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

AI Article Synopsis

  • - Increased ribosomal biogenesis is typically seen during tissue growth (hypertrophy), but its impairment during tissue shrinkage (atrophy) hasn’t been clearly established until now.
  • - Research indicates that high ammonia levels (hyperammonemia), which are common in various chronic diseases, disrupt protein synthesis by reducing ribosomal components and their function in muscle cells and other tissues.
  • - The study reveals that this disruption is caused by decreased levels of cMYC and β-catenin, with the abnormal degradation of β-catenin occurring through a new mechanism involving IKKβ, rather than the usual method involving GSK3β.

Article Abstract

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 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664607PMC
http://dx.doi.org/10.1128/MCB.00451-18DOI Listing

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