Role of TDP-43 in cellular stress responses

哺乳动物细胞具有多种机制来调节细胞从生理和环境应激中恢复。根据遇到的压力类型，可以激活各种信号通路，导致从增殖到生长停滞、衰老或细胞死亡的各种反应。在细胞水平上，对压力的直接反应是形成被称为压力颗粒的细胞质结构。应激颗粒包含各种大的蛋白质复合体，它们协同地维持mRNAs处于沉默状态。我们最近确定的一种蛋白质是TAR DNA结合蛋白(TDP-43)，它是应激颗粒的组成部分。TDP-43是一个被称为异质性核糖核蛋白(HnRNPs)的RNA结合蛋白大家族的成员，其中一些已被报道参与细胞应激反应。这项拟议的研究计划旨在确定TDP-43在细胞应激反应中的作用。该提案结合了多种细胞生物学、生物化学和质谱学方法。参加这个项目的研究生将在这些方法和数据分析方面获得多样化的培训。通过TDP-43了解应激颗粒信号和动力学将对细胞对生理和环境刺激的反应具有广泛的意义。

Mammalian cells possess a variety of mechanisms to mediate a cell's recovery from physiological and environmental stresses. Depending on the type of stress encountered, a variety of signaling pathways can be activated resulting in responses ranging from proliferation to growth arrest, senescence, or cell death. At the cellular level, the immediate response to a stress is the formation of cytoplasmic structures called stress granules. Stress granules contain a variety of large protein complexes which cooperatively maintain mRNAs in a silent state. One protein we have recently identified as being a component of stress granules is TAR DNA binding protein (TDP-43). TDP-43 is a member of a large family of RNA binding proteins known as heterogeneous nuclear ribonucleoproteins (hnRNPs), some of which have been reported to participate in cellular stress responses. The proposed research program aims to define the role of TDP-43 in cellular stress responses. The proposal incorporates a variety of cell biology, biochemistry and mass spectrometry approaches. Graduate students participating in this program will gain a diversified training in these methods as well as data analysis. Understanding stress granule signaling and dynamics via TDP-43 will have wide-reaching implications for cellular responses to physiological and environmental stimuli.