title: Regulation of endoplasmic reticulum turnover by selective autophagy.
abstract: The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Khaminets
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: 1] Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands.
authors.forename: Muriel
authors.initials: M
authors.lastname: Mari
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grumati
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
authors.forename: Masato
authors.initials: M
authors.lastname: Akutsu
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Liebmann
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stolz
authors.affiliation: Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmühlenweg 1, 07743 Jena, Germany.
authors.forename: Sandor
authors.initials: S
authors.lastname: Nietzsche
authors.affiliation: Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Koch
authors.affiliation: 1] Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: Mauthe
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Istvan
authors.initials: I
authors.lastname: Katona
authors.affiliation: Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Qualmann
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: 1] Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Reggiori
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: 1] Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany [2] Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany [3] Institute of Immunology, School of Medicine University of Split, Mestrovicevo setaliste bb, 21 000 Split, Croatia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C545052:Fam134b protein, mouse; C116741:GABARAP protein, human; D047908:Intracellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C522691:RETREG1 protein, human