRNA (pri-miRNA) transcripts to70-nucleotide hairpin precursor miRNA (pre-miRNA), depletes cells of mature miRNA and causes the disappearance of GWBs (Pauley et al., 2006). This suggests that miRNAs are required for the formation of GWBs. Although the possibility that the effect is indirect cannot be ruled out, this seems unlikely because siRNA transfected into Drosha-deficient cells can serve as a surrogate for miRNA and drive the reappearance of GWBs.

The dependence of GWBs on miRNA means that many of the functions attributed to GWBs similarly may depend on miRNAs in mammalian cells. Processes such as translational repression, mRNA decay and storage depend on miRNAs. Furthermore, miRNAs are involved in ARE-mediated degradation events (Jing et al., 2005). All of these processes are associated with GWBs. The primary function of GWBs might therefore be to provide a microenvironment for miRNA-mRNA interactions that lead to translational inhibition and/or mRNA degradation. Whether NMD processes share this requirement for miRNAs requires further study. Nevertheless, if this hypothesis holds, a more appropriate name for these foci in mammalian cells may be miRNA-induced bodies (miRBs).

	Conclusions and perspectives

Top Summary Introduction GWBs uncovered GW body function GW body formation and... Conclusions and perspectives References

 
Recent cell biology and biochemical findings have significantly enhanced our understanding of the spatial regulation of mRNA decay and/or storage within eukaryotic cells, and it is now evident that dynamic cytoplasmic foci, GW/P-bodies, are crucial for these processes. The discovery of a functional link between GWBs and RNAi has been particularly instrumental in allowing us to decipher the complexities of how small RNAs and their cognate proteins are involved in post-transcriptional gene regulation (for reviews, see Engels and Hutvagner, 2006; Eulalio et al., 2007; Jackson and Standart, 2007; Pillai et al., 2007; Rana, 2007).

Our understanding of the cell biology of RNAi and its relationship to GWBs is still limited, however. During the course of writing this review, several articles were published demonstrating that a large fraction of miRNAs and Ago proteins reside in the cytoplasm (Leung et al., 2006; Maroney et al., 2006; Nottrott et al., 2006), in particular on mRNAs being actively translated by polyribosomes (Maroney et al., 2006; Nottrott et al., 2006). Furthermore, inhibiting translation initiation or inducing stress has been shown to result in localization of miRNA and Ago to stress granules (Leung et al., 2006). Data from these studies suggest that miRNPs first associate with and suppress actively translating mRNAs in the cytoplasm prior to completely dropping off ribosomes. Upon miRNA-mediated repression, these mRNA are then believed to be targeted to either stress granules for storage or sorted and shuttled to GWBs for decay. Given the close relationship between GWBs and stress granules, this would not be surprising; however, one needs to be cautious in interpreting the stress granule data because stress granules are generally observed only during a stress response, whereas GWBs are present continuously (Teixeira et al., 2005). Alternatively, inhibition of actively translating polysomes on mRNAs by miRISCs might directly trigger the recruitment of RNP complexes involved in either early stages of GWB formation and/or GWB targeting. Much more work will be needed if we are to completely understand the interactions between GWBs and other mRNP structures and the significance of their heterogeneous composition.

Finally, although numerous studies have demonstrated that RNAi occurs in the cytoplasm of a cell, a growing number of reports suggest that it occurs within the nucleus as well. In particular, recent studies in human cells have implicated the RNAi effector proteins hAgo1 and hAgo2 in the post-transcriptional modulation of gene expression in the nucleus (Robb et al., 2005) and transcriptional silencing (Janowski et al., 2006; Kim et al., 2006). Furthermore, transfection of siRNAs targeting small nuclear RNAs (e.g. 7SK and U6 RNA) leads to their translocation into the nucleus and silencing of the target genes (Berezhna et al., 2006). How the cytoplasmic and nuclear RNAi pathways are interrelated and the relationship between GWBs and nuclear RNAi are currently unclear. Biochemical evidence suggests that these processes are linked by a common requirement for Ago proteins; however, immunofluorescence studies using a newly developed mouse monoclonal antibody specific for hAgo2 show no evidence of nuclear localization of this endogenous protein (Ikeda et al., 2006), which is consistent with our earlier work using polyclonal autoimmune sera (Jakymiw et al., 2006). Regardless, the recent findings that GWBs appear to function in siRNA/miRNA-mediated forms of post-transcriptional regulation, the apparent requirement for GWBs in Drosophila (Schneider et al., 2006) and C. elegans (Ding et al., 2005) development, and the knowledge that small RNAs regulate many cellular activities (Ambros, 2004), including differentiation, stem cell division, and apoptosis, underline the importance of GWBs for many biological processes.

