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The RNA Binding Protein HNRNPK induces p53-dependent nucleolar stress driving ribosompathy

ABSTRACT: The nucleolus is the membraneless organelle in the nucleus mainly responsible for ribosome biogenesis. It is also an excellent stress sensor and any changes on its architecture or composition leads to nucleolar stress deriving in cell cycle arrest and interruption of ribosomal activity. However, nucleolar stress sustained is also a contributing factor to pathologies like aging and cancer, highlighting the importance of its homeostasis in the cells. In this study, we identified and described the pivotal role of the RNA-binding protein Hnrnpk in the ribosome biogenesis and nucleolar dynamics. We developed an in vitro model of Hnrnpk overexpression with CRISPR-Cas9/SAM and an in vivo mouse model of Hnrnpk ubiquitous overexpression. We found that this overexpression disrupted translation and caused alterations in the nucleolar structure, resulting in nucleolar stress with alterations in the levels and localization of the nucleolar components fibrillarin and nucleolin, as well as impaired ribosome biogenesis. These aberrations trigger cell cycle arrest and cell senescence, and the phenotype could be rescued with haploinsufficiency of p53, suggesting that it is a consequence of a p53-dependant nucleolar stress mechanism. Finally, in our mouse model, Hnrnpk overexpression led to an aging phenotype with bone marrow failure and reduced lifespan, similar to a ribosomopathy-like phenotype. Together, our findings identify Hnrnpk as a novel master regulator of ribosome biogenesis and nucleolar homeostasis through p53, providing a new view of the orchestration of nucleolar integrity, ribosome function and cellular senescence.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Pilar Ximenez-Embun

LAB HEAD: Marta Isasa

PROVIDER: PXD046699 | Pride | 2025-06-04

REPOSITORIES: Pride

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			Action	DRS
	20221115_PX_Gallardo_TMT18p_F10.raw	Raw
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	20221115_PX_Gallardo_TMT18p_F13.raw	Raw
	20221115_PX_Gallardo_TMT18p_F14.raw	Raw
	20221115_PX_Gallardo_TMT18p_F15.raw	Raw

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Project description:The nucleolus is a dynamic structure where ribosome subunits are produced. Indeed, nucleoli respond to any change in cellular homeostasis by altering the rate of ribosome biogenesis, thus working as a stress sensor. Consequently, imbalances in ribosome biogenesis promotes changes in morphology and function and can evoke a nucleolar stress and DNA damage responses. These changes in nucleolar architecture and composition, culminating in impaired ribosome biogenesis, prompt the emergence of the nucleolar stress, which manifests as a contributing factor in aging and cancer. Here, we illuminate the pivotal role that the RNA binding protein Hnrnpk plays in orchestrating nucleolar dynamics and sustaining ribosome function. As a ribonucleoprotein, Hnrnpk governs the chaperoning of nascent transcripts to facilitate their processing and subsequent nuclear export for ribosomal integration. When overexpressed, Hnrnpk induces disruptive alterations in nucleolar structure, resulting in stress-like phenotypes; such as unbalances of molecular components, accumulation and delocalization of nucleolin, and decrease expression and occupation of fibrillarin. Consequentially, these aberrations in nucleolar equilibrium engenders a disruption in ribosome biogenesis and concomitantly halts the protein translation machinery. Nucleolin (Ncl) haploinsufficiency is correlated with enlarged nucleoli, increased ribosome components, heightened translational rates translation and a concomitant decrease in lifespan. Thus, an Hnrnpk overexpression-dependent surge of Ncl levels stemming may instigate a decline in nucleolar integrity and perturbations in ribosome biogenesis—an event intimately associated with ribosomopathies and the ensuing syndrome of bone marrow failure syndrome. Intersting, the aging process shares a number of common biological hallmarks with bone marrow failure. Again, alterations in Hnrnpk expression, specifically overexpression triggers nucleolar stress, driving cell cycle arrest and senescence of the cells. Our investigations demonstrate that p53, c-Myc and Ncl haploinsufficiency rescue these Hnrnpk-mediated phenotypes. Collectively, the data begin to decipher novel signaling pathway involved in nucleolar stress - ribosome stress – and p53 driven cell cycle arrest that governs this process. Together, these findings support the idea that nucleolar disturbances contribute to ribosome impairment, thus catalyzing the genesis of hematopoietic anomalies and aging process. Significantly, this study elucidates Hnrnpk as a previously unrecognized master regulator within these intricate ribosomal mechanisms; providing a novel window to view the orchestration of nucleolar integrity, ribosome function, and cellular senescence.

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The RNA Binding Protein HNRNPK induces p53-dependent nucleolar stress driving ribosompathy

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