A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response

被引:168
作者
Winnay, Jonathon N. [1 ]
Boucher, Jeremie [1 ]
Mori, Marcelo A. [1 ]
Ueki, Kohjiro [2 ]
Kahn, C. Ronald [1 ]
机构
[1] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab,Res Div, Boston, MA 02115 USA
[2] Univ Tokyo, Dept Metab Dis, Grad Sch Med, Tokyo, Japan
基金
美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; INSULIN-RESISTANCE; PHOSPHATIDYLINOSITOL; 3-KINASE; ER STRESS; SKELETAL-MUSCLE; MESSENGER-RNA; PURIFICATION METHOD; METABOLIC SYNDROME; P85-ALPHA SUBUNIT; ADIPOSE-TISSUE;
D O I
10.1038/nm.2121
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Class Ia phosphoinositide 3-kinase (PI3K), an essential mediator of the metabolic actions of insulin, is composed of a catalytic (p110 alpha or p110 beta) and regulatory (p85 alpha, p85 beta or p55 gamma) subunit. Here we show that p85 alpha interacts with X-box-binding protein-1 (XBP-1), a transcriptional mediator of the unfolded protein response (UPR), in an endoplasmic reticulum (ER) stress-dependent manner. Cell lines with knockout or knockdown of p85 alpha show marked alterations in the UPR, including reduced ER stress-dependent accumulation of nuclear XBP-1, decreased induction of UPR target genes and increased rates of apoptosis. This is associated with a decreased activation of inositol-requiring protein-1 alpha (IRE1 alpha) and activating transcription factor-6 alpha (ATF6 alpha). Mice with deletion of p85 alpha in liver (L-Pik3r1(-/-)) show a similar attenuated UPR after tunicamycin administration, leading to an increased inflammatory response. Thus, p85 alpha forms a previously unrecognized link between the PI3K pathway, which is central to insulin action, and the regulation of the cellular response to ER stress, a state that when unresolved leads to insulin resistance.
引用
收藏
页码:438 / U120
页数:9
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