Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD

Nat Commun. 2018 Sep 10;9(1):3671. doi: 10.1038/s41467-018-06115-2.


Niemann-Pick type C disease is a fatal, progressive neurodegenerative disorder caused by loss-of-function mutations in NPC1, a multipass transmembrane glycoprotein essential for intracellular lipid trafficking. We sought to define the cellular machinery controlling degradation of the most common disease-causing mutant, I1061T NPC1. We show that this mutant is degraded, in part, by the proteasome following MARCH6-dependent ERAD. Unexpectedly, we demonstrate that I1061T NPC1 is also degraded by a recently described autophagic pathway called selective ER autophagy (ER-phagy). We establish the importance of ER-phagy both in vitro and in vivo, and identify I1061T as a misfolded endogenous substrate for this FAM134B-dependent process. Subcellular fractionation of I1061T Npc1 mouse tissues and analysis of human samples show alterations of key components of ER-phagy, including FAM134B. Our data establish that I1061T NPC1 is recognized in the ER and degraded by two different pathways that function in a complementary fashion to regulate protein turnover.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Brain / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum-Associated Degradation
  • Fibroblasts / metabolism
  • Homozygote
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysosomes / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation
  • Niemann-Pick C1 Protein
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Transport
  • Proteins / genetics
  • Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Vinblastine / pharmacology


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Mutant Proteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • Npc1 protein, mouse
  • Proteins
  • Vinblastine
  • MARCHF6 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex