Maja Radulovic received the Young Talent Grant from the Research Council

LysoDARE - Mechanisms and therapeutic application of lysosome repair

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.