Regulation of Stress granules in response to lysosomal damage

溶酶体损伤是细胞稳态和生存的主要威胁。溶酶体损伤与许多人类疾病以及正常衰老有关。然而，细胞对溶酶体损伤反应的特征、功能和潜在的分子机制（下文称为“溶酶体损伤反应”）仍然难以捉摸。我们的新出版物揭示，溶酶体损伤可以作为迄今为止未被认识的应激颗粒（SG）形成的发起者。SGs是信使核糖核蛋白凝聚体的聚集体，通过抑制大量翻译和促进选择性蛋白质合成，帮助细胞适应溶酶体损伤情况，维持细胞稳态。然而，关于溶酶体损伤如何启动SG形成以及SG如何与溶酶体损伤反应网络连接以组织细胞调节，仍有许多有待了解。SGs已经涉及到几种疾病的病因学，并且操纵SGs正在成为一种有前途的疾病治疗途径。溶酶体损伤作为SG形成的信号将与多种疾病状态相关。因此，研究溶酶体损伤与SGs之间的交集是非常重要的，这既与正常的细胞功能有关，也与广泛的人类疾病中发现的功能失调的溶酶体和SGs有关。我们已经报道了一组基于半乳糖凝集素的溶酶体损伤反应，以识别，修复，循环和替换受损的溶酶体。这种基于半乳糖凝集素的检测和信号转导系统保障溶酶体质量，并启动核心细胞调控mTOR和AMPK信号的下游分解代谢和合成代谢过程。溶酶体损伤时SG形成的发现使溶酶体损伤反应网络考虑到全局翻译重编程。因此，我们的总体目标是确定溶酶体损伤时SG形成的信号通路及其与溶酶体损伤反应网络的连通性，以识别、修复、循环、替换和重编程受损的溶酶体。我们的长期目标是了解细胞对溶酶体损伤的反应。所提出的研究详细阐述了对溶酶体损伤、SG形成的新反应的调控途径，并与我们对基于半乳糖凝集素的溶酶体损伤反应的了解联系起来，可以填补溶酶体损伤领域的空白，扩展SGs网络，并带来当前细胞应激知识的范式转变，打开一个新的研究领域

Lysosomal damage is a major threat to cellular homeostasis and survival. Lysosomal damage has been implicated in many human diseases as well as normal ageing. However, the characterizations, functions and underlying molecular mechanisms of cellular responses to lysosomal damage (referred to as “lysosomal damage responses” hereafter) remain elusive. Our new publication uncovers that lysosomal damage can act as a hitherto unappreciated initiator of stress granule (SG) formation. SGs, the aggregation of messenger ribonucleoprotein condensates, help the cell to adapt to lysosomal damage situation and maintain cellular homeostasis by suppressing bulk translation and promoting selective protein synthesis. However, much remains to be understood regarding how lysosomal damage initiates SG formation as well as how SGs connect to the network of lysosomal damage responses to organize cellular adjustment. SGs have been implicated in the etiology of several disorders, and manipulation of SGs is emerging as a promising therapeutic avenue for disease treatment. The lysosomal damage as a signal for SG formation will be of relevance for multiple disease states. Thus, it is very important to study the intersection between lysosomal damage and SGs, which is relevant both to normal cellular functions and to dysfunctional lysosomes and SGs found in a wide range of human diseases. We have reported a set of galectin-based lysosomal damage responses to recognize, repair, recycle and replace damaged lysosomes. This galectin-based detection and signal-transduction system safeguards lysosomal quality and sets off downstream catabolic and anabolic processes of core cell regulatory mTOR and AMPK signaling. The discovery of SG formation upon lysosomal damage brings the consideration of global translational reprogramming into the network of lysosomal damage responses. Therefore, our overall objective is to identify the signaling pathway of SG formation upon lysosomal damage and its’s connectivity to the network of lysosomal damage responses to recognize, repair, recycle, replace and reprogramme damaged lysosomes. Our long-term goal is to understand cellular responses to lysosomal damage. The proposed studies detail the regulatory pathway of the new response to lysosomal damage, SG formation and link with our knowledge of galectin-based lysosomal damage responses could fill the gap in lysosomal damage field, extend the network of SGs and bring a paradigm shift in the current knowledge of cell stress opening a new field of study Completion of the proposed studies will provide