Evolutionarily conserved regulation of immunity by the splicing factor RNP-6/PUF60

Abstract

<jats:p>Splicing is a vital cellular process that modulates important aspects of animal physiology, yet roles in regulating innate immunity are relatively unexplored. From genetic screens in C. elegans, we identified splicing factor RNP-6/PUF60 whose activity suppresses immunity, but promotes longevity, suggesting a tradeoff between these processes. Bacterial pathogen exposure affects gene expression and splicing in a rnp-6 dependent manner, and rnp-6 gain and loss-of-function activities reveal an active role in immune regulation. Another longevity promoting splicing factor, SFA-1, similarly exerts an immuno-suppressive effect, working downstream or parallel to RNP-6. RNP-6 acts through TIR-1/PMK-1/MAPK signaling to modulate immunity. The mammalian homolog, PUF60, also displays anti-inflammatory properties, and its levels swiftly decrease after bacterial infection in mammalian cells, implying a role in the host response. Altogether our findings demonstrate an evolutionarily conserved modulation of immunity by specific components of the splicing machinery.</jats:p>

Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

“…ageing, C. elegans, cell non-autonomous, health span, immunity, longevity, NHR-49, stress response in literature along with instances of pro-longevity genes that do not alter stress resistance (Arum & Johnson, 2007;Dues et al, 2017;Meissner et al, 2004). Recently, we and others have identified genes that promote longevity but repress stress resilience demonstrating that these attributes are physiologically distinct (Amrit et al, 2019;Kew et al, 2020). Nonetheless, a large fraction of known prolongevity genes promote stress resistance (Zhou et al, 2011), but whether they govern these processes by shared or distinct mechanisms remains largely unknown.…”

Gene duplication to the Y chromosome in Trinidadian Guppies

“…Three, Puf60b, Syngap1a and MARK4 have neurological functions (Table 1). Puf60b is broadly expressed, and has additional immunological functions (Kew et al 2020).…”

“…Mark4 (microtubule affinity regulating kinase 4) has been shown to be involved in microtubule organization in neuronal cells (Trinczek et al 2004). Puf60b has also been recently implicated as well in immune system functions (Kew et al 2020).…”

“…Importantly, all high F ST SNPs in this gene are localized within one exon. Puf60b is broadly expressed, and has both neurological and immune system functions (Low et al 2017; Kew et al 2020). This, in combination with the differences between female and male guppies in predation risk and predator avoidance (Magurran and Nowak 1991; Croft et al 2006) as well as pathogen infection and avoidance (Stephenson et al 2015), suggests that sexual conflict over survival may primarily target loci that play a role in behavior, cognition and the immune system.…”

NHR-49 Acts in Distinct Tissues to Promote Longevity versus Innate Immunity

“…However, in worms, flies and mice, descriptions of long-lived mutants that do not exhibit elevated stress resistance, and vice versa, have existed in literature for long, along with reports of pro-longevity genes that do not alter stress resistance (Arum and Johnson, 2007;Dues et al, 2017;Meissner et al, 2004). Recently, we and others have identified genes that promote longevity but repress stress resilience demonstrating that these attributes are physiologically distinct (Amrit et al, 2019;Kew et al, 2020).…”