	Acknowledgments

 
We thank Jens Lykke-Andersen (University of Colorado) and Tom Hobman (University of Alberta) for their generosity in providing valuable antibody reagents. We apologize to colleagues whose interesting work could not be cited owing to space limitations. This work was supported in part by the National Institutes of Health Grant AI47859 and the Canadian Institutes for Health Research Grant MOP-38034 and the Canadian Breast Cancer Research Foundation Grant 16992.

	Footnotes

 
siRNAs are small RNAs of21 nucleotides in length and are derived from the progressive cleavage of long, perfectly complementary double-stranded RNAs (dsRNAs) by an RNase-III-type endonuclease, Dicer. They can originate from long dsRNAs transiently introduced into cells by transfection or stably expressed hairpin-containing dsRNA precursors derived from DNA constructs. They assemble into an RNA-protein complex known as the RNA-induced silencing complex (RISC or siRISC), which includes Argonaute 2 (Ago2), a key component of RNAi that possesses endonuclease activity. RISC then targets and cleaves perfectly complementary mRNAs, generating 5' and 3' fragments, which are subsequently degraded. MiRNAs are similar in size to siRNAs but originate from hairpin-containing precursors encoded by the genome. These non-coding precursors of miRNAs have double-stranded regions with imperfect complementarity and are sequentially processed by RNase-III-type enzymes Drosha and Dicer into mature miRNAs. The mature miRNAs then assemble into an RNA-protein complex referred to as the miRNA ribonucleoprotein complex (miRNP or miRISC), which is structurally similar to RISC and contains at least one Argonaute protein. Multiple copies of miRNPs are directed to the 3'-UTR of certain mRNAs that have imperfect complementarity to the bound miRNAs. In plants, miRNAs cleave their regulated target mRNA, whereas in mammals miRNAs promote translational repression of the targeted mRNA. Until recently, this was considered the major distinction between siRISC and miRISC in mammalian cells. However, new evidence suggests that miRNAs can also regulate mRNA degradation similarly to siRNAs (Bagga et al., 2005; Jing et al., 2005; Yekta et al., 2004), thus blurring the distinction between the two small-RNA-mediated silencing complexes.

Stress granules are large RNP particles that store non-translating mRNAs when cells are exposed to environmental stresses, but are absent in budding yeast cells.

	References

Top Summary Introduction GWBs uncovered GW body function GW body formation and... Conclusions and perspectives References

 

Ambros, V. (2004). The functions of animal microRNAs. Nature 431, 350-355.[CrossRef][Medline]

Anderson, P. and Kedersha, N. (2006). RNA granules. J. Cell Biol. 172, 803-808.[Abstract/Free Full Text]

Andrei, M. A., Ingelfinger, D., Heintzmann, R., Achsel, T., Rivera-Pomar, R. and Luhrmann, R. (2005). A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies. RNA 11, 717-727.[Abstract/Free Full Text]

Bagga, S., Bracht, J., Hunter, S., Massirer, K., Holtz, J., Eachus, R. and Pasquinelli, A. E. (2005). Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553-563.[CrossRef][Medline]

Bashkirov, V. I., Scherthan, H., Solinger, J. A., Buerstedde, J. M. and Heyer, W. D. (1997). A mouse cytoplasmic exoribonuclease (mXRN1p) with preference for G4 tetraplex substrates. J. Cell Biol. 136, 761-773.[Abstract/Free Full Text]

Behm-Ansmant, I., Rehwinkel, J., Doerks, T., Stark, A., Bork, P. and Izaurralde, E. (2006). mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 20, 1885-1898.[Abstract/Free Full Text]

Berezhna, S. Y., Supekova, L., Supek, F., Schultz, P. G. and Deniz, A. A. (2006). siRNA in human cells selectively localizes to target RNA sites. Proc. Natl. Acad. Sci. USA 103, 7682-7687.[Abstract/Free Full Text]

Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I. and Filipowicz, W. (2006). Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125, 1111-1124.[CrossRef][Medline]

Brengues, M., Teixeira, D. and Parker, R. (2005). Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science 310, 486-489.[Abstract/Free Full Text]

Bruno, I. and Wilkinson, M. F. (2006). P-bodies react to stress and nonsense. Cell 125, 1036-1038.[CrossRef][Medline]

Buchet-Poyau, K., Courchet, J., Hir, H. L., Seraphin, B., Scoazec, J. Y., Duret, L., Domon-Dell, C., Freund, J. N. and Billaud, M. (2007). Identification and characterization of human Mex-3 proteins, a novel family of evolutionarily conserved RNA-binding proteins differentially localized to processing bodies. Nucleic Acids Res. In press.

