Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Nat Commun. 2018 Sep 10;9(1):3671. doi: 10.1038/s41467-018-06115-2.
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.
尼曼-匹克 C 型病是一种致命的、进行性的神经退行性疾病，由 NPC1 的功能丧失突变引起，NPC1 是一种多跨膜糖蛋白，对细胞内脂质运输至关重要。我们试图确定控制最常见致病突变体 I1061T NPC1 降解的细胞机制。我们表明，这种突变体部分通过依赖 MARCH6 的 ERAD 通过蛋白酶体降解。出乎意料的是，我们证明 I1061T NPC1 也被一种称为选择性内质网自噬（ER-phagy）的新描述的自噬途径降解。我们在体外和体内确定了 ER-phagy 的重要性，并将 I1061T 确定为该 FAM134B 依赖性过程的错误折叠内源性底物。I1061T Npc1 小鼠组织的亚细胞分级分离和人样本分析显示 ER-phagy 的关键成分发生改变，包括 FAM134B。我们的数据表明，I1061T NPC1 在 ER 中被识别，并通过两种不同的途径降解，这两种途径以互补的方式发挥作用以调节蛋白质周转。
