Caenorhabditis elegans algn-2 Is Critical for Longevity Conferred by Enhanced Nonsense-Mediated mRNA Decay

Abstract

Nonsense-mediated mRNA decay (NMD) is a biological surveillance mechanism that eliminates mRNA transcripts with premature termination codons. In Caenorhabditis elegans, NMD contributes to longevity by enhancing RNA quality. Here, we aimed at identifying NMD-modulating factors that are crucial for longevity in C. elegans by performing genetic screens. We showed that knocking down each of algn-2/asparagine-linked glycosylation protein, zip-1/bZIP transcription factor, and C44B11.1/FAS apoptotic inhibitory molecule increased the transcript levels of NMD targets. Among these, algn-2 exhibited an age-dependent decrease in its expression and was required for maintaining normal lifespan and for longevity caused by various genetic interventions. We further demonstrated that upregulation of ALGN-2 by inhibition of daf-2/insulin/IGF-1 receptor contributed to longevity in an NMD-dependent manner. Thus, algn-2, a positive regulator of NMD, plays a crucial role in longevity in C. elegans, likely by enhancing RNA surveillance. Our study will help understand how NMD-mediated mRNA quality control extends animal lifespan. INTRODUCTIONEukaryotic cells are equipped with mechanisms that maintain proper gene expression and prevent the production of deleterious proteins. Nonsense-mediated mRNA decay (NMD) is an mRNA quality control mechanism that monitors and degrades abnormal transcripts with premature termination codons (PTCs) (He and Jacobson, 2015;Kim and Maquat, 2019;Kurosaki et al., 2019). NMD targets also include mRNAs with long (>1 kb) 3 0 untranslated regions, upstream open reading frames, or selenocysteine-encoding UGA codons (He and Jacobson, 2015;Kim and Maquat, 2019;Kurosaki et al., 2019). Thus, NMD is crucial for RNA quality surveillance and the maintenance of the correct transcriptome in organisms. Key evolutionarily conserved components of NMD have been identified by using model organisms, including the budding yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. A genetic screen using C. elegans has identified the main NMD components, smg (suppressor with morphological effect on genitalia)-1 through smg-7 (Hodgkin et al., 1989;Mango, 2001). SMG-1 is a phosphatidylinositol 3-kinase-related kinase that phosphorylates SMG-2/UPF1 RNA helicase (Hodgkin et al., 1989;Mango, 2001). This event activates the NMD machinery and leads to the cleavage of target mRNAs via the endonuclease SMG-6 (

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