Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia

Genomic studies have recently identified RPS15 as a new driver gene in aggressive and chemorefractory cases of chronic lymphocytic leukemia (CLL). RPS15 encodes a ribosomal protein whose conserved C-terminal domain extends into the decoding center of the ribosome. We demonstrate that mutations in highly conserved residues of this domain affect protein stability, by increasing its ubiquitin-mediated degradation, and cell-proliferation rates. On the other hand, we show that mutated RPS15 can be loaded into the ribosomes, directly impacting on global protein synthesis and/or translational fidelity in a mutation-specific manner. Quantitative mass spectrometry analyses suggest that RPS15 variants may induce additional alterations in the translational machinery, as well as a metabolic shift at the proteome level in HEK293T and MEC-1 cells. These results indicate that CLL-related RPS15 mutations might act following patterns known for other ribosomal diseases, likely switching from a hypo- to a hyperproliferative phenotype driven by mutated ribosomes. In this scenario, loss of translational fidelity causing altered cell proteostasis can be proposed as a new molecular mechanism involved in CLL pathobiology.

Source: Blood - November 29, 2018 Category: Hematology Authors: Bretones, G., Alvarez, M. G., Arango, J. R., Rodriguez, D., Nadeu, F., Prado, M. A., Valdes-Mas, R., Puente, D. A., Paulo, J. A., Delgado, J., Villamor, N., Lopez-Guillermo, A., Finley, D. J., Gygi, S. P., Campo, E., Quesada, V., Lopez-Otin, C. Tags: Lymphoid Neoplasia Source Type: research