Presentation/Session Information

Session Information

Session Title: Physiology: Aging and Stress I Session Type: Parallel
Session Location: Grand Horizon Ballroom Session Time: Thu, Jun 25 8:30AM - 11:30AM

Presentation Information

Program Number: 28 Presentation Time: 10:06AM - 10:18AM

Presentation Content

The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Development and Longevity.Thomas Heimbucher 1,4, Zheng Liu 1, Carine Bossard 1, Richard McCloskey 6, Andrea C. Carrano 1, Christian G. Riedel 7, Bogdan Tanasa 8, Christian Klammt 1, Bryan R. Fonslow 5, Celine E. Riera 2, Bjorn F. Lillemeier 1, Kenneth Kemphues 6, John R. Yates III 5, Clodagh O'Shea 1, Tony Hunter 1, Andrew Dillin 2,3. 1)Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, La Jolla, CA 92037, USA; 2)Molecular and Cell Biology Department, The University of California, Berkeley, CA 94705, USA; 3)Howard Hughes Medical Institute, The University of California, Berkeley, CA 94705, USA; 4)Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, La Jolla, CA 92037, USA; 5)The Scripps Research Institute, Department of Chemical Physiology, La Jolla, CA 92037, USA; 6)Cornell University, Department of Molecular Biology and Genetics, Ithaca, NY 14853-2703, USA; 7)European Research Institute for the Biology of Aging, University of Groningen, Groningen FA509713 AV, Netherlands; 8)University of California, Department of Medicine, School of Medicine, San Diego, La Jolla, CA 92093, USA

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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