Impaired Ribosomal Biogenesis by Noncanonical Degradation of ?-Catenin during Hyperammonemia.

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 ?-catenin, a transcriptional activator of cMYC. However, unlike the canonical regulation of ?-catenin via glycogen synthase kinase 3? (GSK3?)-dependent degradation, GSK3? expression and phosphorylation were unaltered during hyperammonemia, and depletion of GSK3? did not prevent ammonia-induced degradation of ?-catenin. Overexpression of GSK3?-resistant variants, genetic depletion of I?B kinase ? (IKK?) (activated during hyperammonemia), protein interactions, and in vitro kinase assays showed that IKK? phosphorylated ?-catenin directly. Overexpressing ?-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?-independent, IKK?-dependent impairment of the ?-catenin-cMYC axis.

SUBMITTER: Davuluri G 

PROVIDER: S-EPMC6664607 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature