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. .
Please note: Abstract shown here should NOT be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
The Genetics Society of America
9650 Rockville Pike, Bethesda, MD
Phone: 301-634-7300, Fax: 301-634-7079
Questions and Comments: email@example.com