Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 39, Issue 16, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00451-18
Keywords
beta-catenin; GSK3 beta; IKK beta; hyperammonemia; protein synthesis; ribosomal biogenesis
Categories
Funding
- NIH [RO1 GM119174, RO1 DK 113196, P50 AA024333, R21 AR 71046, UO1 AA021893, 1S10OD023436-01]
- Mikati Foundation
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Increased ribosomal biogenesis occurs during tissue hypertrophy, but whether ribosomal biogenesis is impaired during atrophy is not known. We show that hyperammonemia, which occurs in diverse chronic disorders, impairs protein synthesis as a result of decreased ribosomal content and translational capacity. Transcriptome analyses, real-time PCR, and immunoblotting showed consistent reductions in the expression of the large and small ribosomal protein subunits (RPL and RPS, respectively) in hyperammonemic murine skeletal myotubes, HEK cells, and skeletal muscle from hyperammonemic rats and human cirrhotics. Decreased ribosomal content was accompanied by decreased expression of cMYC, a positive regulator of ribosomal biogenesis, as well as reduced expression and activity of beta-catenin, a transcriptional activator of cMYC. However, unlike the canonical regulation of beta-catenin via glycogen synthase kinase 3 beta(GSK3 beta)-dependent degradation, GSK3 beta expression and phosphorylation were unaltered during hyperammonemia, and depletion of GSK3 beta did not prevent ammonia-induced degradation of beta-catenin. Overexpression of GSK3 beta-resistant variants, genetic depletion of I kappa B kinase beta (IKK beta) (activated during hyperammonemia), protein interactions, and in vitro kinase assays showed that IKK beta phosphorylated beta-catenin directly. Overexpressing beta-catenin restored hyperammonemia-induced perturbations in signaling responses that regulate ribosomal biogenesis. Our data show that decreased protein synthesis during hyperammonemia is mediated via a novel GSK3 beta-independent, IKK beta-dependent impairment of the beta-catenin-cMYC axis.
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