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DOI | 10.1038/s41467-019-08635-x |
Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD | |
Schultz, Mark L.1; Krus, Kelsey L.1; Kaushik, Susmita2; Dang, Derek1; Chopra, Ravi3,4; Qi, Ling5; Shakkottai, Vikram G.4,5; Cuervo, Ana Maria2; Lieberman, Andrew P.1 | |
2019-02-14 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | 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. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000444078300014 |
WOS关键词 | RETICULUM-ASSOCIATED DEGRADATION ; NIEMANN-PICK-DISEASE ; ENDOPLASMIC-RETICULUM ; C DISEASE ; SQUALENE MONOOXYGENASE ; CHOLESTEROL-SYNTHESIS ; LIPID-STORAGE ; PROTEIN ; PROTEOSTASIS ; INSIGHTS |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204221 |
专题 | 资源环境科学 |
作者单位 | 1.Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA; 2.Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA; 3.Univ Michigan, Sch Med, Med Scientist Training Program, Ann Arbor, MI 48109 USA; 4.Univ Michigan, Sch Med, Dept Neurol, Ann Arbor, MI 48109 USA; 5.Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA |
推荐引用方式 GB/T 7714 | Schultz, Mark L.,Krus, Kelsey L.,Kaushik, Susmita,et al. Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD[J]. NATURE COMMUNICATIONS,2019,9. |
APA | Schultz, Mark L..,Krus, Kelsey L..,Kaushik, Susmita.,Dang, Derek.,Chopra, Ravi.,...&Lieberman, Andrew P..(2019).Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD.NATURE COMMUNICATIONS,9. |
MLA | Schultz, Mark L.,et al."Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD".NATURE COMMUNICATIONS 9(2019). |
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