Impaired Ribosomal Biogenesis by Noncanonical Degradation of β-Catenin during Hyperammonemia

Mol Cell Biol. 2019 Jul 29;39(16):e00451-18. doi: 10.1128/MCB.00451-18. Print 2019 Aug 15.


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 β-catenin, a transcriptional activator of cMYC. However, unlike the canonical regulation of β-catenin via glycogen synthase kinase 3β (GSK3β)-dependent degradation, GSK3β expression and phosphorylation were unaltered during hyperammonemia, and depletion of GSK3β did not prevent ammonia-induced degradation of β-catenin. Overexpression of GSK3β-resistant variants, genetic depletion of IκB kinase β (IKKβ) (activated during hyperammonemia), protein interactions, and in vitro kinase assays showed that IKKβ phosphorylated β-catenin directly. Overexpressing β-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 GSK3β-independent, IKKβ-dependent impairment of the β-catenin-cMYC axis.

Keywords: GSK3β; IKKβ; hyperammonemia; protein synthesis; ribosomal biogenesis; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Fibrosis
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism
  • HEK293 Cells
  • Humans
  • Hyperammonemia / genetics
  • Hyperammonemia / metabolism*
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Mice
  • Proteolysis
  • Proteomics
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Rats
  • Ribosome Subunits, Small / genetics*
  • Ribosome Subunits, Small / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction
  • beta Catenin / chemistry*
  • beta Catenin / genetics*


  • CTNNB1 protein, human
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • I-kappa B Kinase