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

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.

Authors

Mark L Schultz¹, Kelsey L Krus¹, Susmita Kaushik², Derek Dang¹, Ravi Chopra^{3

4}, Ling Qi⁵, Vikram G Shakkottai^{4

5}, Ana Maria Cuervo², Andrew P Lieberman⁶

Affiliations

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. [email protected].

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding