Abstract
Class Ia phosphoinositide 3-kinase (PI3K), an essential mediator of the metabolic actions of insulin, is composed of a catalytic (p110alpha or p110beta) and regulatory (p85alphaalpha, p85betaalpha or p55alpha) subunit. Here we show that p85alphaalpha 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 p85alphaalpha 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-1alpha (IRE1alpha) and activating transcription factor-6alphaalpha (ATF6alpha). Mice with deletion of p85alpha in liver (L-Pik3r1(-/-)) show a similar attenuated UPR after tunicamycin administration, leading to an increased inflammatory response. Thus, p85alphaalpha 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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Activating Transcription Factor 6
-
Animals
-
Apoptosis / physiology
-
Cell Line
-
Cell Nucleus / metabolism*
-
Cell Nucleus / physiology
-
DNA-Binding Proteins / metabolism
-
DNA-Binding Proteins / physiology*
-
Endoplasmic Reticulum / metabolism
-
Endoplasmic Reticulum / physiology
-
Endoribonucleases / physiology
-
Gene Knockdown Techniques
-
Insulin / physiology
-
Liver / metabolism
-
Liver / physiology
-
Membrane Proteins / physiology
-
Mice
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphatidylinositol 3-Kinases / physiology*
-
Protein Serine-Threonine Kinases / physiology
-
Regulatory Factor X Transcription Factors
-
Stress, Physiological / physiology
-
Trans-Activators / physiology
-
Transcription Factors / metabolism
-
Transcription Factors / physiology*
-
Tunicamycin / pharmacology
-
Unfolded Protein Response / drug effects
-
Unfolded Protein Response / physiology*
-
X-Box Binding Protein 1
Substances
-
Activating Transcription Factor 6
-
Atf6 protein, mouse
-
DNA-Binding Proteins
-
Insulin
-
Membrane Proteins
-
Regulatory Factor X Transcription Factors
-
Trans-Activators
-
Transcription Factors
-
X-Box Binding Protein 1
-
Xbp1 protein, mouse
-
Tunicamycin
-
Ern1 protein, mouse
-
Protein Serine-Threonine Kinases
-
Endoribonucleases