A Critical Role for PKR Complexes with TRBP in Immunometabolic Regulation and eIF2α Phosphorylation in Obesity

• Metabolic stress triggers interaction between PKR and RISC-loading complex components
• TRBP phosphorylation is induced in metabolic stress and leads to PKR activation
• The TRBP-PKR interaction is critical for JNK activation and eIF2α phosphorylation
• Experimental modulation of TRBP in liver impacts glucose metabolism in obese mice

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.

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