A Critical Role for PKR Complexes with TRBP in Immunometabolic Regulation and eIF2α Phosphorylation in Obesity
| Autor: | Yuka Namiki, Taishi Kimura, Ryan C. Kunz, Gökhan S. Hotamisligil, Cai Zhang, Takahisa Nakamura, Steven P. Gygi, Celvie L. Yuan, Brenna Baccaro |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Eukaryotic Initiation Factor-2
Mice Obese Inflammation Biology Carbohydrate metabolism environment and public health General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice eIF-2 Kinase 0302 clinical medicine Insulin resistance Stress Physiological medicine Glucose homeostasis Animals Humans Obesity Phosphorylation lcsh:QH301-705.5 030304 developmental biology 0303 health sciences EIF-2 kinase Kinase JNK Mitogen-Activated Protein Kinases RNA-Binding Proteins medicine.disease Protein kinase R Cell biology enzymes and coenzymes (carbohydrates) Glucose Biochemistry lcsh:Biology (General) Liver Multiprotein Complexes biology.protein medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 11, Iss 2, Pp 295-307 (2015) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2015.03.021 |
| Popis: | SummaryAberrant 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. |
| Databáze: | OpenAIRE |
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