One of the major determinants of aging in organisms ranging from worms to man are FOXO family transcription factors, which are downstream effectors of Insulin/IGF-1 signaling (IIS). The molecular mechanisms that actively promote DAF16/FOXO stability and function are unknown. Here we identify the deubiquitylating enzyme MATH-33, the C. elegans orthologue of mammalian USP7/HAUSP, as an essential regulator of DAF-16 in C. elegans. MATH-33 antagonizes polyubiquitylation of DAF-16 in C. elegans, stabilizing active DAF-16 protein levels and, as a consequence, influencing DAF-16 functions, such as development, metabolism and longevity. MATH-33 associates with DAF-16 in cellulo dependent on reduced IIS, binds to DAF-16 in vitro and functions as a deubiquitylase by actively removing ubiquitin moieties from DAF-16. We find the E3-ubiquitin ligase rle-1 counteracts the math-33 deubiquitylase activity on DAF-16, providing a dynamic and reversible ubiquitylation mechanism to regulate DAF-16 protein levels. Our findings support a model in which MATH-33 promotes DAF-16 stability in response to decreased IIS by directly modulating its ubiquitylated state, and suggest that regulated oscillations in the stability of DAF-16 protein play an integral role in controlling processes such as development, metabolism and longevity. .
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