1. The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity
- Author
-
Heimbucher, Thomas, Liu, Zheng, Bossard, Carine, McCloskey, Richard, Carrano, Andrea C, Riedel, Christian G, Tanasa, Bogdan, Klammt, Christian, Fonslow, Bryan R, Riera, Celine E, Lillemeier, Bjorn F, Kemphues, Kenneth, Yates, John R, O’Shea, Clodagh, Hunter, Tony, and Dillin, Andrew
- Subjects
Aging ,Genetics ,Underpinning research ,1.1 Normal biological development and functioning ,Animals ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Endopeptidases ,Forkhead Transcription Factors ,Insulin ,Insulin-Like Growth Factor I ,Longevity ,Protein Stability ,Signal Transduction ,Ubiquitination ,Biochemistry and Cell Biology ,Medical Biochemistry and Metabolomics ,Endocrinology & Metabolism - 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.
- Published
- 2015