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

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

Author information

1
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
2
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
3
Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
4
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
5
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
6
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA. liebermn@umich.edu.

Abstract

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.

PMID:
30202070
PMCID:
PMC6131187
DOI:
10.1038/s41467-018-06115-2
[Indexed for MEDLINE]
Free PMC Article

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