Tan Lab

Lysosomal membrane damage is commonly triggered by diverse cellular stressors and is increasingly linked to normal aging and age-related diseases. 

Our recent work uncovered the phosphoinositide- initiated membrane tethering and lipid transport (PITT) pathway as an essential mechanism for rapid lysosomal repair (Nature, 2022). Upon lysosomal membrane damage, a new phosphoinositide messenger, PI4P,  is rapidly produced on lysosomes, which in turn drives the formation of extensive membrane contacts between damaged lysosomes and the endoplasmic reticulum (ER). These new inter-organelle interactions directly mediate rapid lysosomal repair, with important implications for a wide range of lysosomal-related diseases. 

Tau fibril spreading is a major factor contributing to the progression of Alzheimer’s disease (AD). Lysosomal membrane damage by internalized tau fibrils is a key step in tau spreading. Our work shows that defects in PITT pathway markedly increases tau fibril spreading in cell-based assays. We are further characterizing how lysosomal quality control antagonizes tau spreading in vitro and in vivo and explore pharmacological strategies to activate this pathway for AD treatments.  

We are interested in essential inter-organelle communications that maintain cellular homeostasis. Our recent work revealed striking ER-lysosomal interactions upon lysosomal stress. Factors recruited to these membrane contact sites include not only the rapid lysosomal repair machineries but also additional proteins with distinct functions. We are continuing investigating how these factors might contribute to lysosomal quality control in aging and whether these inter-organelle events are triggered in aging or age-related diseases. 

We are also interested in membrane contacts initiated from other organelles such as lipid droplets, peroxisomes, and mitochondria. We are developing new approaches to discover stress-induced inter-organelle communications. 

Most well-known as degradative compartments, lysosomes are multifunctional centers also involved in metabolism, nutrient sensing, and immunity.  Dysfunctional lysosomes are implicated in senescence and autoimmune disorders. We are using high throughput screens to search for the molecular basis of lysosomal dysfunction-induced senescence and inflammation.  We are also trying to understand communications between lysosomal stress and innate immune pathways. 

Under various pathophysiological conditions, including lysosomal storage disorders, aging, infection, and neurodegeneration, lysosomes can

form large vacuoles associated with lysosomal dysfunction. Although lysosomal vacuolation has been observed for decades and is presumed to be an adaptive stress response, its underlying mechanisms

and physiological functions remain poorly  understood. 

Our recent work identifies PDZD8/LYVAC-mediated, directional ER-to-lysosome lipid transfer as an essential mechanism for lysosomal vacuolation (Science 2025). Diverse vacuolating stimuli converged on a common pathway involving lysosomal osmotic stress, lipid signaling, and regulation of LYVAC recruitment and lipid transfer. By linking lysosomal osmotic imbalance to vacuole formation, LYVAC underlies a robust cellular response with broad implications for lysosomal adaptation, osmoresilience, lysosomal storage pathology, and neurodegeneration.