THE KDEL RECEPTOR INDUCES AUTOPHAGY TO PROMOTE THE CLEARANCE OF NEURODEGENERATIVE DISEASE-RELATED PROTEINS
THE KDEL RECEPTOR INDUCES AUTOPHAGY TO PROMOTE THE CLEARANCE OF NEURODEGENERATIVE DISEASE-RELATED PROTEINS
复制标题
KDEL受体诱导自噬促进神经退行性疾病相关蛋白的清除
DOI：
10.1016/j.neuroscience.2011.06.008
复制
发表时间：
2011-09-05
期刊：
影响因子：
3.3
通讯作者：
Wang, G.
中科院分区：
文献类型：
--
作者：
Wang, P.;Li, B.;Wang, G.
内质网（ER）应激参与神经退行性疾病，KDEL （Lys-Asp-Glu-Leu motif）受体（KDELR）在内质网质量控制和内质网应激反应中起关键作用。KDELR的亚细胞分布是动态的，与其配体结合状态和表达水平有关。在这里，我们发现KDELR mRNA在信号素处理后上调，从而诱导内质网应激。此外，过表达的KDELR部分重新分配到溶酶体并激活自噬。R169N突变体是KDELR的配体结合缺陷形式，D193N是KDELR的运输缺陷形式，两者都不能触发自噬。KDELR的过表达激活细胞外信号调节激酶（ERKs）。有丝分裂原细胞外激酶1 （MEK1）抑制剂PD98059可阻断ERKs的活化和KDELR诱导的自噬。一些神经退行性疾病相关蛋白的过表达，如肌萎缩侧索硬化症（ALS）相关的G93A超氧化物歧化酶1 （SOD1）、帕金森病相关的A53T α -突触核蛋白和亨廷顿病相关的扩展亨廷顿蛋白，会增加KDELR的mRNA水平。此外，过表达的KDELR通过自噬促进这些疾病蛋白的清除。综上所述，我们的数据提供了证据，证明KDELR作为一种新的自噬诱导剂，参与了错误折叠的神经退行性疾病相关蛋白的降解。(c) 2011 ibro。Elsevier Ltd.出版。版权所有。
Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases, and the KDEL (Lys-Asp-Glu-Leu motif) receptor (KDELR) plays a key role in ER quality control and in the ER stress response. The subcellular distribution of KDELR is dynamic and related to its ligand binding status and its expression level. Here, we show that KDELR mRNA is upregulated upon thapsigargin treatment, which induces ER stress. Moreover, overexpressed KDELR partially redistributes to the lysosome and activates autophagy. The R169N mutant, a ligand binding-defective form of KDELR, and D193N, a transport-defective form of KDELR, both fail to trigger autophagy. Overexpression of KDELR activates extracellular signal-regulated kinases (ERKs). Both the activation of ERKs and autophagy induced by KDELR could be blocked by PD98059, an inhibitor of mitogen extracellular kinase 1 (MEK1). The overexpression of some neurodegenerative disease-related proteins, such as amyotrophic lateral sclerosis (ALS)-linked G93A superoxide dismutase 1 (SOD1), Parkinson's disease-associated A53T alpha-synuclein and Huntington's disease-related expanded huntingtin, increase the mRNA levels of KDELR. Moreover, the overexpressed KDELR promotes the clearance of these disease proteins through autophagy. Taken together, our data provide evidence that KDELR, as a novel inducer of autophagy, participates in the degradation of misfolded neurodegenerative disease-related proteins. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.