PML2-mediated thread-like nuclear bodies mark late senescence in Hutchinson-Gilford progeria syndrome
PML2-mediated thread-like nuclear bodies mark late senescence in Hutchinson-Gilford progeria syndrome
复制标题
PML2 介导的线状核体标志着 Hutchinson-Gilford 早衰综合征的晚期衰老。
DOI：
10.1111/acel.13147
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发表时间：
2020
期刊：
影响因子：
7.8
通讯作者：
Liu Baohua
中科院分区：
文献类型：
--
作者：
Wang Ming;Wang Lulu;Qian Minxian;Tang Xiaolong;Liu Zuojun;Lai Yiwei;Ao Ying;Huang Yinghua;Meng Yuan;Shi Lei;Peng Linyuan;Cao Xinyue;Wang Zimei;Qin Baoming;Liu Baohua
早老蛋白的积累破坏了核纤层的完整性，导致核结构异常，导致过早衰老，即Hutchinson-Gilford早衰综合征（HGPS）。核亚区室，如PML核体（PML NB），在HGPS发病机制中的作用尚不清楚。在这里，我们发现经典的点状PML NB在HGPS患者成纤维细胞中重组为线状结构，并且它们的存在与衰老的晚期阶段相关。通过免疫共沉淀分析，我们发现法尼基化的Progerin与人PML 2相互作用，这导致了线状PML NB的形成。具体而言，HGPS细胞中的人PML 2而非PML 1过表达促进PML线发育并加速衰老。进一步的免疫荧光显微镜、免疫TRAP和深度测序数据表明，这些不规则的PML NB可能通过干扰HGPS细胞中NB相关的DNA修复和基因表达来促进衰老。这些数据识别了衰老HGPS细胞中PML NB的不规则结构，并支持线状PML NB可能是晚期衰老的一种新型、形态学和功能性生物标志物。
Progerin accumulation disrupts nuclear lamina integrity and causes nuclear structure abnormalities, leading to premature aging, that is, Hutchinson–Gilford progeria syndrome (HGPS). The roles of nuclear subcompartments, such as PML nuclear bodies (PML NBs), in HGPS pathogenesis, are unclear. Here, we show that classical dot‐like PML NBs are reorganized into thread‐like structures in HGPS patient fibroblasts and their presence is associated with late stage of senescence. By co‐immunoprecipitation analysis, we show that farnesylated Progerin interacts with human PML2, which accounts for the formation of thread‐like PML NBs. Specifically, human PML2 but not PML1 overexpression in HGPS cells promotes PML thread development and accelerates senescence. Further immunofluorescence microscopy, immuno‐TRAP, and deep sequencing data suggest that these irregular PML NBs might promote senescence by perturbing NB‐associated DNA repair and gene expression in HGPS cells. These data identify irregular structures of PML NBs in senescent HGPS cells and support that the thread‐like PML NBs might be a novel, morphological, and functional biomarker of late senescence.