Tissue-specific overexpression of the double-stranded RNA transporter SID-1 limits lifespan inC. elegans

Abstract

ABSTRACTIntertissue RNA transport has emerged as a novel signaling mechanism. InC. elegans, this is conferred by the systemic RNAi pathway, in which the limiting step is the cellular import of extracellular RNAs via SID-1. To better understand the physiological role of systemic RNAiin vivo, we modified the function of SID-1 through loss-of-function mutation and tissue-specific overexpression ofsid-1inC. elegans. We observed thatsid-1loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression ofsid-1in intestine, muscle, or neurons rendered worms short-lived. The effects of intestinalsid-1overexpression were reversed by silencing the components of the systemic RNAi pathwaysid-1, sid-2andsid-5, thus implicating RNA transport. Moreover, silencing the miRNA biogenesis proteinspash-1anddcr-1rendered the lifespan of worms with intestinalsid-1overexpression similar to controls. Lastly, we observed that the lifespan decrease produced by tissue-specificsid-1overexpression was dependent on the bacterial food source. Collectively, our data support the notion that systemic RNA signaling is tightly regulated, and unbalancing that process provokes a reduction in lifespan.