The Tumor Suppressor Hnrnpk Induces p53-Dependent Nucleolar Stress To Drive Ribosomopathies

Authors

Pedro Aguilar-Garrido
María Velasco-Estévez
Miguel Ángel Navarro-Aguadero
Álvaro Otero-Sobrino
Marta Ibáñez-Navarro
Miguel Ángel Marugal
María Hernández-Sánchez
Prerna Malaney
Ashley Rodriguez
Oscar Benitez
Xiaroui Zhang
Marisa Jl Aitken
Alejandra Ortiz-Ruiz
Diego Megías
Manuel Pérez
Gadea Mata
Jesús Gomez
Miguel Lafarga
Orlando Domínguez
Osvaldo Graña-Castro
Eduardo Caleiras
Pilar Ximénez-Embun
Marta Isasa
Paloma Jimena de Andres
Sandra Rodríguez-Perales
Raúl Torres-Ruiz
Enrique Revilla
Rosa María García-Martín
Daniel Azorín
Josune Zubicaray
Julián Sevilla
Oleksandra Sirozh
Vanesa Lafarga
Joaquín Martínez-López
Sean M Post
Miguel Gallardo

Publication Date

6-16-2025

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI183697

PMID

40338663

PMCID

PMC12165811

PubMedCentral® Posted Date

5-8-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Tumor Suppressor Protein p53, Animals, Cell Nucleolus, Ribosomes, Mice, Humans, Heterogeneous-Nuclear Ribonucleoprotein K, Cellular Senescence, Mice, Transgenic, Aging, Hematology, Stem cells, Cellular senescence, Hematopoietic stem cells, Mouse models

Published Open-Access

yes

Recommended Citation

Aguilar-Garrido, Pedro; Velasco-Estévez, María; Navarro-Aguadero, Miguel Ángel; et al., "The Tumor Suppressor Hnrnpk Induces p53-Dependent Nucleolar Stress To Drive Ribosomopathies" (2025). Faculty, Staff and Student Publications. 4951.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4951