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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article number3671
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Autophagy
degradation
Degradation
machinery
Proteasome Endopeptidase Complex
Fractionation
mutations
fractionation
Machinery
mice
lipids
Glycoproteins
disorders
Tissue
proteins
Lipids
Neurodegenerative Diseases
Substrates
Mutation
Proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD. / Schultz, Mark L.; Krus, Kelsey L.; Kaushik, Susmita; Dang, Derek; Chopra, Ravi; Qi, Ling; Shakkottai, Vikram G.; Cuervo, Ana Maria; Lieberman, Andrew P.

In: Nature Communications, Vol. 9, No. 1, 3671, 01.12.2018.

Research output: Contribution to journalArticle

Schultz, Mark L. ; Krus, Kelsey L. ; Kaushik, Susmita ; Dang, Derek ; Chopra, Ravi ; Qi, Ling ; Shakkottai, Vikram G. ; Cuervo, Ana Maria ; Lieberman, Andrew P. / Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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