(The) role of RNA quality control and its regulator ALGN-2 in longevity of C. elegans

Abstract

Nonsense-mediated mRNA decay (NMD) is a fundamental biological RNA surveillance system that removes mRNA transcripts with premature termination codons. In Caenorhabditis elegans, NMD contributes to longevity by enhancing RNA quality. In this research, I aimed at investigating NMD-regulating factors that are important for lifespan and longevity in C. elegans by performing various genetic screens. I showed that genetic inhibition of algn-2/asparagine linked glycosylation protein, zip-1/bZIP transcription factor, and C44B11.1/FAS apoptotic inhibitory molecule increased NMD target transcript levels. Among these, algn-2 showed an age-dependent decline in its expression and was required for maintaining normal lifespan in wild-type worms. In addition, algn-2 was required for longevity caused by various genetic interventions. I further characterized that upregulation of ALGN-2 by inhibition of the daf-2/insulin/IGF-1 receptor contributed to long lifespan in an NMD-dependent manner. Thus, I found algn-2, a positive regulator of NMD that plays an important role in longevity in C. elegans, likely by enhancing RNA surveillance. This study will help understand how NMD-mediated mRNA quality control system regulate lifespan at an organismal level. To broaden our understanding of RNA quality control systems and their effects on aging, I also investigated the roles of no-go decay (NGD) and nonstop decay (NSD) factors on longevity. I found that NGD and NSD core factors pelo-1/Pelota and skih-2/Skiv2L were required for long lifespan caused by various regimens, including reduced IIS and DR. In addition, defects in NGD and NSD factors decrease proteostasis by affecting autophagy and regulate lifespan. This study will help understand how NMD, NSD, and NGD-mediated mRNA quality control extends animal lifespan.