The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies.
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2025
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American Society for Clinical Investigation
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Aguilar-Garrido, P., Velasco-Estévez, M., Navarro-Aguadero, M. Á., Otero-Sobrino, Á., Ibáñez-Navarro, M., Marugal, M. Á., Hernández-Sánchez, M., Malaney, P., Rodriguez, A., Benitez, O., Zhang, X., Aitken, M. J., Ortiz-Ruiz, A., Megías, D., Pérez, M., Mata, G., Gomez, J., Lafarga, M., Domínguez, O., Graña-Castro, O., … Gallardo, M. (2025). The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies. The Journal of clinical investigation, 135(12), e183697. https://doi.org/10.1172/JCI183697
Abstract
The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation as the HNRNPK overexpression caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell cycle arrest, senescence, and bone marrow failure phenotype, similar to what is observed in patients with ribosomopathies. Together, our findings identify HNRNPK as a master regulator of ribosome biogenesis and nucleolar homeostasis through p53, providing what we believe to be a new perspective on the orchestration of nucleolar integrity, ribosome function and cellular senescence.
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Author contributions:
MG conceived and planned the study with input from SMP, PM, XZ, MJLA, and JML. PAG, MVE, MANA, AOS, AOR, and MAM designed and performed the culture, cellular, and molecular biology experiments as well as in vivo experiments. MIN designed and performed FCM experiments. MHS and RTR designed and performed the CRISPR-modified cellular models. AR, OB, and SMP performed Northern blotting. PAG, with help from DM, MP, GM, JG, OS, and VL, designed and performed the confocal microscopy experiments. ML designed and performed electron microscopy experiments. OD and OGC designed and performed the RNA-Seq experiments. EC and PJDA designed and performed the IHC mice experiments. JZ, JS, DA, RMGM, and ER obtained patient samples and clinical information and performed the IHC experiments. PXE and MI designed and performed TMTpro experiments. SRP and RTR designed and performed karyotyping experiments. MG wrote the manuscript with the contributions from MVE and PAG. MG supervised the study. All authors approved the final manuscript.