The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements

HeLa cytoplasmic extracts contain both 3′-5′ and 5′-3′ exonuclease activities that may play important roles in mRNA decay. Using an in vitro RNA deadenylation/decay assay, mRNA decay intermediates were trapped using phosphothioate-modified RNAs. These data indicate that 3′-5′ exonucleolytic decay is the major pathway of RNA degradation following deadenylation in HeLa cytoplasmic extracts. Immuno-depletion using antibodies specific for the exosomal protein PM-Sc175 demonstrated that the human exosome complex is required for efficient 3′-5′ exonucleolytic decay. Furthermore, 3′-5′ exonucleolytic decay was stimulated dramatically by AU-rich instability elements (AREs), implicating a role for the exosome in the regulation of mRNA turnover. Finally, PM-Sc175 protein was found to interact specifically with AREs. These data suggest that the interaction between the exosome and AREs plays a key role in regulating the efficiency of ARE-containing mRNA turnover.