Regulation of Stress granules in response to lysosomal damage

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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