Impaired Ribosomal Biogenesis by Noncanonical Degradation of β-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 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.

Identification of FMR1-regulated molecular networks in human neurodevelopment

“…The ribosomal genes regulated by catenin beta 1 were elevated in FMR1 KO dNPC (Supplemental Fig. S11C), consistent with a previous report that catenin beta 1 promotes ribosome biogenesis (Davuluri et al 2019). Taken together, our results show that studying FMR1 at multiple regulatory levels through our network-based approach can identify components of important cellular functions regulated by FMR1 in human neural cells.…”

Sarcopenia and frailty in decompensated cirrhosis

“…Recent bioinformatics analyses of unbiased transcriptomic and proteomic data show impaired mRNA translation, ribosome and mitochondrial dysfunction, and free radical disposal during hyperammonaemia. 53 Similar observations have been reported in response to ethanol across multiple regulatory pathways. 54 Initial reports in preclinical and human muscle tissue showed that hyperammonaemia causes transcriptional upregulation of myostatin, a transforming growth factor b superfamily member that downregulates mTORC1 signalling and increases AMPKa2 phosphorylation, both of which result in decreased protein synthesis and increased autophagic proteolysis.…”

“…Ribosomal biogenesis is decreased during hyperammonaemia, aggravating signalling responses. 53 The decreased ribosomal content and biogenesis in hyperammonaemia is mediated by impaired bcatenin-cMYC signalling. The effect of other mediators and aetiological factors on ribosomal biogenesis is yet to be studied.…”

Inhibiting β-catenin disables nucleolar functions in triple-negative breast cancer

“…The Wnt signaling pathway is a group of multiple signaling streams such as canonical (Wnt/ β-catenin) and non-canonical, as well as Wnt-STOP signaling. Multiple studies using different model systems have provided mechanistic insights into the regulation of ribosome biogenesis via these various streams [45][46][47][48] . Our studies specifically unraveled the contributions of β-catenin signaling in TNBC nucleolar biology.…”