Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation.
Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation.
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HSF1 降解和 UPR 激活的双向相互作用促进 tau 过度磷酸化。
DOI：
10.1371/journal.pgen.1006849
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发表时间：
2017-07
期刊：
影响因子：
4.5
通讯作者：
Liao FF
中科院分区：
文献类型：
--
作者：
Kim E;Sakata K;Liao FF
内质网（ER）中的未折叠蛋白反应（UPR）和细胞质热应激反应是维持细胞健康蛋白稳态所必需的两个主要应激反应系统。这些系统中的任何一个的失败，例如持续的UPR激活或不充分的热休克反应激活，都可能导致神经变性的发展。通过热休克因子1（HSF 1）活化减轻ER应激和增强热休克反应先前已被认为是阿尔茨海默病（AD）-一种流行的和破坏性的tau蛋白病的有吸引力的潜在治疗靶点。理解上述两个系统的相互作用及其在AD中的合作作用仍然是难以捉摸的。在这里，我们报告了在人脑和tau致病性小鼠模型（rTg 4510，PS19和rTg 21221）的研究，确定HSF 1降解和UPR激活作为异常tau发病机制的前体。我们证明，化学ER应激诱导剂引起自噬-溶酶体HSF 1降解，导致大鼠原代神经元中tau蛋白过度磷酸化。此外，永久性HSF 1缺失可导致慢性UPR激活，导致老年HSF 1杂合敲除小鼠海马中tau蛋白磷酸化和聚集异常。UPR激活和HSF 1丢失的有害相互作用在稳定过表达促聚集突变体TauRD ΔK280（N2 a-TauRD ΔK280）的N2 a细胞中加剧。我们提供了这两个应激反应系统是如何内在交织的证据，通过显示编码C/EBP同源蛋白（CHOP）的基因在UPR凋亡途径中的激活促进HSF 1降解，这可能进一步有助于通过ER伴侣HSP 70 α 5（BiP/GRP 78）抑制延长UPR。上调HSF 1通过减少CHOP和增加HSP 70 α 5（BiP/GRP 78）来减轻N2 a-TauRD ΔK280中的tau毒性。我们的工作揭示了两个应激反应系统之间的双向串扰如何促进早期tau病理，并确定HSF 1可能是两个系统中的关键参与者。包括阿尔茨海默病（AD）在内的Tau病的特征在于脑中tau聚集体的积聚，这与细胞蛋白质稳态的失败高度相关。蛋白质稳定可以通过蛋白质质量控制系统来实现，以科普许多应激，例如错误折叠蛋白质的蛋白毒性应激。这种细胞保护系统包括由热休克因子1（HSF 1）激活调节的热休克反应和ER中未折叠蛋白反应。尽管应激反应在维持蛋白质稳态中的重要性，但它们在神经退行性疾病如tau蛋白病中的作用尚不清楚。目前的研究报告了两种应激反应系统，未折叠蛋白反应和HSF 1之间的相互作用如何促进早期tau病理学，并确定HSF 1蛋白降解是人类AD和tau转基因小鼠AD模型中的一个可能的关键参与者。我们在HSF 1杂合基因敲除小鼠的海马中发现了与年龄相关的AD样神经病理学变化。我们推测，HSF 1的损失可能构成了一个机制之间的联系ER压力和tau蛋白过度磷酸化的tau病理。本研究证实了稳定HSF 1蛋白在治疗AD中的潜在治疗意义。
The unfolded protein response (UPR) in the endoplasmic reticulum (ER) and the cytoplasmic heat stress response are two major stress response systems necessary for maintaining proteostasis for cellular health. Failure of either of these systems, such as in sustained UPR activation or in insufficient heat shock response activation, can lead to the development of neurodegeneration. Alleviation of ER stress and enhancement of heat shock response through heat shock factor 1 (HSF1) activation have previously been considered as attractive potential therapeutic targets for Alzheimer’s disease (AD)—a prevalent and devastating tauopathy. Understanding the interplay of the two aforementioned systems and their cooperative role in AD remain elusive. Here we report studies in human brain and tau pathogenic mouse models (rTg4510, PS19, and rTg21221), identifying HSF1 degradation and UPR activation as precursors of aberrant tau pathogenesis. We demonstrate that chemical ER stress inducers caused autophagy-lysosomal HSF1 degradation, resulting in tau hyperphosphorylation in rat primary neurons. In addition, permanent HSF1 loss reversely causes chronic UPR activation, leading to aberrant tau phosphorylation and aggregation in the hippocampus of aged HSF1 heterozygous knock-out mice. The deleterious interplay of UPR activation and HSF1 loss is exacerbated in N2a cells stably overexpressing a pro-aggregation mutant TauRD ΔK280 (N2a-TauRD ΔK280). We provide evidence of how these two stress response systems are intrinsically interweaved by showing that the gene encoding C/EBP-homologous protein (CHOP) activation in the UPR apoptotic pathway facilitates HSF1 degradation, which likely further contributes to prolonged UPR via ER chaperone HSP70 a5 (BiP/GRP78) suppression. Upregulating HSF1 relieves the tau toxicity in N2a-TauRD ΔK280 by reducing CHOP and increasing HSP70 a5 (BiP/GRP78). Our work reveals how the bidirectional crosstalk between the two stress response systems promotes early tau pathology and identifies HSF1 being one likely key player in both systems. Tauopathy including Alzheimer’s disease (AD) is characterized by a build-up of tau aggregates in the brain, highly associated with failure of cellular protein homeostasis. Proteostasis can be achieved by protein quality control system to cope with numerous stresses such as proteotoxic stress from misfolded proteins. This cellular protective system includes heat shock response regulated by heat shock factor 1 (HSF1) activation and unfolded protein response in ER. Despite the importance of stress response in maintaining proteostasis, their role in neurodegenerative diseases like tauopathy is not clearly understood. The current study reports how the interplay between the two stress response systems, unfolded protein response and HSF1 promotes early tau pathology and identifies HSF1 protein degradation being one likely key player in both human AD and tau transgenic mouse AD models. We identify aging-associated AD-like neuropathological changes in the hippocampus of HSF1 heterozygous knock-out mice. We speculate that that HSF1 loss may constitute a mechanistic connection between ER stress and tau hyperphosphorylation in tau pathology. This study demonstrates the potential therapeutic significance of stabilizing HSF1 protein in treating AD.
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DOI：
10.1083/jcb.101.4.1371
发表时间：
1985-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Binder LI;Frankfurter A;Rebhun LI
通讯作者：
Rebhun LI
影响因子：
16.6
作者：
Gomez-Pastor R;Burchfiel ET;Neef DW;Jaeger AM;Cabiscol E;McKinstry SU;Doss A;Aballay A;Lo DC;Akimov SS;Ross CA;Eroglu C;Thiele DJ
通讯作者：
Thiele DJ
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
5.3
作者：
Abisambra, Jose F.;Jinwal, Umesh K.;Dickey, Chad A.
通讯作者：
Dickey, Chad A.
影响因子：
4.7
作者：
BUTLER, M;SHELANSKI, ML
通讯作者：
SHELANSKI, ML