A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box–binding protein-1 to modulate the unfolded protein response
Class Ia phosphoinositide 3-kinase (PI3K), an essential mediator of the metabolic actions of
insulin, is composed of a catalytic (p110α or p110β) and regulatory (p85αα, p85βα or p55α)
subunit. Here we show that p85αα 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 p85αα
show marked alterations in the UPR, including reduced ER stress–dependent accumulation …
insulin, is composed of a catalytic (p110α or p110β) and regulatory (p85αα, p85βα or p55α)
subunit. Here we show that p85αα 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 p85αα
show marked alterations in the UPR, including reduced ER stress–dependent accumulation …
Abstract
Class Ia phosphoinositide 3-kinase (PI3K), an essential mediator of the metabolic actions of insulin, is composed of a catalytic (p110α or p110β) and regulatory (p85αα, p85βα or p55α) subunit. Here we show that p85αα 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 p85αα 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-6αα (ATF6α). Mice with deletion of p85α in liver (L-Pik3r1−/−) show a similar attenuated UPR after tunicamycin administration, leading to an increased inflammatory response. Thus, p85αα 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.
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