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

Abstract

In Caenorhabditis elegans, 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 C. elegans ortholog of the human FOXO1-kinase DYRK1A substantially shortens the prolonged lifespan of daf-2 and glp-1 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, mbk-1 loss still allowed for DAF-16 nuclear accumulation but reduced expression of certain DAF-16 target genes in germline-less, but not in daf-2 mutant animals. These findings indicate that mbk-1 and daf-16 functionally interact in the germline- but not in the daf-2 pathway. Together, our data suggest mbk-1 as a novel regulator of C. elegans longevity upon both, germline ablation and DAF-2 inhibition, and provide evidence for mbk-1 regulating DAF-16 activity in germline-deficient animals.

Glucose negatively affects Nrf2/SKN-1-mediated innate immunity in C. elegans

“…The well-known aging regulator DAF-16 is required for protection against strains that kill C. elegans slowly by gut colonization [19,20]. Recently, DAF-16 is also found to be phosphorylated by MBK-1 [21], a DYRK kinase that promotes resistance to P. aeruginosa [22]. In mammals, several studies suggest Nrf2 to be an important modulator of innate immunity.…”

Investigating autism associated genes in C. elegans reveals candidates with a role in social behaviour

“…50μl of OP50 E.coli at OD 600 of 0.8 was gently spotted on the middle of an unseeded plate. Approximately 18 hours following this, seven L4+1 day old hermaphrodites were picked onto PLOS ONE [40] LOF [40] Defective local search behaviour [ [51] LOF [51] None reported [51] Widely expressed [52] shn [59] Null [59] Reduced lifespan [59] Gonad, nervous system-not otherwise specified [59] mbk-1 pk1389 EK228 6 Deletion to most of kinase domain [60] Putative null [60] Reduced lifespan […”

Emerging topics in C. elegans aging research: Transcriptional regulation, stress response and epigenetics

“…MBK-1, the C. elegans ortholog of the mammalian FOXO1 kinase DYRK1A also modulates DAF-16, but a kinase-substrate relationship has not formally been established (Mack et al, 2017). Nuclear factors also modulate DAF-16 function and they include histone deacetylase SIR-2.1 (Berdichevsky et al, 2006), transcriptional regulator HCF-1 (HCF1) (Li et al, 2008), nuclear mRNA exporter HEL-1 (Seo et al, 2015), the SWI/SNF-complex (Riedel et al, 2013) and, potentially, ZFP-1 (AF10) (Riedel et al, 2013; Singh et al, 2016).…”

The Study of Aging in Caenorhabditis elegans

“…The mechanisms involved in aging in C. elegans have also been studied in other organisms, including mammals. Among these mechanisms are oxidative damage, dietary restriction, reduction in the Insulin/Insulin-like Growth Factor (IGF) signaling pathway and decreased TOR (Target of Rapamycin) signaling [1][2][3][4]. …”

“…One study has found that when mbk-1 is lost, the lifespan of daf-2 is shortened. MBK-1 has been identified as a protein kinase [4].…”