Interactome of different isoforms of RPL22L1 protein in human glioblastoma cells

Glioblastoma multiforme (GBM) is characterized by an exceptionally high intratumoral heterogeneity. However, the molecular mechanisms underlying the origin of different GBM cell populations remain unclear. Here we found that the composition of ribosomes of GBM cells in the tumor core and edge differ due to alternative RNA splicing. The acidic pH in the core switches pre-mRNA splicing of the ribosomal gene RPL22L1 toward the RPL22L1b isoform. This allows cells to survive acidosis, increases stemness and correlates with worse patient outcome. Mechanistically, RPL22L1b promotes RNA splicing by binding to lncMALAT1 in the nucleus, resulting in its degradation. Contrarily, in the tumor edge region, RPL22L1a interacts with ribosomes in cytoplasm and upregulates translation of multiple mRNAs including TP53. We found that RPL22L1 isoform switch is regulated by SRSF4 and identified the compound, that inhibits this process and decreases tumor growth. These findings demonstrate how distinct GBM cell populations arise during tumor growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy. We performed precipitation of RNA that interacts with different isoforms of RPL22L1 protein in glioblastoma cells. Ribosomal RNA was depleted and obtained samples were sequenced using HiSeq 2500 (RIPseq experiment).