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

摘要

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. Author Summary In people, elevated blood levels of the amino acid tyrosine are seen in obese individuals, and these elevations represent a novel risk factor for the development of diabetes. The enzyme tyrosine aminotransferase, which removes tyrosine from the body, has also been identified as a tumor suppressor gene, and this enzyme normally acts to prevent the development of liver cancer. In our work, we identify tyrosine aminotransferase as a regulator of larval development and adult longevity in the non-parasitic worm Caenorhabditis elegans . Worms with mutations impairing tyrosine aminotransferase activity show elevated levels of tyrosine, are prone to arresting development in a larval stage called a dauer, and show increased longevity. Part of the effect of tyrosine aminotransferase is due to inhibitory effects on an insulin-like signaling pathway in the worms. Our work suggests that levels of the amino acid tyrosine are sensed and can lead to changes in cell signaling. These results may provide insights into how tyrosine could be involved in obesity, diabetes, and cancer in people.