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 communication1. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process2,3,4,5,6,7,8. 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 humans9 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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Accessions

Primary accessions

Protein Data Bank

Data deposits

Atomic coordinates of the crystal structure of FAM134B-LIR–LC3A have been deposited in the Protein Data Bank under accession number 4ZDV.

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Acknowledgements

We would like to thank S. Horwitz, K. Rajalingam, C. Behrends and J. Lippincott-Schwartz for cell lines and vectors, N. Mizushima for Atg5–/– and control immortalized MEFs, H.-P. Hauri and H. Farhan for vectors, and S. Gießelmann and K. Schorr for excellent technical assistance. We acknowledge D. McEwan, D. Hoeller, D. Popovic and K. Koch for critical reading of the manuscript and valuable insights. We also thank M. M. Kessels for support. This work was supported by grants from the Deutsche Forschungsgemeinschaft to I.D. (DI 931/3-1), I.K. (KU 1587/2-1, KU 1587/3-1, KU 1587/4-1), C.A.H. (HU 800/5-1, RTG 1715, HU 800/6-1, HU 800/7-1), B.Q. (QU116/6-2, RTG1715), J.W. (WE1406/13-1), the Cluster of Excellence ‘Macromolecular Complexes’ of the Goethe University Frankfurt (EXC115), LOEWE grant Ub-Net and LOEWE Centrum for Gene and Cell therapy Frankfurt and the European Research Council/ERC grant agreement number (250241-LineUb) to I.D. F.R. is supported by ECHO (700.59.003), ALW Open Program (821.02.017 and 822.02.014), DFG-NWO cooperation (DN82-303) and ZonMW VICI (016.130.606) grants. P.G. is supported by the 7.FP, COFUND, Goethe International Postdoc Programme GO-IN, No. 291776.

Author information

Author notes

    • Aliaksandr Khaminets
    •  & Theresa Heinrich

    These authors contributed equally to this work.

    • Ingo Kurth
    • , Christian A. Hübner
    •  & Ivan Dikic

    These authors jointly supervised this work.

Affiliations

  1. Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

    • Aliaksandr Khaminets
    • , Paolo Grumati
    • , Alexandra Stolz
    •  & Ivan Dikic
  2. Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany

    • Theresa Heinrich
    • , Antje K. Huebner
    • , Lutz Liebmann
    • , Ingo Kurth
    •  & Christian A. Hübner
  3. Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands

    • Muriel Mari
    • , Mario Mauthe
    •  & Fulvio Reggiori
  4. Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands

    • Muriel Mari
    • , Mario Mauthe
    •  & Fulvio Reggiori
  5. Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany

    • Masato Akutsu
    •  & Ivan Dikic
  6. Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmühlenweg 1, 07743 Jena, Germany

    • Sandor Nietzsche
  7. Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany

    • Nicole Koch
    •  & Britta Qualmann
  8. Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany

    • Istvan Katona
    •  & Joachim Weis
  9. Institute of Immunology, School of Medicine University of Split, Mestrovicevo setaliste bb, 21 000 Split, Croatia

    • Ivan Dikic

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Contributions

A.K. performed biochemical analyses, immunofluorescence and cellular localization, functional analysis and contributed to interpretation of data and manuscript writing and preparation. T.H. characterized Fam134b–/– mice, carried out FAM134B topology analysis and contributed to manuscript preparation. M.Mar. performed transmission electron microscopy of cells and neurons in culture. P.G. performed apoptosis and autophagy analysis, and contributed to manuscript preparation and writing. A.K.H. generated the Fam134b–/– mouse model and was involved in mouse phenotyping. M.A. performed crystal structure assay. L.L. performed the electrophysiological analysis of Fam134b–/– mice. S.N., I. Ka. and J.W. performed transmission electron microscopy on murine tissues. A.S. performed fractionation and autophagy flux experiments. M.Mau. carried out the assay for the turnover of long-lived proteins. N.K. performed liposome assays, B.Q. supervised liposome assays. F.R., I.Ku., C.A.H. and I.D. designed the study, analysed data and wrote the manuscript. I.Ku., C.A.H. and I.D. contributed equally to the study. All the authors discussed the results and the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ingo Kurth or Christian A. Hübner or Ivan Dikic.

Extended data

Supplementary information

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    Supplementary Information

    This file contains the Western blot scans for figures 1, 3, 4 in the main paper and extended data figures 1, 2, 4, 5, 6, 7, 8. It also contains Supplementary Tables 1 and 2.

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https://doi.org/10.1038/nature14498

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