BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
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DOI：
10.1371/journal.pbio.1000415
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发表时间：
2010-07-06
期刊：
影响因子：
9.8
通讯作者：
Walter P
中科院分区：
文献类型：
--
作者：
Pincus D;Chevalier MW;Aragón T;van Anken E;Vidal SE;El-Samad H;Walter P
未折叠蛋白响应的计算建模和实验揭示了er -驻地伴侣蛋白BiP在微调系统响应动力学中的作用。未折叠蛋白反应（UPR）是一种细胞内信号通路，可抵消内质网（ER）中损害蛋白质折叠的可变应力。因此，普遍定期审议被认为是一个根据需要精细调节内质网蛋白折叠能力和内质网丰度的稳态调节器。内质网应激传感器Ire1被未折叠蛋白激活的机制以及内质网伴侣蛋白BiP在Ire1调控中的作用尚不清楚。在这里，我们表明UPR通过调节Ire1信号传导的持续时间来匹配其输出与应力的大小。BiP结合Ire1的作用是使Ire1对低水平的应激脱敏，并在有利的折叠条件恢复到内质网时促进其失活。我们提出，从机制上讲，BiP通过隔离非活性Ire1分子来实现这些功能，从而为寡聚化和活化提供屏障，并提供稳定的相互作用，促进去寡聚化和失活。因此，BiP与Ire1的结合或从Ire1中释放并不像之前提出的那样有助于开关UPR。相比之下，BiP为不活跃的Ire1分子提供缓冲，通过调节Ire1活性的敏感性和动态，确保适当的反应来恢复内质网的蛋白质折叠稳态。分泌蛋白和跨膜蛋白构成真核细胞产生的每三种蛋白质中的一种。许多这些蛋白质最初在内质网（ER）中折叠和组装。各种生理和环境条件可增加对内质网的需求，使内质网蛋白折叠机制不堪重负。为了恢复内质网应激的稳态，细胞激活了一种称为未折叠蛋白反应（UPR）的细胞内信号通路，根据需要调节内质网的折叠能力。它的失败会损害细胞活力，并与许多疾病状态有关。在这项研究中，我们定量地询问普遍定期审议的稳态能力。我们得出了内质网应力传感器Ire1如何与其结合伙伴BiP（一种高度冗余的内质网伴侣）合作以微调UPR活性的机制模型。在预测计算模型和实验之间移动，我们表明Ire1的BiP释放不是激活Ire1的开关；相反，BiP调节Ire1的激活和失活动态。BiP与Ire1的结合及其解离以内质网应力依赖的方式缓冲了系统对轻度应力的影响。此外，当去除压力时，BiP结合加速Ire1失活。我们得出结论，BiP与Ire1结合可以通过调节其敏感性和关闭动力学来微调UPR的动态行为。Ire1和BiP之间相互作用的这种功能可能是其他低聚物形成和分解必须精细调节的系统的一般范例。
Computational modeling and experimentation in the unfolded protein response reveals a role for the ER-resident chaperone protein BiP in fine-tuning the system's response dynamics. The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity. Secreted and membrane-spanning proteins constitute one of every three proteins produced by a eukaryotic cell. Many of these proteins initially fold and assemble in the endoplasmic reticulum (ER). A variety of physiological and environmental conditions can increase the demands on the ER, overwhelming the ER protein folding machinery. To restore homeostasis in response to ER stress, cells activate an intracellular signaling pathway called the unfolded protein response (UPR) that adjusts the folding capacity of the ER according to need. Its failure impairs cell viability and has been implicated in numerous disease states. In this study, we quantitatively interrogate the homeostatic capacity of the UPR. We arrive at a mechanistic model for how the ER stress sensor Ire1 cooperates with its binding partner BiP, a highly redundant ER chaperone, to fine-tune UPR activity. Moving between a predictive computational model and experiments, we show that BiP release from Ire1 is not the switch that activates Ire1; rather, BiP modulates Ire1 activation and deactivation dynamics. BiP binding to Ire1 and its dissociation in an ER stress-dependent manner buffers the system against mild stresses. Furthermore, BiP binding accelerates Ire1 deactivation when stress is removed. We conclude that BiP binding to Ire1 serves to fine-tune the dynamic behavior of the UPR by modulating its sensitivity and shutoff kinetics. This function of the interaction between Ire1 and BiP may be a general paradigm for other systems in which oligomer formation and disassembly must be finely regulated.
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DOI：
10.1083/jcb.200907074
发表时间：
2009-11-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Schuck S;Prinz WA;Thorn KS;Voss C;Walter P
通讯作者：
Walter P
影响因子：
7.8
作者：
Kimata, Yukio;Ishiwata-Kimata, Yuki;Ito, Tatsuhiko;Hirata, Aiko;Suzuki, Tomohide;Oikawa, Daisuke;Takeuchi, Masato;Kohno, Kenji
通讯作者：
Kohno, Kenji
影响因子：
3.3
作者：
Kawahara, T;Yanagi, H;Mori, K
通讯作者：
Mori, K
在细胞内信号网络中，剂量到延伸的编码和信号超出饱和度。
影响因子：
4.3
作者：
Behar, Marcelo;Hao, Nan;Dohlman, Henrik G.;Elston, Timothy C.
通讯作者：
Elston, Timothy C.
DOI：
10.1006/bbrc.2000.3987
发表时间：
2000-12-20
影响因子：
3.1
作者：
Okamura, K;Kimata, Y;Kohno, K
通讯作者：
Kohno, K