title: 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.
authors.affiliation: Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Annabel A
authors.initials: AA
authors.lastname: Ferguson
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ; Center for Healthy Aging, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Sudipa
authors.initials: S
authors.lastname: Roy
authors.affiliation: Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Kaitlyn N
authors.initials: KN
authors.lastname: Kormanik
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Yongsoon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Dumas
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Ritov
authors.affiliation: Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America ; Departments of Internal Medicine and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hu
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ; Center for Healthy Aging, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America ; GRECC, South Texas VA Health Care System, San Antonio, Texas, United States of America.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Fisher
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D009154:Mutation; D034622:RNA Interference; D011972:Receptor, Insulin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014443:Tyrosine / Q000235:genetics* / Q000378:metabolism; D014444:Tyrosine Transaminase / Q000235:genetics*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D014444:Tyrosine Transaminase; D011972:Receptor, Insulin