The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies

作者：Pedro Aguilar-Garrido, María Velasco‐Estevez, Miguel Ángel Navarro-Aguadero, Alvaro Otero-Sobrino, Marta Ibáñez-Navarro, Miguel Ángel Marugal, María Hernández‐Sánchez, Prerna Malaney, Ashley Rodriguez, Oscar Benitez, Xiaorui Zhang, Marisa J.L. Aitken, Alejandra Ortiz-Ruiz, Diego Megı́as, Manuel Pérez‐Martínez, Gadea Mata, Jesús Gómez, Miguel Lafarga, Orlando Domı́nguez, Osvaldo Graña‐Castro, Eduardo Caleiras, Pilar Ximénez‐Embún, Marta Isasa, Paloma Jimena de Andres, Sandra Rodríguez, Raúl Torres, Enrique Revilla, Rosa García-Martín, Daniel Azorín, Josune Zubicaray, Julián Sevilla, Oleksandra Sirozh, Vanesa Lafarga, Joaquín Martínez‐López, Sean M. Post, Miguel Gallardo · 发表于：Journal of Clinical Investigation · 年份：2025 · DOI：10.1172/jci183697 · 被引用次数：4 · 研究领域：RNA modifications and cancer、PARP inhibition in cancer therapy、RNA Research and Splicing

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.