A Krüppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans

Nat Commun. 2014 May 8;5:3772. doi: 10.1038/ncomms4772.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / biosynthesis
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Caloric Restriction*
  • Diet / methods
  • Intestinal Mucosa / metabolism
  • Kruppel-Like Transcription Factors / biosynthesis
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Longevity / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Trans-Activators / metabolism
  • Ubiquitin-Protein Ligases / biosynthesis
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Caenorhabditis elegans Proteins
  • Klf-1 protein, C elegans
  • Kruppel-Like Transcription Factors
  • Pha-4 protein, C elegans
  • RNA, Small Interfering
  • Trans-Activators
  • wwp-1 protein, C elegans
  • Ubiquitin-Protein Ligases