Letter abstract
Nature Cell Biology 11, 1143 - 1149 (2009)
Published online: 16 August 2009 | Corrected online: 8 September 2009 | doi:10.1038/ncb1929
There is an Erratum (October 2009) associated with this Letter.
Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity
Derrick J. Gibbings1, Constance Ciaudo1, Mathieu Erhardt1 & Olivier Voinnet1
In animals, P-bodies or GW-bodies appear to cause the congregation of proteins involved in microRNA (miRNA)-mediated post-transcriptional silencing. The localization of P-bodies does not overlap with that of known organelles and are thus considered independent of lipid bilayers. Nonetheless, an miRNA effector protein, argonaute 2 (AGO2), was initially identified as membrane-associated, and some miRNAs have been found in secreted vesicles (exosomes) that derive from endo-lysosomal compartments called multivesicular bodies (MVBs). Proteins can be sorted in a ubiquitin-dependent manner into MVBs by three heteromeric subcomplexes, collectively termed ESCRT (endosomal sorting complex required for transport), to be further secreted in exosomes and/or degraded by the lysosome. Here we show that GW-bodies containing GW182 and AGO2, two main components of the RNA-induced silencing complex (RISC), are distinct from P-bodies due to their congregation with endosomes and MVBs. Moreover, miRNAs and miRNA-repressible mRNAs are enriched at these cellular membranes, suggesting that endosomes and/or MVBs are sites of miRNA-loaded RISC (miRISC) accumulation and, possibly, action. We further show that purified exosome-like vesicles secreted by MVBs are considerably enriched in GW182, but not P-body components, AGO2 or miRNA-repressible mRNA. Moreover, cells depleted of some ESCRT components show compromised miRNA-mediated gene silencing and over-accumulate GW182, which associates with ubiquitylated proteins. Therefore, GW182, possibly in association with a fraction of miRNA-loaded AGO2, is sorted into MVBs for secretion and/or lysosomal degradation. We propose that this process promotes continuous assembly or disassembly of membrane-associated miRISCs, which is possibly required for miRNA loading or target recognition and subsequent silencing.
- IBMP-CNRS, UPR2357 Université de Strasbourg, 12 rue du Général Zimmer, 67084 Strasbourg Cedex, France.
Correspondence to: Olivier Voinnet1 e-mail: olivier.voinnet@ibmp-ulp.u-strasbg.fr
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