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

Abstract

SUMMARY 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.

Multiple forms of PKR present in the nuclei of acute leukemia cells represent an active kinase that is responsive to stress

“…In addition to phosphorylating eIF2a, PKR has been demonstrated to phosphorylate and regulate p53, inhibitor kB kinase, the B56a regulatory subunit of protein phosphatase 2A, RNA helicase, insulin receptor substrate-1 and cell division cycle-2. [3][4][5][6] Recent data indicate that PKR is required for the tumor suppressor function of PTEN. PTEN, through its PDZ domain and independent of phosphatase activity, was demonstrated to enhance cytoplasmic activation of PKR.…”

Structure of the kinase domain of human RNA-dependent protein kinase with K296R mutation reveals a face-to-face dimer

“…The dsRBD contains a conserved αβββα fold with two α-helices that pack against a single face of a three-stranded antiparallel β-sheet. The C-terminal domain of PKR is a catalytic domain, which has a typical protein kinase structure; its N-terminal lobe is mostly β-sheet, and its C-terminal lobe is predominantly helical [8].…”

Loss of stress response as a consequence of viral infection: implications for disease and therapy

“…PKR is an intracellular pathogen stress sensor that responds to double-stranded RNA and interferon. PKR also responds to endoplasmic reticulum stress and inflammation due to nutrient excess (Nakamura et al 2010; this topic is discussed further in "Implications and extensions" section). Activated PKR arrests protein synthesis and Hsp translation via phosphorylation of translation initiation factor eIF2α (Van Der Kelen et al 2009;see Fig.…”

“…In fact, Hotamışlıgil and colleagues have proposed that PKR acts as a pathogen sensor that sparks inflammatory processes basic to metabolic disease pathogenesis. They suggest that PKR activation plays a key role in initiating both type 1 and 2 diabetes, and note that PKR activation in hepatitis C may contribute to the high prevalence of diabetes associated with this infection (Nakamura et al 2010). Relevantly, both types of diabetes are associated with impaired cellular stress response, and are ameliorated by restoration of the stress response (Hooper 2007;van Eden et al 2005;Wieten et al 2010).…”