Carmichael, J. B., Stoica, C., Parker, H., McCaffery, J. M., Simmonds, A. J. and Hobman, T. C. (2006). RNA interference effector proteins localize to mobile cytoplasmic puncta in Schizosaccharomyces pombe. Traffic 7, 1032-1044.[CrossRef][Medline]

Chu, C. Y. and Rana, T. M. (2006). Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 4, e210.[CrossRef][Medline]

Coller, J. and Parker, R. (2004). Eukaryotic mRNA decapping. Annu. Rev. Biochem. 73, 861-890.[CrossRef][Medline]

Coller, J. and Parker, R. (2005). General translational repression by activators of mRNA decapping. Cell 122, 875-886.[CrossRef][Medline]

Cougot, N., Babajko, S. and Seraphin, B. (2004). Cytoplasmic foci are sites of mRNA decay in human cells. J. Cell Biol. 165, 31-40.[Abstract/Free Full Text]

Ding, L., Spencer, A., Morita, K. and Han, M. (2005). The developmental timing regulator AIN-1 interacts with miRISCs and may target the argonaute protein ALG-1 to cytoplasmic P bodies in C. elegans. Mol. Cell 19, 437-447.[CrossRef][Medline]

Doma, M. K. and Parker, R. (2006). Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature 440, 561-564.[CrossRef][Medline]

Engels, B. M. and Hutvagner, G. (2006). Principles and effects of microRNA-mediated post-transcriptional gene regulation. Oncogene 25, 6163-6169.[CrossRef][Medline]

Eulalio, A., Behm-Ansmant, I. and Izaurralde, E. (2007). P bodies: at the crossroads of post-transcriptional pathways. Nat. Rev. Mol. Cell Biol. 8, 9-22.[CrossRef][Medline]

Eystathioy, T., Chan, E. K., Tenenbaum, S. A., Keene, J. D., Griffith, K. and Fritzler, M. J. (2002). A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles. Mol. Biol. Cell 13, 1338-1351.[Abstract/Free Full Text]

Eystathioy, T., Jakymiw, A., Chan, E. K., Seraphin, B., Cougot, N. and Fritzler, M. J. (2003). The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies. RNA 9, 1171-1173.[Abstract/Free Full Text]

Fasken, M. B. and Corbett, A. H. (2005). Process or perish: quality control in mRNA biogenesis. Nat. Struct. Mol. Biol. 12, 482-488.[CrossRef][Medline]

Fenger-Gron, M., Fillman, C., Norrild, B. and Lykke-Andersen, J. (2005). Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping. Mol. Cell 20, 905-915.[CrossRef][Medline]

Ferraiuolo, M. A., Basak, S., Dostie, J., Murray, E. L., Schoenberg, D. R. and Sonenberg, N. (2005). A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay. J. Cell Biol. 170, 913-924.[Abstract/Free Full Text]

Filipowicz, W., Jaskiewicz, L., Kolb, F. A. and Pillai, R. S. (2005). Post-transcriptional gene silencing by siRNAs and miRNAs. Curr. Opin. Struct. Biol. 15, 331-341.[CrossRef][Medline]

Fukuhara, N., Ebert, J., Unterholzner, L., Lindner, D., Izaurralde, E. and Conti, E. (2005). SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway. Mol. Cell 17, 537-547.[CrossRef][Medline]

Ikeda, K., Satoh, M., Pauley, K. M., Fritzler, M. J., Reeves, W. H. and Chan, E. K. (2006). Detection of the argonaute protein Ago2 and microRNAs in the RNA induced silencing complex (RISC) using a monoclonal antibody. J. Immunol. Methods 317, 38-44.[CrossRef][Medline]

Ingelfinger, D., Arndt-Jovin, D. J., Luhrmann, R. and Achsel, T. (2002). The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci. RNA 8, 1489-1501.[Abstract]

Jackson, R. J. and Standart, N. (2007). How do microRNAs regulate gene expression? Sci. STKE 2007, re1.[Abstract/Free Full Text]

Jakymiw, A., Lian, S., Eystathioy, T., Li, S., Satoh, M., Hamel, J. C., Fritzler, M. J. and Chan, E. K. (2005). Disruption of GW bodies impairs mammalian RNA interference. Nat. Cell Biol. 7, 1267-1274.[Medline]

