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 ()
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Mark L. Schultz: University of Michigan School of Medicine
Kelsey L. Krus: University of Michigan School of Medicine
Susmita Kaushik: Albert Einstein College of Medicine
Derek Dang: University of Michigan School of Medicine
Ravi Chopra: University of Michigan Medical School
Ling Qi: University of Michigan
Vikram G. Shakkottai: University of Michigan Medical School
Ana Maria Cuervo: Albert Einstein College of Medicine
Andrew P. Lieberman: University of Michigan School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06115-2

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