The E 3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1 b

Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferatoractivated receptor coactivator (PGC)-1b, and Syvn1 mutants showed upregulation of PGC-1b target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1b by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1b and a potential therapeutic target in obesity treatment.

[1]  S. Kersten,et al.  The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism. , 2014, Cell metabolism.

[2]  T. Nakajima,et al.  Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis , 2014, Genes & development.

[3]  J. Gómez-Reino,et al.  Adipokines, Metabolic Syndrome and Rheumatic Diseases , 2014, Journal of immunology research.

[4]  K. Mamchaoui,et al.  Unveiling the degradative route of the V247M α-sarcoglycan mutant responsible for LGMD-2D , 2014, Human molecular genetics.

[5]  Ann M. Thomas,et al.  Role of Nuclear Receptors in Lipid Dysfunction and Obesity-Related Diseases , 2013, Drug Metabolism and Disposition.

[6]  Vineta Fellman,et al.  Mitochondrial respiration in human viable platelets--methodology and influence of gender, age and storage. , 2013, Mitochondrion.

[7]  M. González-Gay,et al.  Rheumatoid arthritis: Obesity impairs efficacy of anti-TNF therapy in patients with RA , 2012, Nature Reviews Rheumatology.

[8]  S. Aratani,et al.  RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis , 2012, International journal of molecular medicine.

[9]  L. Makowski,et al.  The inflammation highway: metabolism accelerates inflammatory traffic in obesity , 2012, Immunological reviews.

[10]  R. Kaufman,et al.  The impact of the unfolded protein response on human disease , 2012, The Journal of cell biology.

[11]  B. Spiegelman,et al.  Development of insulin resistance in mice lacking PGC-1α in adipose tissues , 2012, Proceedings of the National Academy of Sciences.

[12]  M. Blüher,et al.  A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism , 2012, Nature.

[13]  L. Velloso,et al.  Endoplasmic reticulum stress, obesity and diabetes. , 2012, Trends in molecular medicine.

[14]  Jiandie D. Lin,et al.  PGC-1 coactivators in the control of energy metabolism. , 2011, Acta biochimica et biophysica Sinica.

[15]  J. Bressan,et al.  Peroxisome proliferator-activated receptor: effects on nutritional homeostasis, obesity and diabetes mellitus. , 2011, Nutricion hospitalaria.

[16]  S. Friedman,et al.  E3 Ubiquitin Ligase Synoviolin Is Involved in Liver Fibrogenesis , 2010, PloS one.

[17]  G. Firestein,et al.  Role of Interleukin 17 in Arthritis Chronicity through Survival of Synoviocytes via Regulation of Synoviolin Expression , 2010, PloS one.

[18]  An-fang Cui,et al.  PGC-1 beta-regulated mitochondrial biogenesis and function in myotubes is mediated by NRF-1 and ERR alpha. , 2010, Mitochondrion.

[19]  Riccardo Bernasconi,et al.  Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates , 2010, The Journal of cell biology.

[20]  P. Puigserver,et al.  GCN5-mediated Transcriptional Control of the Metabolic Coactivator PGC-1β through Lysine Acetylation* , 2009, The Journal of Biological Chemistry.

[21]  M. Lazar,et al.  New developments in adipogenesis , 2009, Trends in Endocrinology & Metabolism.

[22]  R. Scarpulla.  Transcriptional paradigms in mammalian mitochondrial biogenesis and function. , 2008, Physiological reviews.

[23]  S. Yamasaki,et al.  Cytoplasmic destruction of p53 by the endoplasmic reticulum‐resident ubiquitin ligase ‘Synoviolin’ , 2007, The EMBO journal.

[24]  G. Hotamisligil,et al.  Inflammation and metabolic disorders , 2006, Nature.

[25]  O. MacDougald,et al.  Adipocyte differentiation from the inside out , 2006, Nature Reviews Molecular Cell Biology.

[26]  K. Calhoun,et al.  The proinflammatory cytokines IL-1β and TNF-α induce the expression of Synoviolin, an E3 ubiquitin ligase, in mouse synovial fibroblasts via the Erk1/2-ETS1 pathway , 2006, Arthritis research & therapy.

[27]  B. Mougin,et al.  Overexpression of synoviolin in peripheral blood and synoviocytes from rheumatoid arthritis patients and continued elevation in nonresponders to infliximab treatment. , 2006, Arthritis and rheumatism.

[28]  R. Scarpulla,et al.  Nuclear control of respiratory gene expression in mammalian cells , 2006, Journal of cellular biochemistry.

[29]  S. Yamasaki,et al.  Rheumatoid arthritis as a hyper-endoplasmic reticulum-associated degradation disease , 2005, Arthritis research & therapy.

[30]  A. Fukamizu,et al.  Relevance of nuclear localization and functions of RNA helicase A. , 2005, International journal of molecular medicine.

[31]  S. Yamasaki,et al.  Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. , 2003, Genes & development.

[32]  Satoko Aratani,et al.  Antithetic Effects of MBD2a on Gene Regulation , 2003, Molecular and Cellular Biology.

[33]  Y. Kamei,et al.  PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Jiandie D. Lin,et al.  Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. , 2003, The Journal of biological chemistry.

[35]  Jiandie D. Lin,et al.  PGC-1beta in the regulation of hepatic glucose and energy metabolism. , 2003, The Journal of biological chemistry.

[36]  D. Kressler,et al.  The PGC-1-related Protein PERC Is a Selective Coactivator of Estrogen Receptor α* , 2002, The Journal of Biological Chemistry.

[37]  Andrew P McMahon,et al.  Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. , 2002, Developmental biology.

[38]  Jiandie D. Lin,et al.  Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. , 2002, The Journal of biological chemistry.

[39]  Dual Roles of RNA Helicase A in CREB-Dependent Transcription , 2001, Molecular and Cellular Biology.

[40]  R. Scarpulla,et al.  PGC-1-Related Coactivator, a Novel, Serum-Inducible Coactivator of Nuclear Respiratory Factor 1-Dependent Transcription in Mammalian Cells , 2001, Molecular and Cellular Biology.

[41]  Bruce M. Spiegelman,et al.  Towards a molecular understanding of adaptive thermogenesis , 2000, Nature.

[42]  I. Wickelgren,et al.  Obesity: How Big a Problem? , 1998, Science.

[43]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[44]  B. Spiegelman,et al.  ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Montminy,et al.  Role of CBP/P300 in nuclear receptor signalling , 1996, Nature.

[46]  F. Gage,et al.  The Signal-Dependent Coactivator CBP Is a Nuclear Target for pp90RSK , 1996, Cell.