title: A Krüppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans.
abstract: The HECT ubiquitin E3 ligase WWP-1 is a positive regulator of lifespan in response to dietary restriction (DR) in Caenorhabditis elegans. However, substrates of WWP-1 for ubiquitylation in the DR pathway have not yet been identified. Here we identify the C. elegans Krüppel-like factor, KLF-1, as an essential and specific regulator of DR-induced longevity and a substrate for ubiquitylation by WWP-1. Knockdown of klf-1 suppresses the extended lifespan of both DR animals and wwp-1-overexpressing animals, indicating that KLF-1 functions within the same pathway as WWP-1. In addition, overexpression of klf-1 in the intestine is sufficient to extend the lifespan of WT animals on an ad libitum diet, and requires wwp-1 or pha-4/FoxA. We demonstrate that WWP-1 directly interacts with KLF-1 and mediates multiple monoubiquitylation of KLF-1 in vitro and in cellulo. Our data support a model in which modulation of KLF-1 by WWP-1 regulates diet-restriction-induced longevity.
authors.affiliation: 1] Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2].
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Carrano
authors.affiliation: 1] Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] The Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
authors.affiliation: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D031204:Caloric Restriction; D004032:Diet / Q000379:methods; D007413:Intestinal Mucosa / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015534:Trans-Activators / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D029742:Caenorhabditis elegans Proteins; C532590:Klf-1 protein, C elegans; D051741:Kruppel-Like Transcription Factors; C113277:Pha-4 protein, C elegans; D034741:RNA, Small Interfering; D015534:Trans-Activators; C413402:wwp-1 protein, C elegans; D044767:Ubiquitin-Protein Ligases