title: The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity.
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.
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Molecular and Cell Biology Laboratory, Glenn Center for Aging Research, La Jolla, CA 92037, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Heimbucher
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Carine
authors.initials: C
authors.lastname: Bossard
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853-2703, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: McCloskey
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Carrano
authors.affiliation: European Research Institute for the Biology of Aging, University of Groningen, Groningen FA509713 AV, the Netherlands.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Riedel
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tanasa
authors.affiliation: Nomis Center for Immunobiology and Microbial Pathogenesis, Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Klammt
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Fonslow
authors.affiliation: Molecular and Cell Biology Department, University of California, Berkeley, CA 94705, USA.
authors.forename: Celine E
authors.initials: CE
authors.lastname: Riera
authors.affiliation: Nomis Center for Immunobiology and Microbial Pathogenesis, Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Bjorn F
authors.initials: BF
authors.lastname: Lillemeier
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853-2703, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kemphues
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Clodagh
authors.initials: C
authors.lastname: O'Shea
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: hunter@salk.edu.
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.affiliation: Molecular and Cell Biology Department, University of California, Berkeley, CA 94705, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94705, USA. Electronic address: dillin@berkeley.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity; D055550:Protein Stability; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; C108831:daf-16 protein, C elegans; D007334:Insulin-Like Growth Factor I; D010450:Endopeptidases; C580970:MATH-33 protein, C elegans