GW182 and argonaute 2 (AGO2) are core proteins of the RNA interference complex. GW182 is a scaffolding protein that physically associates with AGO2 and bridges its interactions with other proteins. A fundamental problem in biology is how scaffolding proteins adapt or contribute to differing functional demands within cells. Here we test the necessity for human GW182 proteins (paralogs TNRC6A, TNRC6B, and TNRC6C) for several mechanisms of small duplex RNA-mediated control of gene expression, including translational silencing by miRNAs, translational silencing by siRNAs, transcriptional silencing, transcriptional activation, and splicing. We find that GW182 is required for transcriptional activation and for the activity of miRNAs but is dispensable for the regulation of splicing, transcriptional silencing, and the action of siRNAs. AGO2, by contrast, is necessary for each of these processes. Our data suggest that GW182 does not alter AGO2 to make it active. Instead, GW182 organizes protein complexes around AGO2. Sometimes this higher level of organization is necessary, and sometimes it is not. AGO2 and GW182 offer an example for how a partnership between a scaffolding protein and a functional protein can be powerful but not obligatory.
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