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

Thomas Heimbucher, Zheng Liu, Carine Bossard, Richard McCloskey, Andrea C. Carrano, Christian G. Riedel, Bogdan Tanasa, Christian Klammt, Bryan R. Fonslow, Celine E. Riera, Bjorn F. Lillemeier, Kenneth Kemphues, John R. Yates, Clodagh O'Shea, Tony Hunter*, Andrew Dillin

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)151-163
Number of pages13
JournalCell metabolism
Volume22
Issue number1
DOIs
Publication statusPublished - 7-Jul-2015

Keywords

  • TRANSCRIPTION FACTOR DAF-16
  • CAENORHABDITIS-ELEGANS
  • LIFE-SPAN
  • C-ELEGANS
  • REGULATES LONGEVITY
  • GENE-EXPRESSION
  • STRESS
  • INSULIN/IGF-1
  • MODULATION
  • USP7

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