Research

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The Tan Lab studies core principles of cell biology in aging, with a particular interest in basic molecular mechanisms underlying cellular homeostasis and stress response. Organelle stress and damage are significant risk factors in human aging and various diseases. Our lab aims to elucidate the molecular mechanisms involved in sensing and resolving organelle stress in mammalian cells. Current research topics include:

• Lysosomal quality control in aging and neurodegeneration
• Inter-organelle communication in cell homeostasis
• Lysosomal stress in innate immunity and age-related inflammation

We seek to uncover essential, unifying principles behind complex stress responses through unbiased approaches. Our multidisciplinary methods encompass molecular biology, biochemistry, cell biology, genetics, structural biology, in vitro reconstitution, proteomics, lipidomics, and transcriptomics to dissect these underlying mechanisms.

We aim to answer several fundamental questions in lysosomal quality control: 

①How is lysosomal function compromised in disease and aging? 

②How do our cells sense lysosomal abnormality? 

③What are the key pathways activated by lysosomal dysfunction? 

④How to restore lysosomal activity for disease treatment? 

In line with our goal to answer these fundamental questions, we are working on several projects to further study the sensing, repairing, and functional restoration of damaged lysosomes. We are also searching for principles dominating lysosomal communication with other organelles as well as the role for lysosomal stress response in inter-cellular communications in aging and organismal pathophysiology.  

Defects in lysosomal function have been increasingly linked to normal aging and age-related diseases. Lysosomal membrane permeabilization (LMP), a hallmark of lysosomal-related diseases, is commonly triggered by diverse cellular stressors. LMP must be rapidly resolved to maintain cellular homeostasis. 

Our recent work uncovered LMP-induced lipid signaling as an essential mechanism for rapid lysosomal repair. Upon lysosomal membrane damage, a new phosphoinositide messenger is rapidly produced on lysosomes, which in turn drives the formation of extensive, new 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. We are further investigating the role of this pathway in aging. 

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, suggesting that efficient rapid lysosomal membrane repair would suppress tau spreading and AD progression. Our prelim work shows that defects in rapid lysosomal repair markedly increased 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 the therapeutic purpose of AD.  

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 tethers. 

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.