title: A critical role for PKR complexes with TRBP in Immunometabolic regulation and eIF2α phosphorylation in obesity.
abstract: Aberrant 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.
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: takahisa.nakamura@cchmc.org.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Kunz
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Taishi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Celvie L
authors.initials: CL
authors.lastname: Yuan
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Brenna
authors.initials: B
authors.lastname: Baccaro
authors.affiliation: Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0063, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Namiki
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Harvard-MIT Broad Institute, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: ghotamis@hsph.harvard.edu.
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008820:Mice, Obese; D046912:Multiprotein Complexes / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D015852:Eukaryotic Initiation Factor-2; D005947:Glucose; D048031:JNK Mitogen-Activated Protein Kinases; D046912:Multiprotein Complexes; D016601:RNA-Binding Proteins; D019892:eIF-2 Kinase; D000099253:Trans-Activation Responsive RNA-Binding Protein
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