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Mutations in the ribosomal protein Rpl10 (uL16) can be drivers of T-cell acute lymphoblastic leukemia (T-ALL). We previously showed that these T-ALL mutations disrupt late cytoplasmic maturation of the 60S ribosomal subunit, blocking the release of the trans-acting factors Nmd3 and Tif6 in  S .  cerevisiae . Consequently, these mutant ribosomes do not efficiently pass the cytoplasmic quality control checkpoint and are blocked from engaging in translation. Here, we characterize suppressing mutations of the T-ALL-related  rpl10-R98S  mutant that bypass this block and show that the molecular defect of  rpl10-R98S  is a failure to release Nmd3 from the P site. Suppressing mutations were identified in Nmd3 and Tif6 that disrupted interactions between Nmd3 and the ribosome, or between Nmd3 and Tif6. Using an  in vitro  system with purified components, we found that Nmd3 inhibited Sdo1-stimulated Efl1 activity on mutant  rpl10-R98S  but not wild-type 60S subunits. Importantly, this inhibition was overcome  in vitro  by mutations in Nmd3 that suppressed  rpl10-R98S in vivo . These results strongly support a model that Nmd3 must be dislodged from the P site to allow Sdo1 activation of Efl1, and define a failure in the removal of Nmd3 as the molecular defect of the T-ALL-associated  rpl10-R98S  mutation.

The T-cell leukemia related rpl10-R98S mutant traps the 60S export adapter Nmd3 in the ribosomal P site in yeast