Alternative RNA splicing modulates ribosomal composition and determines the spatial phenotype of glioblastoma cells

Larionova, T.D.; Bastola, S.; Aksinina, T.E.; Anufrieva, K.S.; Wang, J.; Shender, V.O.; Andreev, D.E.; Kovalenko, T.F.; Arapidi, G.P.; Shnaider, P.V.; Kazakova, A.N.; Latyshev, Y.A.; Tatarskiy, V.V.; Shtil, A.A.; Moreau, P.; Giraud, F.; Li Chaoxi; Wang, Y.; Rubtsova, M.P.; Dontsova, O.A.; Condro, M.; Ellingson, B.M.; Shakhparonov, M.I.; Kornblum, H.I.; Nakano, I.; Pavlyukov, M.S.

Авторы: Larionova Tatyana D., Bastola Soniya, Aksinina Tatiana E., Anufrieva Ksenia S., Wang Jia, Shender Victoria O., Andreev Dmitriy E., Kovalenko Tatiana F., Arapidi Georgij P., Shnaider Polina V., Kazakova Anastasia N., Latyshev Yaroslav A., Tatarskiy Victor V., Shtil Alexander A., Moreau Pascale, Giraud Francis, Li Chaoxi, Wang Yichan, Rubtsova Maria P., Dontsova Olga A., Condro Michael, Ellingson Benjamin M., Shakhparonov Mikhail I., Kornblum Harley I., Nakano Ichiro, Pavlyukov Marat S.
Журнал: Nature Cell Biology
Номер: 24
Год издания: 2022
Издательство: Nature Publishing Group
Местоположение издательства: United Kingdom
Первая страница: 1541
Последняя страница: 1557
DOI: 10.1038/s41556-022-00994-w
Аннотация: Glioblastoma (GBM) is characterized by exceptionally high intratumoral heterogeneity. However, the molecular mechanisms underlying the origin of different GBM cell populations remain unclear. Here, we found that the compositions of ribosomes of GBM cells in the tumour core and edge differ due to alternative RNA splicing. The acidic pH in the core switches before messenger RNA splicing of the ribosomal gene RPL22L1 towards the RPL22L1b isoform. This allows cells to survive acidosis, increases stemness and correlates with worse patient outcome. Mechanistically, RPL22L1b promotes RNA splicing by interacting with lncMALAT1 in the nucleus and inducing its degradation. Contrarily, in the tumour edge region, RPL22L1a interacts with ribosomes in the cytoplasm and upregulates the translation of multiple messenger RNAs including TP53. We found that the RPL22L1 isoform switch is regulated by SRSF4 and identified a compound that inhibits this process and decreases tumour growth. These findings demonstrate how distinct GBM cell populations arise during tumour growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy.
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Alternative RNA splicing modulates ribosomal composition and determines the spatial phenotype of glioblastoma cellsстатья