Activation of the dsRNA-Activated Protein Kinase PKR in Mitochondrial Dysfunction and Inflammatory Stress in Metabolic Syndrome

Author(s): Neetu Sud , Angela C. Rutledge , Kaichao Pan , Qiaozhu Su .

Journal Name: Current Pharmaceutical Design

Volume 22 , Issue 18 , 2016

Abstract:

Background: The double stranded RNA (dsRNA)-activated protein kinase PKR is a well-established protein kinase that is activated by dsRNA during viral infection, and it inhibits global protein synthesis by phosphorylating the alpha subunit of eukaryotic initiation factor 2 (eIF2). Recent studies have greatly broadened the recognized physiological activities of PKR by demonstrating its fundamental role in inflammatory signaling, particularly in chronic, low-grade inflammation induced by metabolic disorders, known as metaflammation. Metaflammation is initiated by the activation of the NOD-like receptor (NLR), leucine-rich repeat, pyrin domaincontaining 3 (NLRP3) gene by mitochondrial reactive oxygen species (ROS). A protein complex defined as the metaflammasome is assembled in the course of metaflammation. This complex integrates nutritional signaling with cellular stress, inflammatory components, and insulin action and is essential in maintaining metabolic homeostasis. PKR is a key constituent of the metaflammasome and interacts directly with several inflammatory kinases, such as inhibitor B (IB) kinase (IKK) and c-Jun N-terminal kinase (JNK), insulin receptor substrate 1 (IRS1), and component of the translational machinery such as eIF2. Conclusion: This review highlights recent findings in PKR-mediated metaflammation and its association with the onset of metabolic syndrome in both human and animal models, with a focus on the molecular and biochemical pathways that underlie the progression of obesity, insulin resistance, and type-2 diabetes.

Keywords: dsRNA-Activated Protein Kinase PKR, Mitochondrial dysfunction, ER stress, Metaflammation, Metabolic diseases.

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Article Details

VOLUME: 22
ISSUE: 18
Year: 2016
Page: [2697 - 2703]
Pages: 7
DOI: 10.2174/1381612822666160202141845
Price: $58

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