Format

Send to

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

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

Author information

1
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Molecular and Cell Biology Laboratory, Glenn Center for Aging Research, La Jolla, CA 92037, USA.
2
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
3
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853-2703, USA.
4
European Research Institute for the Biology of Aging, University of Groningen, Groningen FA509713 AV, the Netherlands.
5
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6
Nomis Center for Immunobiology and Microbial Pathogenesis, Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
7
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
8
Molecular and Cell Biology Department, University of California, Berkeley, CA 94705, USA.
9
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: hunter@salk.edu.
10
Molecular and Cell Biology Department, University of California, Berkeley, CA 94705, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94705, USA. Electronic address: dillin@berkeley.edu.

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.

PMID:
26154057
PMCID:
PMC4502596
DOI:
10.1016/j.cmet.2015.06.002
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center