The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity

Cell Metab. 2015 Jul 7;22(1):151-63. doi: 10.1016/j.cmet.2015.06.002.

Abstract

FOXO family transcription factors are downstream effectors of Insulin/IGF-1 signaling (IIS) and major determinants of aging in organisms ranging from worms to man. The molecular mechanisms that actively promote DAF16/FOXO stability and function are unknown. Here we identify the deubiquitylating enzyme MATH-33 as an essential DAF-16 regulator in IIS, which stabilizes active DAF-16 protein levels and, as a consequence, influences DAF-16 functions, such as metabolism, stress response, and longevity in C. elegans. MATH-33 associates with DAF-16 in cellulo and in vitro. MATH-33 functions as a deubiquitylase by actively removing ubiquitin moieties from DAF-16, thus counteracting the action of the RLE-1 E3-ubiquitin ligase. Our findings support a model in which MATH-33 promotes DAF-16 stability in response to decreased IIS by directly modulating its ubiquitylation state, suggesting that regulated oscillations in the stability of DAF-16 protein play an integral role in controlling processes such as metabolism and longevity.

Publication types

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

MeSH terms

  • Animals
  • Caenorhabditis elegans / chemistry
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / metabolism*
  • Endopeptidases / metabolism*
  • Forkhead Transcription Factors / chemistry
  • Forkhead Transcription Factors / metabolism*
  • Insulin / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Longevity
  • Protein Stability
  • Signal Transduction
  • Ubiquitination

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Insulin
  • daf-16 protein, C elegans
  • Insulin-Like Growth Factor I
  • Endopeptidases
  • MATH-33 protein, C elegans

Associated data

  • GEO/GSE70117