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Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation

机译：HSF1降解和UPR激活的双向相互作用促进tau过度磷酸化

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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.
机译：内质网（ER）中未折叠的蛋白质反应（UPR）和细胞质热应激反应是维持蛋白质稳定以维持细胞健康所必需的两个主要应激反应系统。这些系统中的任何一个发生故障，例如持续的UPR激活或热休克响应激活不足，都可能导致神经变性的发展。通过热休克因子1（HSF1）的激活来缓解ER应力并增强热休克反应，以前被认为是阿尔茨海默氏病（AD）（一种普遍且具破坏性的tauopathy）的诱人潜在治疗靶标。了解上述两个系统之间的相互作用以及它们在AD中的协同作用仍然难以捉摸。在这里，我们报告在人类大脑和tau致病性小鼠模型（rTg4510，PS19和rTg21221）中进行的研究，这些研究确定了HSF1降解和UPR激活是异常tau发病机理的前体。我们证明化学内质网应激诱导物引起自噬溶酶体HSF1降解，导致大鼠原代神经元中的tau过度磷酸化。此外，永久性HSF1丢失会反向导致慢性UPR激活，导致老年HSF1杂合敲除小鼠海马中异常的tau磷酸化和聚集。在稳定过表达促聚集突变体TauRDΔK280（N2a-TauRDΔK280）的N2a细胞中，UPR激活和HSF1丢失的有害相互作用加剧了。我们通过显示UPR凋亡途径中编码C / EBP同源蛋白（CHOP）激活的基因促进HSF1降解，从而提供了这两种应激反应系统如何相互交织的证据，这可能进一步通过ER伴侣HSP70 a5延长了UPR （BiP / GRP78）抑制。 HSF1的上调通过降低CHOP和增加HSP70 a5（BiP / GRP78）减轻N2a-TauRDΔK280中的tau毒性。我们的工作揭示了两个压力反应系统之间的双向串扰如何促进早期tau病理，并确定HSF1是两个系统中的一个可能的关键参与者。

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