title: Liver ubiquitome uncovers nutrient-stress-mediated trafficking and secretion of complement C3.
abstract: Adaptation to changes in nutrient availability is crucial for cells and organisms. Posttranslational modifications of signaling proteins are very dynamic and are therefore key to promptly respond to nutrient deprivation or overload. Herein we screened for ubiquitylation of proteins in the livers of fasted and refed mice using a comprehensive systemic proteomic approach. Among 1641 identified proteins, 117 were differentially ubiquitylated upon fasting or refeeding. Endoplasmic reticulum (ER) and secretory proteins were enriched in the livers of refed mice in part owing to an ER-stress-mediated response engaging retro-translocation and ubiquitylation of proteins from the ER. Complement C3, an innate immune factor, emerged as the most prominent ER-related hit of our screen. Accordingly, we found that secretion of C3 from the liver and primary hepatocytes as well as its dynamic trafficking are nutrient dependent. Finally, obese mice with a chronic nutrient overload show constitutive trafficking of C3 in the livers despite acute changes in nutrition, which goes in line with increased C3 levels and low-grade inflammation reported for obese patients. Our study thus suggests that nutrient sensing in the liver is coupled to release of C3 and potentially its metabolic and inflammatory functions.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Helena de Fatima
authors.initials: HF
authors.lastname: Magliarelli
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH), Zurich, Switzerland.
authors.forename: Mariette
authors.initials: M
authors.lastname: Matondo
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.|Nouvel Hôpital Civil, Laboratoire de Biochimie et de Biologie Moléculaire, Université de Strasbourg, Strasbourg, France.
authors.forename: Gergő
authors.initials: G
authors.lastname: Mészáros
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Goginashvili
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Erbs
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Mihlan
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.|Faculty of Science, University of Zurich, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolfrum
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH), Zurich, Switzerland.|Faculty of Science, University of Zurich, Zurich, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Izabela
authors.initials: I
authors.lastname: Sumara
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France.|Nouvel Hôpital Civil, Laboratoire de Biochimie et de Biologie Moléculaire, Université de Strasbourg, Strasbourg, France.
authors.forename: Romeo
authors.initials: R
authors.lastname: Ricci
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005247:Feeding Behavior; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D020543:Proteome / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism; D013312:Stress, Physiological; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D003176:Complement C3; D020543:Proteome; D014452:Ubiquitins