A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response (Nat Med, 2010, 16:438-445)

報告日期: 2010/12/21
報告時間: 15:10/16:00
報告學生: 王智揚
講評老師: 吳佳慶

Full text: http://basicmed.med.ncku.edu.tw/admin/up_img/991228-1.pdf

A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box–binding protein-1 to modulate the unfolded protein response
Jonathon N Winnay, Jeremie Boucher, Marcelo A Mori, Kohjiro Ueki & C Ronald Kahn
Nature Medicine. 2010;16:438-45.
Speaker : Chih-Yang Wang
Commentator : Dr. Chia-Ching Wu
Time : 2010/12/21 15:10
Place : Room 602
Class Ia phosphoinositide 3-kinase (PI3K) is composed of a catalytic (p110α or p110β) and regulatory (p85α, p85β or p55γ) subunit. Alterations in insulin stimulation of PI3K activity have been observed in mouse models of obesity, as well as in humans with type 2 diabetes. The endoplasmic reticulum (ER) stress response has been strongly implicated in the pathophysiology of diabetes, affecting both insulin sensitivity in liver and fat, and the survival of pancreatic beta cells. To date there has been no evidence establishing a direct link between the PI3K pathway and ER stress. The author wish to investigate p85α would interacts with X-box–binding protein-1 (XBP-1), a transcriptional mediator of the unfolded protein response (UPR), in an ER stress-dependent manner. Cell lines with knockout of p85α 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-1α (IRE1α) and activating transcription factor-6α ATF6α). Mice with deletion of p85α in liver (L-Pik3r1−/−) show a similar attenuated UPR after tunicamycin treatment which increased inflammatory response. The p85α regulatory subunit of PI3K interacts with XBP-1 in an ER stress–dependent manner and that this interaction is essential in the ER stress response. This link between the regulatory subunit of PI3K and the cellular response to ER stress provides a new therapeutic target for the treatment of diseases in which the UPR is activated, such as obesity and type 2 diabetes
1. Park SW et al, The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med.2010;16:429-37. 
2. Wek RC et al, Obesity: stressing about unfolded proteins. Nat Med.2010;6:374-6.