Jakymiw, A., Ikeda, K., Fritzler, M. J., Reeves, W. H., Satoh, M. and Chan, E. K. (2006). Autoimmune targeting of key components of RNA interference. Arthritis Res. Ther. 8, R87.[CrossRef][Medline]

Janowski, B. A., Huffman, K. E., Schwartz, J. C., Ram, R., Nordsell, R., Shames, D. S., Minna, J. D. and Corey, D. R. (2006). Involvement of AGO1 and AGO2 in mammalian transcriptional silencing. Nat. Struct. Mol. Biol. 13, 787-792.[CrossRef][Medline]

Jing, Q., Huang, S., Guth, S., Zarubin, T., Motoyama, A., Chen, J., Di Padova, F., Lin, S. C., Gram, H. and Han, J. (2005). Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623-634.[CrossRef][Medline]

Kedersha, N., Stoecklin, G., Ayodele, M., Yacono, P., Lykke-Andersen, J., Fitzler, M. J., Scheuner, D., Kaufman, R. J., Golan, D. E. and Anderson, P. (2005). Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J. Cell Biol. 169, 871-884.[Abstract/Free Full Text]

Keene, J. D. and Lager, P. J. (2005). Post-transcriptional operons and regulons co-ordinating gene expression. Chromosome Res. 13, 327-337.[CrossRef][Medline]

Kim, D. H., Villeneuve, L. M., Morris, K. V. and Rossi, J. J. (2006). Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nat. Struct. Mol. Biol. 13, 793-797.[CrossRef][Medline]

Leung, A. K., Calabrese, J. M. and Sharp, P. A. (2006). Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. Proc. Natl. Acad. Sci. USA 103, 18125-18130.[Abstract/Free Full Text]

Liu, J., Rivas, F. V., Wohlschlegel, J., Yates, J. R., III, Parker, R. and Hannon, G. J. (2005a). A role for the P-body component GW182 in microRNA function. Nat. Cell Biol. 7, 1261-1266.[Medline]

Liu, J., Valencia-Sanchez, M. A., Hannon, G. J. and Parker, R. (2005b). MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat. Cell Biol. 7, 719-723.[CrossRef][Medline]

Lykke-Andersen, J. (2002). Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay. Mol. Cell. Biol. 22, 8114-8121.[Abstract/Free Full Text]

Lykke-Andersen, J. and Wagner, E. (2005). Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes Dev. 19, 351-361.[Abstract/Free Full Text]

Maroney, P. A., Yu, Y., Fisher, J. and Nilsen, T. W. (2006). Evidence that microRNAs are associated with translating messenger RNAs in human cells. Nat. Struct. Mol. Biol. 13, 1102-1107.[CrossRef][Medline]

Matranga, C., Tomari, Y., Shin, C., Bartel, D. P. and Zamore, P. D. (2005). Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123, 607-620.[CrossRef][Medline]

Meister, G. and Tuschl, T. (2004). Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343-349.[CrossRef][Medline]

Meister, G., Landthaler, M., Peters, L., Chen, P. Y., Urlaub, H., Luhrmann, R. and Tuschl, T. (2005). Identification of novel argonaute-associated proteins. Curr. Biol. 15, 2149-2155.[CrossRef][Medline]

Nottrott, S., Simard, M. J. and Richter, J. D. (2006). Human let-7a miRNA blocks protein production on actively translating polyribosomes. Nat. Struct. Mol. Biol. 13, 1108-1114.[CrossRef][Medline]

Pauley, K. M., Eystathioy, T., Jakymiw, A., Hamel, J. C., Fritzler, M. J. and Chan, E. K. (2006). Formation of GW bodies is a consequence of microRNA genesis. EMBO Rep. 7, 904-910.[CrossRef][Medline]

Pillai, R. S., Bhattacharyya, S. N., Artus, C. G., Zoller, T., Cougot, N., Basyuk, E., Bertrand, E. and Filipowicz, W. (2005). Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science 309, 1573-1576.[Abstract/Free Full Text]

Pillai, R. S., Bhattacharyya, S. N. and Filipowicz, W. (2007). Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol. 17, 118-126.[Medline]

Rana, T. M. (2007). Illuminating the silence: understanding the structure and function of small RNAs. Nat. Rev. Mol. Cell Biol. 8, 23-36.[CrossRef][Medline]

Rand, T. A., Petersen, S., Du, F. and Wang, X. (2005). Argonaute2 cleaves the anti-guide strand of siRNA during RISC activation. Cell 123, 621-629.[CrossRef][Medline]

