Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude.
Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude.
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DOI：
10.7554/elife.27518
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发表时间：
2017-12-18
期刊：
影响因子：
7.7
通讯作者：
van Anken E
中科院分区：
文献类型：
--
作者：
Bakunts A;Orsi A;Vitale M;Cattaneo A;Lari F;Tadè L;Sitia R;Raimondi A;Bachi A;van Anken E
内质网(ER)折叠能力不足会激活未折叠蛋白反应(UPR)以恢复内环境平衡。然而，UPR如何实现内质网稳态调整的研究很少，因为在大多数研究中，引发的内质网应激是无法克服的。在这里，我们证明了由免疫球蛋白M(S)分泌重链的持续表达引起的蛋白抑制剂损伤在HeLa细胞中具有良好的耐受性。在µS表达后，其水平暂时超过内质网伴侣蛋白BIP，导致急性、全面的UPR激活。一旦BIP再次超过，UPR就会转变为慢性、亚最大激活，这表明UPR以比率的方式感知内质网应激。在这个过程中，ER扩大了大约三倍，并由BiP主导。由于UPR对于HeLa-µS模型中成功的内质网稳态调整至关重要，因此它为剖析UPR如何评估和缓解内质网应激的错综复杂提供了一个理想的系统。
Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves ER homeostatic readjustment is poorly investigated, as in most studies the ER stress that is elicited cannot be overcome. Here we show that a proteostatic insult, provoked by persistent expression of the secretory heavy chain of immunoglobulin M (µs), is well-tolerated in HeLa cells. Upon µs expression, its levels temporarily eclipse those of the ER chaperone BiP, leading to acute, full-geared UPR activation. Once BiP is in excess again, the UPR transitions to chronic, submaximal activation, indicating that the UPR senses ER stress in a ratiometric fashion. In this process, the ER expands about three-fold and becomes dominated by BiP. As the UPR is essential for successful ER homeostatic readjustment in the HeLa-µs model, it provides an ideal system for dissecting the intricacies of how the UPR evaluates and alleviates ER stress.