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

Authors
  • Thomas Heimbucher
  • Z, Liu
  • C, Bossard
  • R, Mccloskey
  • Ac, Carrano
  • Cg, Riedel
  • B, Tanasa
  • C, Klammt
  • Br, Fonslow
  • Ce, Riera
  • Bf, Lillemeier
  • K, Kemphues
  • 3rd, Yates Jr
  • C, O Shea
  • Tony Hunter
  • A, Dillin
Type
Published Article
Journal
Cell Metabolism
Publisher
Elsevier
Volume
22
Issue
1
Pages
151–163
Identifiers
DOI: 10.1016/j.cmet.2015.06.002
Source
Hunter Lab
License
Unknown

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.

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