An Anti-aging Protein Kinase VRK-1 Promotes Longevity through Activation of AMPK via Phosphorylation

Abstract

An evolutionarily conserved nuclear serine-threonine protein kinase vaccinia virus-related kinase 1(VRK-1) regulates cell division and germline proliferation in Caenorhabditis elegans. However, whether VRK-1 functions in post-mitotic cells remain elusive. Here we demonstrated that VRK-1 in somatic cells increases lifespan through activating a longevity-promoting energy sensor AMP-activated protein kinase (AMPK) via phosphorylation. We first showed that VRK-1 was expressed in the nucleus of somatic cells in various tissues throughout lifetime. Importantly, overexpressing vrk-1 in the somatic cells extended lifespan, whereas null mutation in vrk-1 decreased lifespan. By analyzing transcriptomic changes regulated by vrk-1, we found that VRK-1 upregulated many downstream target genes of AMPK. Furthermore, AMPK was required for the longevity conferred by vrk-1 overexpression. These data suggest a functional connection between VRK-1 and AMPK. We demonstrated that both C. elegans VRK-1 and human VRK1 directly phosphorylated AMPK. Together, our data suggest that VRK-1 is an evolutionarily conserved AMPK-activating upstream kinase and the VRK-1-to-AMPK signal is critical for promoting longevity.1