Orchestrated protein and DNA quality control plays a major role in preventing premature aging and promoting longevity in many species. Several recent studies have shown that RNA quality control is also critical for longevity. Nonsense-mediated mRNA decay (NMD) is a biological surveillance mechanism that eliminates mRNA transcripts with premature termination codons. We previously showed that NMD in Caenorhabditis elegans contributes to longevity by enhancing RNA quality (Son et al., 2017, Nat. Comm.). Here, we aimed at identifying NMD-modulating factors that affect longevity in C. elegans by performing RNAi and mutagenesis screens. From a genome-wide RNAi screen using a sensitized NMD-responsive GFP reporter strain,
smg-1(
tm849);
sec-23p::gfp::lacZ(PTC) (Longman et al., 2007, Genes Dev.), we identified several NMD-modulating factors:
algn-2/asparagine-linked glycosylation protein,
zip-1/bZIP transcription factor, and C44B11.1/FAS apoptotic inhibitory molecule. We further showed that knocking down each of
algn-2,
zip-1, and C44B11.1 increased the levels of the
rpl-7A transcript, an established endogenous NMD target. We found that two of the mutants isolated from our mutagenesis screen displayed decreased
rpl-7A transcript levels. We further characterized
algn-2, which exhibited an age-dependent decrease in its expression and was required for maintaining normal lifespan. We showed that knocking down
algn-2 significantly reduced longevity conferred by various genetic interventions, including
daf-2/insulin/IGF-1 receptor mutations, dietary restriction mimetic
eat-2 mutations, and mitochondrial respiration-defective
isp-1 mutations. We further demonstrated that genetic inhibition of
daf-2/insulin/IGF-1 receptor upregulated ALGN-2, which contributed to long lifespan in an NMD dependent manner. Thus, upregulation of ALGN-2 conferred by reduced insulin/IGF-1 signaling enhances NMD in C. elegans. Overall, our study identified novel modulators of NMD, including
algn-2, which plays key roles in RNA quality control and organismal longevity. Our study will help understand how NMD-mediated mRNA quality control extends animal lifespan.