Rehwinkel, J., Behm-Ansmant, I., Gatfield, D. and Izaurralde, E. (2005). A crucial role for GW182 and the DCP1:DCP2 decapping complex in miRNA-mediated gene silencing. RNA 11, 1640-1647.[Abstract/Free Full Text]

Robb, G. B., Brown, K. M., Khurana, J. and Rana, T. M. (2005). Specific and potent RNAi in the nucleus of human cells. Nat. Struct. Mol. Biol. 12, 133-137.[CrossRef][Medline]

Schneider, M. D., Najand, N., Chaker, S., Pare, J. M., Haskins, J., Hughes, S. C., Hobman, T. C., Locke, J. and Simmonds, A. J. (2006). Gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development. J. Cell Biol. 174, 349-358.[Abstract/Free Full Text]

Segal, S. P., Dunckley, T. and Parker, R. (2006). Sbp1p affects translational repression and decapping in Saccharomyces cerevisiae. Mol. Cell. Biol. 26, 5120-5130.[Abstract/Free Full Text]

Sen, G. L. and Blau, H. M. (2005). Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies. Nat. Cell Biol. 7, 633-636.[CrossRef][Medline]

Sen, G. L. and Blau, H. M. (2006). A brief history of RNAi: the silence of the genes. FASEB J. 20, 1293-1299.[Abstract/Free Full Text]

Sheth, U. and Parker, R. (2003). Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science 300, 805-808.[Abstract/Free Full Text]

Sheth, U. and Parker, R. (2006). Targeting of aberrant mRNAs to cytoplasmic processing bodies. Cell 125, 1095-1109.[CrossRef][Medline]

Stoecklin, G., Mayo, T. and Anderson, P. (2006). ARE-mRNA degradation requires the 5'-3' decay pathway. EMBO Rep. 7, 72-77.[CrossRef][Medline]

Tanaka, K. J., Ogawa, K., Takagi, M., Imamoto, N., Matsumoto, K. and Tsujimoto, M. (2006). RAP55, a cytoplasmic mRNP component, represses translation in Xenopus oocytes. J. Biol. Chem. 281, 40096-40106.[Abstract/Free Full Text]

Teixeira, D., Sheth, U., Valencia-Sanchez, M. A., Brengues, M. and Parker, R. (2005). Processing bodies require RNA for assembly and contain nontranslating mRNAs. RNA 11, 371-382.[Abstract/Free Full Text]

Unterholzner, L. and Izaurralde, E. (2004). SMG7 acts as a molecular link between mRNA surveillance and mRNA decay. Mol. Cell 16, 587-596.[CrossRef][Medline]

Valencia-Sanchez, M. A., Liu, J., Hannon, G. J. and Parker, R. (2006). Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20, 515-524.[Abstract/Free Full Text]

Van Dijk, E., Cougot, N., Meyer, S., Babajko, S., Wahle, E. and Seraphin, B. (2002). Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures. EMBO J. 21, 6915-6924.[CrossRef][Medline]

van Hoof, A. and Parker, R. (1999). The exosome: a proteasome for RNA? Cell 99, 347-350.[CrossRef][Medline]

Wilczynska, A., Aigueperse, C., Kress, M., Dautry, F. and Weil, D. (2005). The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules. J. Cell Sci. 118, 981-992.[Abstract/Free Full Text]

Wilusz, C. J. and Wilusz, J. (2004). Bringing the role of mRNA decay in the control of gene expression into focus. Trends Genet. 20, 491-497.[CrossRef][Medline]

Yang, W. H., Yu, J. H., Gulick, T., Bloch, K. D. and Bloch, D. B. (2006). RNA-associated protein 55 (RAP55) localizes to mRNA processing bodies and stress granules. RNA 12, 547-554.[Abstract/Free Full Text]

Yang, Z., Jakymiw, A., Wood, M. R., Eystathioy, T., Rubin, R. L., Fritzler, M. J. and Chan, E. K. (2004). GW182 is critical for the stability of GW bodies expressed during the cell cycle and cell proliferation. J. Cell Sci. 117, 5567-5578.[Abstract/Free Full Text]

Yekta, S., Shih, I. H. and Bartel, D. P. (2004). MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594-596.[Abstract/Free Full Text]

Yu, J. H., Yang, W. H., Gulick, T., Bloch, K. D. and Bloch, D. B. (2005). Ge-1 is a central component of the mammalian cytoplasmic mRNA processing body. RNA 11, 1795-1802.[Abstract/Free Full Text]

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