title: trappc11 is required for protein glycosylation in zebrafish and humans.
abstract: Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a "stressed UPR." Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in thetrappc11gene, which encodes a component of the transport protein particle (TRAPP) complex.trappc11mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation intrappc11mutants that is associated with reduced levels of lipid-linked oligosaccharides (LLOs) and compensatory up-regulation of genes in the terpenoid biosynthetic pathway that produces the LLO anchor dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopies the stressed UPR seen intrappc11mutants and is synthetically lethal withtrappc11mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction intrappc11mutants. Of importance, in human cells, depletion of TRAPPC11, but not other TRAPP components, causes protein hypoglycosylation, and lipid droplets accumulate in fibroblasts from patients with theTRAPPC11mutation. These data point to a previously unanticipated and conserved role for TRAPPC11 in LLO biosynthesis and protein glycosylation in addition to its established function in vesicle trafficking.
authors.affiliation: Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Charles
authors.initials: C
authors.lastname: DeRossi
authors.affiliation: Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ana
authors.initials: A
authors.lastname: Vacaru
authors.affiliation: Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ruhina
authors.initials: R
authors.lastname: Rafiq
authors.affiliation: Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ayca
authors.initials: A
authors.lastname: Cinaroglu
authors.affiliation: Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Dru
authors.initials: D
authors.lastname: Imrie
authors.affiliation: Department of Pediatrics and Mindich Institute for Child Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Shikha
authors.initials: S
authors.lastname: Nayar
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Baryshnikova
authors.affiliation: Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada.
authors.forename: Miroslav P
authors.initials: MP
authors.lastname: Milev
authors.affiliation: Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stanga
authors.affiliation: Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Dhara
authors.initials: D
authors.lastname: Kadakia
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ningguo
authors.initials: N
authors.lastname: Gao
authors.affiliation: Department of Pediatrics and Mindich Institute for Child Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Jaime
authors.initials: J
authors.lastname: Chu
authors.affiliation: Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lehrman
authors.affiliation: Department of Biology, Concordia University, Montreal, QC H4B 1R6, Canada Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Sacher
authors.affiliation: Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 kirsten.edepli@nyu.edu.
authors.forename: Kirsten C
authors.initials: KC
authors.lastname: Sadler
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000069059:Atorvastatin / Q000494:pharmacology; D004286:Dolichols / Q000096:biosynthesis / Q000235:genetics; D006031:Glycosylation; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism*; D013729:Terpenes / Q000378:metabolism / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004286:Dolichols; D008055:Lipids; D009844:Oligosaccharides; C000613447:TRAPPC11 protein, human; C504613:TRAPPC11 protein, zebrafish; D013729:Terpenes; D033921:Vesicular Transport Proteins; D029961:Zebrafish Proteins; D000069059:Atorvastatin