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 Apr;16(4):438-45. doi: 10.1038/nm.2121. Epub 2010 Mar 28.

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
  • Phosphatidylinositol 3-Kinases
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases