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

•DAF-16/FoxO polyubiquitylation and stability regulate metabolism and longevity•The DUB MATH-33 stabilizes DAF-16 protein levels in Insulin/IGF-1 signaling (IIS)•math-33 controls daf-16-mediated functions, such as metabolism and longevity in IIS•The E3-ubiquitin ligase rle-1 counteracts math-33 functions on DAF-16

SummaryFOXO 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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