Double-Stranded RNA-Dependent Protein Kinase Links Pathogen Sensing with Stress and Metabolic Homeostasis

Takahisa Nakamura, Masato Furuhashi, Ping Li, Haiming Cao, Gurol Tuncman, Nahum Sonenberg, Cem Z. Gorgun, Gökhan S. Hotamisligil

Research output: Contribution to journalArticlepeer-review

358 Citations (Scopus)

Abstract

As chronic inflammation is a hallmark of obesity, pathways that integrate nutrient- and pathogen sensing pathways are of great interest in understanding the mechanisms of insulin resistance, type 2 diabetes, and other chronic metabolic pathologies. Here, we provide evidence that double-stranded RNA-dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. Dietary and genetic obesity features marked activation of PKR in adipose and liver tissues and absence of PKR alleviates metabolic deterioration due to nutrient or energy excess in mice. These findings demonstrate PKR as a critical component of an inflammatory complex that responds to nutrients and organelle dysfunction.

Original languageEnglish
Pages (from-to)338-348
Number of pages11
JournalCell
Volume140
Issue number3
DOIs
Publication statusPublished - 2010 Feb 5
Externally publishedYes

Keywords

  • CELLBIO
  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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