The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation.
The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation.
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DOI：
10.1038/nm.2099
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发表时间：
2010-04
期刊：
影响因子：
82.9
通讯作者：
Ozcan, Umut
中科院分区：
文献类型：
--
作者：
Park, Sang Won;Zhou, Yingjiang;Lee, Justin;Lu, Allen;Sun, Cheng;Chung, Jason;Ueki, Kohjiro;Ozcan, Umut
尽管X-box结合蛋白-1 （XBP-1）是未折叠蛋白反应（UPR）的主要调节因子之一，但人们对XBP-1的调节因子知之甚少。在这里，我们发现磷脂酰肌醇3-激酶（PI3K）的调控亚基，p85α（由Pik3r1编码）和p85β（由Pik3r2编码）形成异源二聚体，被胰岛素治疗破坏。这种异源二聚化的破坏允许p85的单体与剪接形式的XBP-1 （XBP-1）相互作用，并增加核易位。在ob/ob小鼠中，p85和xbp -1之间的相互作用丧失，导致xbp -1向细胞核的易位严重缺陷，从而导致内质网（ER）应激的解决。当p85α和p85β在ob/ob小鼠肝脏中过表达时，这些缺陷得到改善。我们的研究结果定义了一个以前未知的胰岛素受体信号通路，并为肥胖期间内质网应激的发展提供了新的机制见解。
Despite the fact that X-box binding protein-1 (XBP-1) is one of the main regulators of the unfolded protein response (UPR), the modulators of XBP-1 are poorly understood. Here, we show that the regulatory subunits of phosphotidyl inositol 3-kinase (PI3K), p85α (encoded by Pik3r1) and p85β (encoded by Pik3r2) form heterodimers that are disrupted by insulin treatment. This disruption of heterodimerization allows the resulting monomers of p85 to interact with, and increase the nuclear translocation of, the spliced form of XBP-1 (XBP-1s). The interaction between p85 and XBP-1s is lost in ob/ob mice, resulting in a severe defect in XBP-1s translocation to the nucleus and thus in the resolution of endoplasmic reticulum (ER) stress. These defects are ameliorated when p85α and p85β are overexpressed in the liver of ob/ob mice. Our results define a previously unknown insulin receptor signaling pathway and provide new mechanistic insight into the development of ER stress during obesity.
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影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
10.5
作者：
Nishitoh, H;Matsuzawa, A;Ichijo, H
通讯作者：
Ichijo, H
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
DOI：
10.1083/jcb.200406136
发表时间：
2004-10-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sriburi R;Jackowski S;Mori K;Brewer JW
通讯作者：
Brewer JW
影响因子：
56.9
作者：
Özcan, U;Cao, Q;Hotamisligil, GS
通讯作者：
Hotamisligil, GS