Novel functions of nuclear transport factors in cellular homeostasis

核转运因子在细胞稳态中的新功能

• 批准号: RGPIN-2020-05104
• 负责人: Stochaj, Ursula
• 金额: $ 2.33万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763304
• 关键词: Novel; functions; nuclear; transport; factors

Nuclear transport factors participate in different aspects of eukaryotic cell physiology. Their contributions range from cell growth to scaling, aging and death. Recent studies suggest new functions for nuclear transport factors that are related to RNA homeostasis and the stress response. In support of this model, our group demonstrated that importin-a1 binds polyA-RNA. We further showed that all importin-a sub-families associate with cytoplasmic stress granules. Stress granules contain a diverse set of proteins and RNAs. As membraneless compartments, they assemble through phase separation. Our laboratory also established links between nuclear transport factors and cytoplasmic granules that accumulate damaged RNA. These unique compartments are not stress granules. To date, clear experimental evidence shows that nuclear transport factors are essential regulators of cell compartments that form by phase separation. Specifically, nuclear transport factors have emerged as pillars of a multi-layered quality control network that scrutinizes RNA granules in the cytoplasm. The underlying molecular mechanisms are poorly understood. Our research program will address these central biological questions. To this end, we have established three independent in vitro and in vivo model systems of increasing complexity. SHORT-TERM OBJECTIVES. We will characterize novel biological functions of nuclear transport factors that are linked to protein and RNA homeostasis. LONG-TERM GOALS. Our research program will (i) define the protein and RNA quality control network that is driven by nuclear transport factors, and (ii) dissect the mechanisms through which this network modulates biological processes that ultimately determine cell fate. HYPOTHESES. Based on our ongoing studies, we propose that (1) nuclear transport factors control granulostasis; (2) nuclear transport factors regulate RNA homeostasis in the cytoplasm. SPECIFIC AIMS. We will test our hypotheses in cell-free, cellular and organismal model systems. In particular, we will: (1) Define the role of nuclear transport factors for stress granule assembly, dynamics, dissolution and fibrillization; (2) Characterize cytoplasmic RNA damage granules. IMPACT. Based on results we recently obtained, our research program takes a novel and exciting direction that explores the unexpected and ill-defined functions of nuclear transport factors as they relate to cytoplasmic RNA granules. We will focus on the underlying biological mechanisms that are largely unknown. Thus, our research will identify the contributions of nuclear transport factors to a complex quality control system that regulates cellular homeostasis. These important biological processes are relevant to all eukaryotic cells. The insights generated by us will help define basic principles that promote cellular homeostasis. We will achieve this through rigorous and multidisciplinary research that uses state-of-the-art methods and instrumentation.

核运输因子参与真核细胞生理的不同方面。它们的贡献范围从细胞生长到结垢、衰老和死亡。最近的研究表明，与RNA动态平衡和应激反应相关的核运输因子具有新的功能。为了支持这一模型，我们的团队证明了Importin-A1与Polya-RNA结合。我们进一步表明，所有的Importin-a亚家族都与细胞质应激颗粒有关。应激颗粒包含一组不同的蛋白质和RNA。作为无膜室，它们通过相分离组装在一起。我们的实验室还建立了核运输因子和积累受损RNA的细胞质颗粒之间的联系。这些独特的隔间不是压力颗粒。到目前为止，明确的实验证据表明，核运输因子是通过相分离形成的细胞隔间的基本调节因素。具体地说，核运输因子已经成为一个多层质量控制网络的支柱，该网络仔细检查细胞质中的RNA颗粒。其潜在的分子机制还知之甚少。我们的研究计划将解决这些核心的生物学问题。为此，我们已经建立了三个独立的体外和体内模型系统，这些系统的复杂性越来越高。短期目标。我们将描述与蛋白质和RNA动态平衡相关的核运输因子的新生物学功能。长期目标。我们的研究计划将(I)定义由核运输因素驱动的蛋白质和RNA质量控制网络，并(Ii)剖析该网络调节最终决定细胞命运的生物过程的机制。假设。根据我们正在进行的研究，我们提出：(1)核运输因子控制颗粒稳定；(2)核运输因子调节细胞质中的RNA动态平衡。明确的目标。我们将在无细胞、细胞和生物模型系统中测试我们的假设。特别是，我们将：(1)确定核运输因子在应激颗粒组装、动力学、溶解和纤化中的作用；(2)表征细胞质RNA损伤颗粒。冲击力。基于我们最近获得的结果，我们的研究计划采取了一个新的和令人兴奋的方向，探索核运输因子与细胞质RNA颗粒相关的意外和未定义的功能。我们将把重点放在基本未知的潜在生物学机制上。因此，我们的研究将确定核运输因子在调节细胞内稳态的复杂质量控制系统中的作用。这些重要的生物学过程与所有真核细胞都有关。我们产生的见解将有助于定义促进细胞动态平衡的基本原则。我们将通过使用最先进的方法和仪器的严格和多学科研究来实现这一目标。