Deficiency of ribosomal protein S26, which is mutated in a subset of patients with Diamond Blackfan anemia, impairs erythroid differentiation

Abstract

Introduction: Diamond Blackfan anemia (DBA) is a rare congenital disease characterized by defective maturation of the erythroid progenitors in the bone marrow, for which treatment involves steroids, chronic transfusions, or hematopoietic stem cells transplantation. Diamond Blackfan anemia is caused by defective ribosome biogenesis due to heterozygous pathogenic variants in one of 19 ribosomal protein (RP) genes. The decreased number of functional ribosomes leads to the activation of pro-apoptotic pathways and to the reduced translation of key genes for erythropoiesis.Results and discussion: Here we characterized the phenotype of RPS26-deficiency in a cell line derived from human umbilical cord blood erythroid progenitors (HUDEP-1 cells). This model recapitulates cellular hallmarks of Diamond Blackfan anemia including: imbalanced production of ribosomal RNAs, upregulation of pro-apoptotic genes and reduced viability, and shows increased levels of intracellular calcium. Evaluation of the expression of erythroid markers revealed the impairment of erythroid differentiation in RPS26-silenced cells compared to control cells.Conclusions: In conclusion, for the first time we assessed the effect of RPS26 deficiency in a human erythroid progenitor cell line and demonstrated that these cells can be used as a scalable model system to study aspects of DBA pathophysiology that have been refractory to detailed investigation because of the paucity of specific cell types affected in this disorder.

Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions

“…Therefore, the activity of this chaperon may play an important role in modulating RAN translation via Rps26 assembly or disassembly from ribosomal subunits, also during different stresses (Yang & Karbstein, 2022). Moreover, mutations in genes encoding RPS26 and TSR2 were associated with hematopoiesis impairment that underlies the genetic blood disorder Diamond-Blackfan anemia (DBA) (Piantanida et al , 2022; Li et al , 2023; Doherty et al , 2010). Previously, analyses of DBA patient cells and RPS26-depleted HeLa cells found alterations in ribosome biogenesis and pre-rRNA processing (Doherty et al , 2010).…”

“…It was demonstrated that cells with mutated C-terminus of RPS26 were more resistant to glucose starvation, than the wild type cells (Havkin-Solomon et al , 2023). Moreover, RPS26 was shown to be involved in other cellular processes such as the DNA damage response (Cui et al , 2013), activation of the mTOR signaling pathway (Havkin-Solomon et al , 2023) and cellular lineage differentiation by preferential translation of certain transcripts (Piantanida et al , 2022; Li et al , 2022). We evaluated global changes in the human cellular proteome under RPS26 depletion and found that the expression level was significantly changed in approximately 20% of human proteins, while most proteins’ expression levels remained intact (Figure 3A, Supplementary List).…”