Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16

Cell Metab. 2011 May 4;13(5):505-16. doi: 10.1016/j.cmet.2011.03.017.

Abstract

Arginine methylation is a widespread posttranslational modification of proteins catalyzed by a family of protein arginine methyltransferases (PRMTs). It is well established that PRMTs are implicated in various cellular processes, but their physiological roles remain unclear. Using nematodes with a loss-of-function mutation, we show that prmt-1, the major asymmetric arginine methyltransferase, is a positive regulator of longevity in C. elegans. This regulation is dependent on both its enzymatic activity and DAF-16/FoxO transcription factor, which is negatively regulated by AKT-mediated phosphorylation downstream of the DAF-2/insulin signaling. prmt-1 is also required for stress tolerance and fat storage but not dauer formation in daf-2 mutants. Biochemical analyses indicate that PRMT-1 methylates DAF-16, thereby blocking its phosphorylation by AKT. Disruption of PRMT-1 induces phosphorylation of DAF-16 with a concomitant reduction in the expression of longevity-related genes. Thus, we provide a mechanism by which asymmetric arginine dimethylation acts as an antiaging modification in C. elegans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arginine / genetics*
  • Arginine / metabolism
  • Blotting, Western
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation*
  • Immunoprecipitation
  • Insulin / genetics
  • Insulin / metabolism
  • Longevity / genetics*
  • Methylation*
  • Molecular Sequence Data
  • Mutation / genetics
  • Phosphorylation
  • Polymerase Chain Reaction
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Insulin
  • Transcription Factors
  • daf-16 protein, C elegans
  • Arginine
  • Protein-Arginine N-Methyltransferases
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt