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

Mark L Schultz; Kelsey L Krus; Susmita Kaushik; Derek Dang; Ravi Chopra; Ling Qi; Vikram G Shakkottai; Ana Maria Cuervo; Andrew P Lieberman

doi:10.1038/s41467-018-06115-2

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

Journal article

Open access

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

Mark L Schultz, Kelsey L Krus, Susmita Kaushik, Derek Dang, Ravi Chopra, Ling Qi, Vikram G Shakkottai, Ana Maria Cuervo and Andrew P Lieberman

Nature communications, Vol.9(1), pp.3671-13

09/10/2018

DOI: 10.1038/s41467-018-06115-2

PMCID: PMC6131187

PMID: 30202070

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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.

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

Proteasome Endopeptidase Complex - metabolism

Protein Transport

Proteins - genetics

Proteins - metabolism

Ubiquitin-Protein Ligases - genetics

Ubiquitin-Protein Ligases - metabolism

Vinblastine - pharmacology

Details

Title: Subtitle: Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD
Creators: Mark L Schultz - Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
Kelsey L Krus - University of Michigan
Susmita Kaushik - Albert Einstein College of Medicine
Derek Dang - University of Michigan
Ravi Chopra - University of Michigan
Ling Qi - University of Michigan
Vikram G Shakkottai - University of Michigan
Ana Maria Cuervo - Albert Einstein College of Medicine
Andrew P Lieberman - University of Michigan
Resource Type: Journal article
Publication Details: Nature communications, Vol.9(1), pp.3671-13
DOI: 10.1038/s41467-018-06115-2
PMID: 30202070
PMCID: PMC6131187
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R01 DK120047 / NIDDK NIH HHS R01 NS085054 / NINDS NIH HHS R37 AG021904 / NIA NIH HHS T32 GM007863 / NIGMS NIH HHS R01 NS063967 / NINDS NIH HHS T32 NS007222 / NINDS NIH HHS P30 AG038072 / NIA NIH HHS R35 GM130292 / NIGMS NIH HHS P01 AG031782 / NIA NIH HHS R01 GM113188 / NIGMS NIH HHS
Language: English
Date published: 09/10/2018
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
Record Identifier: 9984366372302771

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