LysoDARE - Mechanisms and therapeutic application of lysosome repair

In the intricate world of cells, tiny membrane-enclosed spherical organelles termed lysosomes stand as guardians of waste recycling. Lysosomes house a cocktail of enzymes, which break down worn-out cellular organelles, other debris and eliminate toxic components. In this way, lysosomes maintain cellular fitness. But compromised lysosomes can also pose a threat to cell’s health. When lysosome membrane integrity is disrupted, their content leaks out, and this can have harmful effects on cellular function, or lead to diseases such as neurodegenerative diseases and cancer. Therefore, it is vital that pathogens and other insults that seek to damage lysosomes are met with a rapid response to ensure lysosome integrity and overall cell survival. We recently discovered a safeguard mechanism that cells use to monitor and repair the leaky lysosomes. However, we still lack a complete understanding of how exactly lysosome surveillance happens in cells, and several important questions remain. In this proposal, I am aiming to thoroughly investigate which molecular machineries are activated immediately after lysosome membrane damage, and how their function is coordinated to repair damaged lysosomes. Results achieved may allow us to develop ways to keep these microscopic recycling centers of the cell in a proper state to ensure cellular and overall organismal health.

Lysosomal degradative activity is vital for cellular and organismal health and its dysfunction is linked to metabolic, inflammatory and autoimmune disorders, neurodegenerative diseases, and cancer. Lysosomal membrane permeabilization, a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors. Therefore, it is vital that lysosome damaging agents such as pathogens and other insults are met with a rapid response to ensure lysosome integrity and overall cell survival. Given the high frequency of lysosomal membrane permeabilization in diseases and physiological aging, lysosomal membrane damage and repair (LysoDARE) is a closely guarded process. In two recent publications, I have unveiled that the endosomal sorting complex required for transport (ESCRT)- machinery and endoplasmic reticulum (ER)-to-lysosome contact sites mediate rapid repair of damaged lysosomes. Activated within minutes after injury, the ESCRT complex seals small lesions in lysosomal membranes and ensures cell survival. Following membrane damage, the resident lipids lost at the site of injury are replaced through ER-to-lysosome mediated lipid supply enabling completion of the restoration process and sustaining cellular integrity. However, the signals that activate these processes and mechanism(s) of membrane repair remain unknown and are therefore the focus of this proposal. Importantly, pharmacological or photochemical destabilization of cancer cell lysosomes is being tested for cancer therapies since rupture of lysosomes causes cell death. We also propose to investigate whether inhibition of the LysoDARE pathways can be used to potentiate lysosome-directed cancer therapy.