Jurnal Internasional Perubahan pola sintesis protein global dan kesetiaan translasi pada leukemia limfositik kronis yang direspon RPS15
Recent genomic studies identified RPS15 as a new gene driver in cases of aggressive and chemorefractory chronic lymphocytic leukemia (CLL). RPS15 encodes a ribosome protein that stores the C-terminal domain extending to the decoding center of the ribosome. We show that mutations in highly sustainable residues from this domain affect protein stability, by increasing ubiquitin mediation degradation, and cell proliferation rates. On the other hand, we show that mutated RPS15 can be loaded into the ribosome, directly impacting global protein synthesis and / or translation fidelity in a mutation-specific manner. Quantitative mass spectrometry analysis shows that the RPS15 variant can cause additional changes in translation machinery, as well as metabolic shifts at the proteom level in HEK293T and MEC-1 cells. These results suggest that CLL-related RPS15 mutations may act following a pattern known for other ribosomes, possibly switching from hypo- to hyperproliferative phenotypes driven by mutated ribosomes. In this scenario, loss of translation loyalty causes changes in cell proteostasis can be proposed as new molecular mechanisms involved in CLL pathobiology.