Regulation of endoplasmic reticulum turnover by selective autophagy

Nature. 2015 Jun 18;522(7556):354-8. doi: 10.1038/nature14498. Epub 2015 Jun 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Autophagy / physiology*
  • Biomarkers / metabolism
  • Cell Line
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / metabolism*
  • Female
  • Gene Deletion
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysosomes / metabolism
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Phagosomes / metabolism
  • Protein Binding
  • Sensory Receptor Cells / metabolism
  • Sensory Receptor Cells / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Biomarkers
  • Fam134b protein, mouse
  • GABARAP protein, human
  • Intracellular Signaling Peptides and Proteins
  • Map1lc3b protein, mouse
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • RETREG1 protein, human
  • light chain 3, human

Associated data

  • PDB/4ZDV