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肿瘤抑制因子HNRNPK诱导p53依赖性核仁应激以驱动核糖体病。

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

作者信息

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

机构信息

Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.

H12O-CNIO Haematological Malignancies Clinical Research Unit, CNIO, Madrid, Spain.

出版信息

J Clin Invest. 2025 May 8;135(12). doi: 10.1172/JCI183697. eCollection 2025 Jun 16.

DOI:10.1172/JCI183697
PMID:40338663
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12165811/
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.

摘要

核仁是一种无膜细胞器，也是一种出色的应激传感器。其结构或组成的任何变化都会导致核仁应激，进而导致细胞周期停滞和核糖体活性中断，而这是衰老和癌症中的关键因素。在本研究中，我们鉴定并描述了RNA结合蛋白HNRNPK在核糖体和核仁动态变化中的关键作用。我们构建了内源性HNRNPK过表达的体外模型和全身性HNRNPK过表达的体内小鼠模型。这些模型显示，由于HNRNPK过表达导致核仁结构改变，从而引起翻译过程中断，进而导致p53依赖性核仁应激、细胞周期停滞、衰老和骨髓衰竭表型，这与核糖体病患者中观察到的情况相似。总之，我们的研究结果表明，HNRNPK是通过p53调控核糖体生物合成和核仁稳态的主要调节因子，为核仁完整性、核糖体功能和细胞衰老的调控提供了一个全新的视角。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/277bd64f1938/jci-135-183697-g233.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/21a85b7ad86b/jci-135-183697-g228.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/43b3a85138de/jci-135-183697-g229.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/09c9d2095a56/jci-135-183697-g230.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/89f0d09cd3df/jci-135-183697-g231.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/8eb1191b97a7/jci-135-183697-g232.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/277bd64f1938/jci-135-183697-g233.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/21a85b7ad86b/jci-135-183697-g228.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/43b3a85138de/jci-135-183697-g229.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/09c9d2095a56/jci-135-183697-g230.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/89f0d09cd3df/jci-135-183697-g231.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/8eb1191b97a7/jci-135-183697-g232.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ee4/12165811/277bd64f1938/jci-135-183697-g233.jpg

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本文引用的文献

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Mol Cell. 2024 Apr 18;84(8):1527-1540.e7. doi: 10.1016/j.molcel.2024.02.031. Epub 2024 Mar 22.
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Human NOP2/NSUN1 regulates ribosome biogenesis through non-catalytic complex formation with box C/D snoRNPs.人类 NOP2/NSUN1 通过与 box C/D snoRNPs 形成非催化复合物来调节核糖体生物发生。
Nucleic Acids Res. 2022 Oct 14;50(18):10695-10716. doi: 10.1093/nar/gkac817.
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Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward.
靶向癌症中的核糖体生物合成：经验教训与未来方向
Cancers (Basel). 2022 Apr 24;14(9):2126. doi: 10.3390/cancers14092126.
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p53 at the crossroad of DNA replication and ribosome biogenesis stress pathways.p53 在 DNA 复制和核糖体生物发生应激途径的十字路口。
Cell Death Differ. 2022 May;29(5):972-982. doi: 10.1038/s41418-022-00999-w. Epub 2022 Apr 20.
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The nucleolus as a multiphase liquid condensate.核仁作为一个多相的液态凝聚物。
Nat Rev Mol Cell Biol. 2021 Mar;22(3):165-182. doi: 10.1038/s41580-020-0272-6. Epub 2020 Sep 1.
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