TY - JOUR
T1 - Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD
AU - Schultz, Mark L.
AU - Krus, Kelsey L.
AU - Kaushik, Susmita
AU - Dang, Derek
AU - Chopra, Ravi
AU - Qi, Ling
AU - Shakkottai, Vikram G.
AU - Cuervo, Ana Maria
AU - Lieberman, Andrew P.
N1 - Funding Information:
We thank Dr. Daniel Ory for the gift of I1061T Npc1 mice, Drs. Billy Tsai, Andrew Brown, and Ivan Dikic for providing plasmids, and Dr. Cristin Davidson for sharing the NPC1 staining protocol. We are grateful to Kayla Capper for creating the scientific illustration. This work was supported by the U.S. National Institutes of Health (R01 NS063967 to A.P.L., T32 NS007222 to M.L.S., R01 GM113188 to L.Q., R01 NS085054 to V.G.S., and P01 AG031782 to A.M.C.), SOAR-VPN (to A.P.L. and A.M.C), the University of Michigan Protein Folding Diseases Initiative, and the University of Pennsylvania Orphan Disease Center (to A.P.L.).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-06115-2
DO - 10.1038/s41467-018-06115-2
M3 - Article
C2 - 30202070
AN - SCOPUS:85053202256
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3671
ER -
