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

ABSTRACT: 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 both 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 both 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.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Chronic Lymphocytic Leukemia

SUBMITTER: Miguel Prado  

LAB HEAD: Daniel J Finley

PROVIDER: PXD010924 | Pride | 2019-09-09

REPOSITORIES: Pride