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：
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
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/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

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.

项目摘要细胞衰老是由无法弥补的外在或内在应力激活的编程生长停滞。在某些情况下，衰老可能是有益的，例如胚胎期间的组织稳态发育或抑制肿瘤。但是，如果被衰老细胞持续分泌，则促炎细胞因子，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并矛盾地促进肿瘤发生。衰老细胞的遗传学或药理清除率有效地改善了啮齿动物模型中的寿命和健康范围。因此，靶向衰老已经出现预防或治疗衰老合并症和癌症的有希望的治疗策略。但是，如何不可逆的衰老程序被诱导并维持在压力细胞中仍然知之甚少。细胞利用原发性纤毛将环境线索转化为各种细胞信号增殖，分化和组织稳态。纤毛功能障碍导致广泛的综合征共同称为纤毛病的疾病。使用辐照，我们发现强调人成纤维细胞或上皮细胞表现出瞬时纤毛生物发生。令人惊讶的是，FBF1，过渡纤维的组成部分（TFS）在睫状底部，意外地转移到临时性白血病核体（PML-NBS）中压力细胞。 PML-NB是高度动态的蛋白质核结构，在调节应力诱导的反应，包括衰老和凋亡。 FBF1有效耗竭废除压力引起的PML-NB上调和相关的衰老开始，而FBF1 过表达显示相反的效果。我们的初步研究表明，应力诱导的PML-NB FBF1的易位由一个独特的纤毛模块调节，该模块包括乔伯特综合征蛋白ARL3和 ARL13B和相结合的酶UBC9。进一步的蛋白质组学研究揭示了新型FBF1 与PML-NB生物发生和/或功能有关的相互作用者（PML，53BP1和BRD4）。值得注意的是 FBF1TM1A/TM1A小鼠一生都显着减轻衰老负担，可能会进一步防止辐射引起的脆弱。因此，我们的初步数据表明了令人兴奋的范式压力诱导的纤毛蛋白FBF1的TF到PML-NB易位对于衰老至关重要哺乳动物细胞的启动。在这里，我们建议使用互补方法来解决机理问题，包括睫状ARL3-ARL13B-UBC9模块如何调节FBF1 Sumoylation和PML-NB 易位（AIM 1），以及PML-NB相关的FBF1如何促进胁迫细胞中的衰老（AIM 2）。以及对体内衰老中FBF1途径的生理重要性的扩展分析鼠标模型（AIM 3），该项目将有可能将基本发现桥接到下一代预防或治疗与衰老相关的病理的治疗策略。