The role of mRNA turnover in ageing of Caenorhabditis elegans

Abstract

Alterations of general or specific mRNA levels are a universal manifestation of the ageingprocess (Cookson, 2011). During their existence, mRNAs are constantly decorated by dynamicallychanging factors, which form messenger ribonucleoprotein (mRNP) complexes anddetermine the fate of an mRNA. Mechanisms that control mRNA turnover in the cytoplasm havebeen described in great detail but whether they might be involved in the regulation of ageingis unknown (Anderson and Kedersha, 2009; Decker and Parker, 2012). Bulk mRNA decay ineukaryotes is initiated by irreversible shortening of the poly(A)-tail, subsequent decapping andfinal 5’ to 3’ degradation (Houseley and Tollervey, 2009). We present compelling evidence thatEDC-3, a highly conserved modulator of decapping, is a novel determinant of ageing in C. elegans.Decapping has been shown to regulate protein synthesis by competing with the mechanismof translation initiation. Congruently, we find that EDC-3 regulates protein synthesis andlifespan in interaction with the previously described translation initiation factor IFE-2, an isoformof the human eIF4E, which has a conserved role in the control of ageing. We demonstrate thatEDC-3 and IFE-2 mediated regulation of C. elegans lifespan happens specifically in neuronaltissue and governs neural integrity. Further, we show that loss of EDC-3 protects from oxidativeand heat induced stress and that lifespan extension depends on the activity of Nrf-like xenobiotic-response factor SKN-1 and heat shock response factor HSF-1. Also, longevity upon loss ofEDC-3 triggers a ROS induced hormesis response that depends on SKN-1 activity.Most mRNPs accumulate in distinct cellular foci termed processing bodies (P-bodies)or stress granules, which store mRNAs stalled in modes of degradation or translation initiation(Sheth and Parker, 2003, reviewed in Decker and Parker, 2012; Franks and Lykke-Andersen,2008). Decapping factors, including EDC-3, are part of P-bodies, while IFE-2 localizes to stressgranules in C. elegans. We establish an increased formation of P-bodies and stress granulesand their co-localization upon specific stress insults and during age in the nematode, therebydefining them as biomarkers of ageing. It is unknown, whether mRNP granule formation iscause or consequence of mRNA decay and stress response (Eulalio et al., 2007). We demonstrate,that loss of SKN-1 contributes to an increased formation of P-bodies upon oxidativestress. Curiously, down-regulation of HSF-1 prevents P-body assembly specifically upon heatstress and causes age-related granulation of IFE-2. These results implicate that mRNP aggregationis a transcriptionally controlled process that contributes to maintenance of cellular stressresponse and ageing.Unexpectedly, we find that HSF-1 suppresses transcription, stability and nuclear granulationof IFE-2 during ageing. These granules co-localize with components of P-bodies at thenuclear envelope, which also have been shown to be involved in transcription regulation in thenucleus (summarized in Reines, 2012). Excitingly, we observe decreased localization of IFE-2 in the nucleus, upon depletion of EDC-3. Our findings suggest that HSF-1 modulates IFE-2function and localization during ageing, and that IFE-2 also serves as nuclear mRNP exportfactor in C. elegans. Thus, IFE-2 likely mediates the effects of the heat stress response on bothmRNA translation and degradation to influence ageing.