The protein kinase MBK-1 contributes to lifespan extension in daf-2 mutant and germline-deficient Caenorhabditis elegans

Abstract

In <i>Caenorhabditis elegans</i>, reduction of insulin/IGF-1 like signaling and loss of germline stem cells both increase lifespan by activating the conserved transcription factor DAF-16 (FOXO). While the mechanisms that regulate DAF-16 nuclear localization in response to insulin/IGF-1 like signaling are well characterized, the molecular pathways that act in parallel to regulate DAF-16 transcriptional activity, and the pathways that couple DAF-16 activity to germline status, are not fully understood at present. Here, we report that inactivation of MBK-1, the <i>C. elegans</i> ortholog of the human FOXO1-kinase DYRK1A substantially shortens the prolonged lifespan of <i>daf-2</i> and <i>glp-1</i> mutant animals while decreasing wild-type lifespan to a lesser extent. On the other hand, lifespan-reduction by mutation of the MBK-1-related kinase HPK-1 was not preferential for long-lived mutants. Interestingly, <i>mbk-1</i> loss still allowed for DAF-16 nuclear accumulation but reduced expression of certain DAF-16 target genes in germline-less, but not in <i>daf-2</i> mutant animals. These findings indicate that <i>mbk-1</i> and <i>daf-16</i> functionally interact in the germline- but not in the <i>daf-2</i> pathway. Together, our data suggest <i>mbk-1</i> as a novel regulator of <i>C. elegans</i> longevity upon both, germline ablation and DAF-2 inhibition, and provide evidence for <i>mbk-1</i> regulating DAF-16 activity in germline-deficient animals.