TATN-1 Mutations Reveal a Novel Role for Tyrosine as a Metabolic Signal That Influences Developmental Decisions and Longevity in Caenorhabditis elegans

Abstract

Recent work has identified changes in the metabolism of the aromatic amino acid tyrosine as a risk factor for diabetes and a contributor to the development of liver cancer. While these findings could suggest a role for tyrosine as a direct regulator of the behavior of cells and tissues, evidence for this model is currently lacking. Through the use of RNAi and genetic mutants, we identify tatn-1, which is the worm ortholog of tyrosine aminotransferase and catalyzes the first step of the conserved tyrosine degradation pathway, as a novel regulator of the dauer decision and modulator of the daf-2 insulin/IGF-1-like (IGFR) signaling pathway in Caenorhabditis elegans. Mutations affecting tatn-1 elevate tyrosine levels in the animal, and enhance the effects of mutations in genes that lie within the daf-2/insulin signaling pathway or are otherwise upstream of daf-16/FOXO on both dauer formation and worm longevity. These effects are mediated by elevated tyrosine levels as supplemental dietary tyrosine mimics the phenotypes produced by a tatn-1 mutation, and the effects still occur when the enzymes needed to convert tyrosine into catecholamine neurotransmitters are missing. The effects on dauer formation and lifespan require the aak-2/AMPK gene, and tatn-1 mutations increase phospho-AAK-2 levels. In contrast, the daf-16/FOXO transcription factor is only partially required for the effects on dauer formation and not required for increased longevity. We also find that the controlled metabolism of tyrosine by tatn-1 may function normally in dauer formation because the expression of the TATN-1 protein is regulated both by daf-2/IGFR signaling and also by the same dietary and environmental cues which influence dauer formation. Our findings point to a novel role for tyrosine as a developmental regulator and modulator of longevity, and support a model where elevated tyrosine levels play a causal role in the development of diabetes and cancer in people.

Tyrosine Detoxification Is an Essential Trait in the Life History of Blood-Feeding Arthropods

“…However, long-term high levels of tyrosine in plasma have been associated with insulin resistance [19,20] and, in a few mammal species, tyrosine crystal formation in the eyes was observed after long-term administration of HPPD inhibitors, a condition that reverted after cessation of the treatment [4,17]. Moreover, in Caenorhabditis elegans, TAT or HPPD knockout even increased the lifespan [21,22]. Thus, in contrast to what has been previously reported for other (non-hematophagous) organisms, detoxification of dietary tyrosine is a priority in R. prolixus.…”

Pharmacologic targeting of sirtuin and PPAR signaling improves longevity and mitochondrial physiology in respiratory chain complex I mutant Caenorhabditis elegans

“…Resveratrol treatment, by signaling through AKT and FOXO1, may effectively increase flux through gluconeogenesis (Park et al, 2010), thereby leading to a reduction in accumulated serine levels. With respect to tyrosine, worms also contain orthologous genes responsible for the metabolism of tyrosine, which may directly affect the activity of stress and longevity pathways including daf-2 /insulin signaling and daf-16 / FOXO (Ferguson et al, 2013), which we have previously implicated in the cellular response to RC impairment (Zhang et al, 2013). …”

Developmental roles of tyrosine metabolism enzymes in the blood-sucking insect Rhodnius prolixus

“…Tyrosine accumulation due to the knockout of TAT promoted the arrest of larval development at the dauer stage and even extended its lifespan [20]. In contrast to C. elegans, the knockdown of TAT and HPPD in R. prolixus fourth-stage nymphs reduced their survival, presenting the same lethal phenotype previously observed in were injected into the thorax on day 1 BBM and day 2 PBM, or on day 2 PBM and day 5 PBM.…”