A Critical Role for PKR Complexes With TRBP in Immunometabolic Regulation and eIF2α Phosphorylation in Obesity

Cell Rep. 2015 Apr 14;11(2):295-307. doi: 10.1016/j.celrep.2015.03.021. Epub 2015 Apr 2.

Abstract

Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation and c-Jun N-terminal kinase (JNK) activation. We show that TRBP phosphorylation is induced in the setting of metabolic stress, leading to PKR activation. Suppression of hepatic TRBP reduced inflammation, JNK activity, and eIF2α phosphorylation and improved systemic insulin resistance and glucose metabolism, while TRBP overexpression exacerbated the impairment in glucose homeostasis in obese mice. These data indicate that the association between PKR and TRBP integrates metabolism with translational control and inflammatory signaling and plays important roles in metabolic homeostasis and disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Eukaryotic Initiation Factor-2 / biosynthesis
  • Glucose / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • JNK Mitogen-Activated Protein Kinases / biosynthesis
  • JNK Mitogen-Activated Protein Kinases / genetics
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Obese
  • Multiprotein Complexes / genetics
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Phosphorylation
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Stress, Physiological
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*

Substances

  • Eukaryotic Initiation Factor-2
  • Multiprotein Complexes
  • RNA-Binding Proteins
  • trans-activation responsive RNA-binding protein
  • eIF-2 Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Glucose