A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis.
A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis.
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DOI：
10.1016/j.celrep.2018.05.093
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发表时间：
2018-06-26
期刊：
影响因子：
8.8
通讯作者：
van Oosten-Hawle P
中科院分区：
文献类型：
--
作者：
O'Brien D;Jones LM;Good S;Miles J;Vijayabaskar MS;Aston R;Smith CE;Westhead DR;van Oosten-Hawle P
在后生动物中，经历蛋白毒性应激的组织诱导“跨细胞伴侣信号传导”（TCS），其激活远端组织中的分子伴侣，如HSP-90。这种形式的组织间通讯是如何介导上调系统性伴侣蛋白表达的，以及它是否可以用来防止蛋白质错误折叠疾病仍然是悬而未决的问题。使用秀丽隐杆线虫，我们确定了系统性应激信号通路的关键组成部分，该通路将先天免疫应答与蛋白质稳态维持联系起来。我们发现，轻微扰动的神经元或肠道蛋白质稳态激活TCS通过加塔锌指转录因子PQM-1。PQM-1通过先天免疫相关跨膜蛋白CLEC-41协调神经元激活的TCS，而精氨酸激活的TCS依赖于天冬氨酸蛋白酶ASP-12。两种TCS途径均可诱导肌细胞中的hsp-90，并促进Aβ3-42相关毒性的改善。这可能对蛋白质稳态功能障碍相关疾病的治疗具有重要意义。PQM-1在神经元或肠道中被激活以诱导TCS介导的hsp-90表达神经元诱导的TCS通过PQM-1/CLEC-41信号传导介导肠道诱导的TCS通过PQM-1/ASP-12信号传导介导TCS通过PQM-1是蛋白质稳态和减少淀粉样蛋白β错误折叠所需的奥布莱恩等人。发现加塔转录因子PQM-1作为跨细胞伴侣信号传导（TCS）的介导剂发挥作用。根据发送组织，PQM-1激活神经元特异性或神经氨酸特异性TCS途径，触发远端组织中的hsp-90表达。TCS介导的hsp-90诱导减少淀粉样蛋白β寡聚化和毒性。
In metazoans, tissues experiencing proteotoxic stress induce “transcellular chaperone signaling” (TCS) that activates molecular chaperones, such as hsp-90, in distal tissues. How this form of inter-tissue communication is mediated to upregulate systemic chaperone expression and whether it can be utilized to protect against protein misfolding diseases remain open questions. Using C. elegans, we identified key components of a systemic stress signaling pathway that links the innate immune response with proteostasis maintenance. We show that mild perturbation of proteostasis in the neurons or the intestine activates TCS via the GATA zinc-finger transcription factor PQM-1. PQM-1 coordinates neuron-activated TCS via the innate immunity-associated transmembrane protein CLEC-41, whereas intestine-activated TCS depends on the aspartic protease ASP-12. Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Aβ3-42-associated toxicity. This may have powerful implications for the treatment of diseases related to proteostasis dysfunction. PQM-1 is activated in the neurons or gut to induce TCS-mediated hsp-90 expression Neuron-induced TCS is mediated via PQM-1/CLEC-41 signaling Intestine-induced TCS is mediated via PQM-1/ASP-12 signaling TCS via PQM-1 is required for proteostasis and reduces amyloid beta misfolding O’Brien et al. find that the GATA transcription factor PQM-1 functions as a mediator of transcellular chaperone signaling (TCS). Depending on the sender tissue, PQM-1 activates a neuron-specific or intestine-specific TCS route that triggers hsp-90 expression in remote tissues. TCS-mediated hsp-90 induction reduces amyloid beta oligomerization and toxicity.
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影响因子：
64.8
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10.5
作者：
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