2. Academic Validation
  3. Regulation of endoplasmic reticulum turnover by selective autophagy

Regulation of endoplasmic reticulum turnover by selective autophagy

  • Nature. 2015 Jun 18;522(7556):354-8. doi: 10.1038/nature14498.
Aliaksandr Khaminets 1,  Theresa Heinrich 2,  Muriel Mari 3,  Paolo Grumati 1,  Antje K Huebner 2,  Masato Akutsu 4,  Lutz Liebmann 2,  Alexandra Stolz 1,  Sandor Nietzsche 5,  Nicole Koch 6,  Mario Mauthe 3,  Istvan Katona 7,  Britta Qualmann 6,  Joachim Weis 7,  Fulvio Reggiori 3,  Ingo Kurth 2,  Christian A Hübner 2,  Ivan Dikic 8
Affiliations

Affiliations

  • 1 Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
  • 2 Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany.
  • 3 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.
  • 4 Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
  • 5 Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmühlenweg 1, 07743 Jena, Germany.
  • 6 Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
  • 7 Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany.
  • 8 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.
PMID: 26040720 DOI: 10.1038/nature14498
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.

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