A novel cilium-to-nucleus axis promotes cellular senescence

一种新的纤毛到细胞核轴促进细胞衰老

• 批准号: 10414471
• 负责人: Jinghua Hu
• 金额: $ 32.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414471
• 关键词: ARL3 gene; Abbreviations; Acute Promyelocytic Leukemia; Address; Adenosine Diphosphate; Affect; Age; Aging; Animal Model; Animals; Apoptosis; Architecture; Binding; Binding Proteins; Biogenesis; Biology; Bromodomain; Cell Aging; Cell Nucleus; Cells; Cellular Stress; Cilia; Clinic; Cues; Cultured Cells; Data; Devices; Disease; Embryonic Development; Enzymes; Epithelial Cells; Eukaryotic Cell; Exhibits; Fiber; Fibroblasts; Functional disorder; Genetic; Goals; Growth; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Heterogeneity; Homeostasis; Human; Human body; Inflammatory; Joubert syndrome; Life; Link; Longevity; Malignant Neoplasms; Mammalian Cell; Modeling; Modification; Molecular; Mus; Mutate; Nuclear; Nuclear Protein; Nuclear Structure; Organ; Pathogenesis; Pathology; Pathway interactions; Peptide Hydrolases; Pharmacology; Physiological; Play; Proteins; Proteomics; Radiation; Regulation; Resources; Rodent Model; Role; Seminal; Sensory; Signal Transduction; Somatic Cell; Stress; Structure; Sumoylation Pathway; Surface; Syndrome; TP53 gene; Therapeutic; Tissues; Tumor Suppression; Ubiquitin; Up-Regulation; aged; base; chemokine; ciliopathy; cilium biogenesis; comorbidity; cytokine; design; frailty; healthspan; healthy aging; improved; in vivo; in vivo Model; irradiation; mouse model; novel; novel strategies; novel therapeutics; overexpression; p53-binding protein 1; prevent; programs; response; senescence; transcription factor PML; tumorigenesis

Project Summary Cellular senescence is a programmed growth arrest activated by irreparable extrinsic or intrinsic stresses. Senescence can be beneficial in certain circumstances, such as tissue homeostasis during embryonic development or tumor suppression. However, if persistently secreted by senescent cells, the proinflammatory cytokines, chemokines, proteases, and growth factors are actually major drivers for aging and age-associated diseases and, paradoxically, promote tumorigenesis. Genetic or pharmacological clearance of senescent cells effectively improves lifespan and healthspan in rodent models. As such, targeting senescence has emerged as a promising therapeutic strategy to prevent or treat aging comorbidities and cancer. However, how the irreversible senescence program is induced and maintained in stressed cells remains poorly understood. Cells utilize primary cilia to convert environmental cues into diverse cellular signalings that govern proliferation, differentiation, and tissue homeostasis. Cilia dysfunction leads to a wide spectrum of syndromic disorders that are collectively termed ciliopathies. Using irradiation, we discovered that stressed human fibroblasts or epithelial cells exhibit transient cilia biogenesis. Strikingly, FBF1, a component of transition fibers (TFs) at the ciliary base, unexpectedly translocates to promyelocytic leukaemia nuclear bodies (PML-NBs) in stressed cells. PML-NBs are highly dynamic proteinaceous nuclear structures with instrumental roles in regulating stress-induced responses, including senescence and apoptosis. FBF1 depletion effectively abolishes stress-induced PML-NB upregulation and associated senescence initiation, whereas FBF1 overexpression shows the opposite effects. Our initial studies indicated that the stress-induced PML-NB translocation of FBF1 is regulated by a distinct cilia module comprising Joubert syndrome proteins ARL3 and ARL13B and the SUMO-conjugating enzyme UBC9. Further proteomic studies revealed novel FBF1 interactors (PML, 53BP1, and BRD4) implicated in PML-NB biogenesis and/or function. Remarkably, Fbf1tm1a/tm1a mice exhibit a significantly reduced senescence burden throughout life and could be further protected against irradiation-induced frailty. Our preliminary data thus suggest an exciting paradigm that a stress-induced TF-to-PML-NB translocation of ciliary protein FBF1 is essential for senescence initiation in mammalian cells. Here, we propose to use complementary approaches to address mechanistic questions, including how the ciliary ARL3-ARL13B-UBC9 module regulates FBF1 SUMOylation and PML-NB translocation (Aim 1), and how PML-NB-associated FBF1 promotes senescence in stressed cells (Aim 2). Together with the extended analysis of the physiological importance of FBF1 pathway in in vivo senescence mouse models (Aim 3), this project will potentially bridge the fundamental discovery to the next generation of therapeutic strategies for preventing or treating senescence-associated pathologies.

项目摘要 细胞衰老是由不可修复的外在或内在压力激活的程序性生长停滞。 衰老在某些情况下是有益的，例如胚胎期间的组织动态平衡。 发展或抑制肿瘤。然而，如果由衰老细胞持续分泌，促炎症 细胞因子、趋化因子、蛋白酶和生长因子实际上是衰老和年龄相关的主要驱动因素 疾病，矛盾的是，还会促进肿瘤的形成。衰老细胞的遗传或药物清除 有效提高啮齿动物模型的寿命和健康寿命。因此，针对衰老的研究已经成为 一种很有希望的治疗策略，可以预防或治疗衰老、合并症和癌症。然而，如何 在应激的细胞中诱导和维持不可逆的衰老程序仍然知之甚少。 细胞利用初级纤毛将环境信号转换为不同的细胞信号，这些信号支配着 增殖、分化和组织动态平衡。纤毛功能障碍导致一系列综合征 统称为纤毛疾病的疾病。利用辐射，我们发现有压力的人类 成纤维细胞或上皮细胞表现出短暂的纤毛生物发生。令人惊讶的是，FBF1，过渡纤维的一种成分 (TFS)在睫状体基底部，居然移位到早幼粒细胞白血病核体(PML-NBS)。 紧张的细胞。PML-NBS是一种高度动态的蛋白质核结构，在 调节应激诱导的反应，包括衰老和细胞凋亡。FBF1有效耗尽 取消应激诱导的PML-NB上调和相关的衰老启动，而FBF1 过度表达则表现出相反的效果。我们的初步研究表明，应激诱导的PML-NB FBF1的转位受一个不同的纤毛模块调节，该模块包括Joubert综合征蛋白ARL3和 Arl13b和相扑结合酶UBC9。进一步的蛋白质组学研究发现了新的FBF1 相互作用因子(PML、53BP1和BRD4)参与PML-NB的生物发生和/或功能。值得注意的是， Fbf1tm1a/tm1a小鼠在一生中表现出显著的衰老负担，并可能进一步 防止辐射引起的脆弱。因此，我们的初步数据表明，一个令人兴奋的范例是 应激诱导纤毛蛋白FBF1 Tf-to-PML-NB易位是衰老所必需的 在哺乳动物细胞中的起始。在这里，我们建议使用互补的方法来解决机械性 问题，包括纤毛ARL3-Arl13b-UBC9模块如何调节FBF1 SUMO化和PML-NB 易位(目标1)，以及PML-NB相关的FBF1如何促进应激细胞的衰老(目标2)。 并对FBF1通路在体内衰老中的生理意义进行了扩展分析 小鼠模型(目标3)，该项目将潜在地将基础发现与下一代 预防或治疗衰老相关病理的治疗策略。