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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Protein Data Bank
Atomic coordinates of the crystal structure of FAM134B-LIR–LC3A have been deposited in the Protein Data Bank under accession number 4ZDV.
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.
Extended data figures
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
Neuroscience Letters (2019)