Article

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

Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Cell (Impact Factor: 33.12). 02/2010; 140(3):338-48. DOI: 10.1016/j.cell.2010.01.001
Source: PubMed

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.

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    • "JNK activity was found induced in many tissues of obese and insulinresistant mice (Hirosumi et al. 2002) (Fig. 2). Mechanistically, JNK activation can occur through the induction of endoplasmic reticulum stress (Hotamisligil 2010), depending on the activity of double-stranded RNA-dependent protein kinase (PKR) (Nakamura et al. 2010). Alternatively, saturated fatty acids through binding of toll-like receptors (Shi et al. 2006; Tsukumo et al. 2007) or through activation of the protein kinase C-mediated activation of the mixed-lineage protein kinase (MLK) group of MAP kinase kinase kinases (MAPKKKs) (Kant et al. 2013) may also activate JNK. "
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    • "Notably, PKR activity is highly correlated with JNK activation, and in turn, JNK may phosphorylate TRBP, indicating a regulatory loop between these kinases via TRBP, which may be key to their activation in metabolic context. As the assembly of PKR with RLC is highly associated with PKR and JNK activation, and because PKR can also participate in inflammatory activity (Carvalho-Filho et al., 2012; Lu et al., 2012; Nakamura et al., 2010), TRBP phosphorylation may be a core component of a signaling node representing the metabolic inflammasome (metaflammasome ). Finally, our findings indicate that the inhibition of PKR and TRBP function may result in simultaneous relief from multiple stress responses and may provide new opportunities for clinical applications against chronic stress-related diseases, including obesity-induced metabolic disease and cancer. "
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