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

基本信息

批准号：
10627992
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
项目类别：
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/10627992
关键词：
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 Communication 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 Physiological Play Probability Proliferating Proteins Proteomics Radiation Regulation Resources Rodent Model Role Seminal Sensory Signal Transduction Somatic Cell Stress Structure Sumoylation Pathway Surface TP53 gene Therapeutic Tissues Toxic effect 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 pharmacologic prevent programs response senescence transcription factor PML tumorigenesis

项目摘要

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.

项目概要细胞衰老是由不可修复的外在或内在应激激活的程序性生长停滞。衰老在某些情况下可能是有益的，例如胚胎期间的组织稳态发展或抑制肿瘤。然而，如果衰老细胞持续分泌，促炎细胞细胞因子、趋化因子、蛋白酶和生长因子实际上是衰老和与年龄相关的主要驱动因素疾病，并且矛盾的是，促进肿瘤发生。衰老细胞的遗传或药理学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出现预防或治疗衰老合并症和癌症的一种有前景的治疗策略。然而，如何在应激细胞中诱导和维持不可逆转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化为多种细胞信号来控制增殖、分化和组织稳态。纤毛功能障碍导致多种综合征统称为纤毛病的疾病。通过辐射，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。引人注目的是，FBF1，过渡纤维的一个组成部分（TF）在睫状基部，意外地易位到早幼粒细胞白血病核体（PML-NB）应激细胞。 PML-NB 是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。有效消除 FBF1 消除应激诱导的 PML-NB 上调和相关的衰老起始，而 FBF1 过度表达会产生相反的效果。我们的初步研究表明，应激诱导的 PML-NB FBF1 的易位由独特的纤毛模块调节，该纤毛模块包含 Joubert 综合征蛋白 ARL3 和 ARL13B 和 SUMO 结合酶 UBC9。进一步的蛋白质组学研究揭示了新的 FBF1 与 PML-NB 生物发生和/或功能有关的相互作用因子（PML、53BP1 和 BRD4）。值得注意的是， Fbf1tm1a/tm1a 小鼠在整个生命过程中表现出显着减轻的衰老负担，并且可能进一步防止辐射引起的虚弱。因此，我们的初步数据表明了一个令人兴奋的范式：应激诱导的纤毛蛋白FBF1从TF到PML-NB的易位对于衰老至关重要在哺乳动物细胞中起始。在这里，我们建议使用补充方法来解决机械问题问题，包括纤毛 ARL3-ARL13B-UBC9 模块如何调节 FBF1 SUMOylation 和 PML-NB 易位（目标 1），以及 PML-NB 相关 FBF1 如何促进应激细胞衰老（目标 2）。连同FBF1通路在体内衰老中的生理重要性的扩展分析小鼠模型（目标 3），该项目有可能将基本发现与下一代模型联系起来预防或治疗衰老相关病理的治疗策略。