A role for eIF5A in translational control of stress-inducible proteins in multiple myeloma cell lines.

Impaired protein folding in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR), which can induce apoptosis during prolonged ER stress. ER stress is therapeutically targeted in plasma cell malignancies, such as multiple myeloma (MM), but these treatments remain noncurative, and UPR signaling in B-cell malignancies is incompletely understood. A targeted CRISPR-Cas9 screen in RPMI-8226 cells exposed to thapsigargin identified known ER stress regulators (XBP1, IRE1, and calreticulin) and the translation factor eIF5A (eukaryotic translation initiation factor 5A), whose role in ER stress remains unclear. Competition assays showed that eIF5A depletion is detrimental under basal conditions but confers a proliferation advantage during thapsigargin treatment. Inducible EIF5A knockouts confirmed reduced sensitivity specifically to thapsigargin, loss of eIF5A had no or sensitizing effects on cell death induced by other ER stress drugs. Polysome profiling revealed that not general translation, but the translation of specific mRNA transcripts coding for UPR components and apoptotic proteins was affected by eIF5A depletion. Correspondingly, EIF5A KO cells showed reduced thapsigargin-induced UPR activation. In conclusion, these findings indicate that loss of eIF5A alters the stress response in MM cells.