LAUSR

Simple Summary In eukaryotes, the elimination of the protective cap from 5′ end of messenger RNA (mRNA) by the decapping complex is an important mechanism of mRNA decay and translation, affecting several cellular processes. In the nematode C. elegans, perturbations in decapping activity slow development and shorten the lifespan. A microarray analysis performed in mid-aged nematodes with reduced decapping activity revealed a specific role for decapping in the suppression of spermatogenic genes in germ cells during ageing. In addition, the expression of many innate immunity and detoxification genes were upregulated in the somatic cells of the mutant nematodes, despite the lack of pathogens. This upregulation appears to be mediated by the effect of aberrant decapping on both the mRNA stability and the nuclear translocation of the transcription factor PQM-1, which controls the expression of those immunity/detoxification genes. Although the decapping-mediated induction of immunity was found to be detrimental for the normal lifespan, it mitigates the paralysis in a C. elegans model of polyglutamine toxicity. These results reinforce the selectivity of decapping in the regulation of gene expression and provide a link between mRNA decapping and innate immunity in older ages that could serve as a protective mechanism for disturbed proteostasis, commonly associated with human neurodegenerative diseases. Abstract Removal of the 5′ cap structure of RNAs (termed decapping) is a pivotal event in the life of cytoplasmic mRNAs mainly catalyzed by a conserved holoenzyme, composed of the catalytic subunit DCP2 and its essential cofactor DCP1. While decapping was initially considered merely a step in the general 5′-3′ mRNA decay, recent data suggest a great degree of selectivity that plays an active role in the post-transcriptional control of gene expression, and regulates multiple biological functions. Studies in Caenorhabditis elegans have shown that old age is accompanied by the accumulation of decapping factors in cytoplasmic RNA granules, and loss of decapping activity shortens the lifespan. However, the link between decapping and ageing remains elusive. Here, we present a comparative microarray study that was aimed to uncover the differences in the transcriptome of mid-aged dcap-1/DCP1 mutant and wild-type nematodes. Our data indicate that DCAP-1 mediates the silencing of spermatogenic genes during late oogenesis, and suppresses the aberrant uprise of immunity gene expression during ageing. The latter is achieved by destabilizing the mRNA that encodes the transcription factor PQM-1 and impairing its nuclear translocation. Failure to exert decapping-mediated control on PQM-1 has a negative impact on the lifespan, but mitigates the toxic effects of polyglutamine expression that are involved in human disease.