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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


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.


  1. 1.

    , & Endoplasmic reticulum architecture: structures in flux. Curr. Opin. Cell Biol. 18, 358–364 (2006)

  2. 2.

    & The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011)

  3. 3.

    , , , & Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J. Cell Biol. 187, 525–536 (2009)

  4. 4.

    , , , & Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein. Proc. Natl Acad. Sci. USA 108, 7832–7837 (2011)

  5. 5.

    , , & Starvation triggers the delivery of the endoplasmic reticulum to the vacuole via autophagy in yeast. Traffic 6, 56–65 (2005)

  6. 6.

    , & Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, e423 (2006)

  7. 7.

    et al. Cell cycle-dependent induction of autophagy, mitophagy and reticulophagy. Cell Cycle 6, 2263–2267 (2007)

  8. 8.

    & Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol. 17, 279–285 (2007)

  9. 9.

    et al. Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy. Nature Genet. 41, 1179–1181 (2009)

  10. 10.

    , & Cargo recognition and trafficking in selective autophagy. Nature Cell Biol. 16, 495–501 (2014)

  11. 11.

    , & Biogenesis and cargo selectivity of autophagosomes. Annu. Rev. Biochem. 80, 125–156 (2011)

  12. 12.

    , , & Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell 53, 167–178 (2014)

  13. 13.

    et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505–516 (2009)

  14. 14.

    et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011)

  15. 15.

    et al. Structural basis for phosphorylation-triggered autophagic clearance of Salmonella. Biochem. J. 454, 459–466 (2013)

  16. 16.

    , , , & A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124, 573–586 (2006)

  17. 17.

    et al. Mechanisms determining the morphology of the peripheral ER. Cell 143, 774–788 (2010)

  18. 18.

    , & ER-phagy mediates selective degradation of endoplasmic reticulum independently of the core autophagy machinery. J. Cell Sci. 127, 4078–4088 (2014)

  19. 19.

    , & Reticulophagy and ribophagy: regulated degradation of protein production factories. Int. J. Cell Biol. 2012, 182834 (2012)

  20. 20.

    et al. A spastic paraplegia mouse model reveals REEP1-dependent ER shaping. J. Clin. Invest. 123, 4273–4282 (2013)

  21. 21.

    & Membrane-shaping disorders: a common pathway in axon degeneration. Brain 137, 3109–3121 (2014)

  22. 22.

    & Emerging themes of ER organization in the development and maintenance of axons. Curr. Opin. Neurobiol. 20, 531–537 (2010)

  23. 23.

    , & A simple embedding technique for monolayer neuronal cultures grown in plastic flasks. Acta Anat. 107, 221–223 (1980)

  24. 24.

    , , & The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. Dev. Cell 26, 9–18 (2013)

  25. 25.

    et al. Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature (2015)

  26. 26.

    , , & Network organization of the human autophagy system. Nature 466, 68–76 (2010)

  27. 27.

    et al. Golgi inheritance in mammalian cells is mediated through endoplasmic reticulum export activities. Mol. Biol. Cell 17, 990–1005 (2006)

  28. 28.

    , , & Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000)

  29. 29.

    et al. Subdomain-specific localization of CLIMP-63 (p63) in the endoplasmic reticulum is mediated by its luminal alpha-helical segment. J. Cell Biol. 153, 1287–1300 (2001)

  30. 30.

    et al. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 9, 493–501 (2003)

  31. 31.

    et al. Rab GTPase-activating proteins in autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol. Cell. Biol. 32, 1733–1744 (2012)

  32. 32.

    et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004)

  33. 33.

    , , & The transmembrane domain of a carboxyl-terminal anchored protein determines localization to the endoplasmic reticulum. J. Biol. Chem. 272, 1970–1975 (1997)

  34. 34.

    , & siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J. Biol. Chem. 282, 25464–25474 (2007)

  35. 35.

    et al. Mouse hepatitis coronavirus RNA replication depends on GBF1-mediated ARF1 activation. PLoS Pathog. 4, e1000088 (2008)

  36. 36.

    & Cryosectioning and immunolabeling. Nature Protocols 2, 2480–2491 (2007)

  37. 37.

    et al. A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system. PLoS Genet. 9, e1003988 (2013)

  38. 38.

    , & Animal models of nociception. Pharmacol. Rev. 53, 597–652 (2001)

Download references


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.


  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


  1. Search for Aliaksandr Khaminets in:

  2. Search for Theresa Heinrich in:

  3. Search for Muriel Mari in:

  4. Search for Paolo Grumati in:

  5. Search for Antje K. Huebner in:

  6. Search for Masato Akutsu in:

  7. Search for Lutz Liebmann in:

  8. Search for Alexandra Stolz in:

  9. Search for Sandor Nietzsche in:

  10. Search for Nicole Koch in:

  11. Search for Mario Mauthe in:

  12. Search for Istvan Katona in:

  13. Search for Britta Qualmann in:

  14. Search for Joachim Weis in:

  15. Search for Fulvio Reggiori in:

  16. Search for Ingo Kurth in:

  17. Search for Christian A. Hübner in:

  18. Search for Ivan Dikic in:


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

PDF files

  1. 1.

    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.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.