Title: The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity.
Authors: 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 3rd, John R; O'Shea, Clodagh; Hunter, Tony; Dillin, Andrew
Published In Cell Metab, (2015 Jul 07)
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.
PubMed ID: 26154057
MeSH Terms: Animals; Caenorhabditis elegans Proteins/chemistry; Caenorhabditis elegans Proteins/metabolism*; Caenorhabditis elegans/chemistry; Caenorhabditis elegans/physiology*; Endopeptidases/metabolism*; Forkhead Transcription Factors/chemistry; Forkhead Transcription Factors/metabolism*; Insulin-Like Growth Factor I/metabolism; Insulin/metabolism; Longevity; Protein Stability; Signal Transduction; Ubiquitination