Studies cellular principles of aging and age-related pathology
Organelle stress and damages are common risk factors in human aging and diseases. A major goal of our lab is elucidating the molecular mechanisms underlying the sensing and resolution of organelle stress in mammalian cells. Current research topics include lysosomal quality control in aging and neurodegeneration, inter-organelle communications in cell homeostasis, and lysosomal stress in innate immunity and age-related inflammation. We search for essential, unifying principles behind complex stress responses through unbiased approaches, and dissect underlying mechanisms with multidisciplinary methods including molecular biology, biochemistry, cell biology, and genetics.
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 (Nature, 2022). 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 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.
Xun J, Zhang Z, Lv B, Lu D, Yang H, Shang G, Tan JX. A conserved ion channel function of STING mediates non-canonical autophagy and cell death. bioRxiv. 2023:2023-08.
Trends in Cell Biology. 2023. DOI:https://doi.org/10.1016/j.tcb.2023.01.001
Tan, JX, Finkel, T. A phosphoinositide signalling pathway mediates rapid lysosomal repair. Nature. (2022). https://doi.org/10.1038/s41586-022-05164-4
Tan X, Anderson RA. Keeping in touch with the ER network. Science. 2017;12;356(6338): 584-585.
Tan X, Thapa N, Sun Y, Anderson RA. A kinase independent role for EGF receptor in autophagy initiation. Cell. 2015;160(1-2):145-60.
Tan X, Thapa N, Liao Y, Choi S, Anderson RA. PtdIns(4,5)P2 signaling regulates ATG14 and autophagy. PNAS. 2016;113(39):10896-901. doi: 10.1073/pnas.1523145113.
Tan X, Sun Y, Thapa N, Liao Y, Hedman AC, Anderson RA. LAPTM4B is a PtdIns(4,5)P2 effector that regulates EGFR signaling, lysosomal sorting, and degradation. EMBO J. 2015; 34(4):475-90.
Tan JX, Finkel T. Autophagy goes nuclear. Nature Cell Biology. 2020;22(10):1159-61.
Tan JX, Finkel T. Mitochondria as intracellular signaling platforms in health and disease. Journal of Cell Biology. 2020;219(5): e202002179.
Tan X, Sun L, Chen J, Chen ZJ. Detection of microbial infections through innate immune sensing of nucleic acids. Annual Review of Microbiology. 2018;72:447-78.
Tan X, Lambert PF, Rapraeger AC, Anderson RA. Stress-induced EGFR trafficking: mechanisms, functions, and therapeutic implications. Trends Cell Biol. 2016;26(5):352-66.
Gui X, Yang H, Li T, Tan X, Shi P, Du F, Chen ZJ. Autophagy Induction via STING Trafficking Is a Primordial Function of the cGAS Pathway. Nature. 2019;567(7747):262-266.
We bioRxiv'ed a manuscript - A conserved ion channel function of STING in non-canonical autophagy and cell death. Congratulations to all the co-authors!
Awishi Mondal joined our lab as a rotation student.
Our recent work on lysosomal repair is published online today at Nature. Congratulations!
Genetic Engineering & Biotechnology News: Longevity Depends on Prompt Repair of Lysosomal Breaches (genengnews.com)
BioArt： Nature | 溶酶体损伤修复的核心机制
We are seeking talented and passionate scientists from all stages to join our team. We support all team members to succeed in both research and career. Training and mentoring are important aspects integrated into all team members' career development plans.
If you are interested in joining us, please email jay.tan at pitt.edu a cover letter (summarizing your previous training, research interests, and career goals), CV, and contact information for three references.
We are searching for a highly motivated postdoctoral fellow to join us in studying lysosomal stress in innate immunity and age-related inflammation. Excellent training opportunities will be provided in both research and career development as well as in exploring new directions with established screening approaches in the lab. The candidate is expected to seek independent positions in academia when moving forward from this position.
We are recruiting graduate students and research technicians with 0-3 years of research experience to join us in studying lysosomal quality control in aging and Alzheimer's disease. We have established a robust research program on these topics and will provide extensive training in cell biology, molecular biology, biochemistry, advanced biochemistry, genetics, and mouse models.
Research technicians should have a bachelor's degree and are expected to apply for Ph.D. or M.D. programs when moving forward from the lab.
We have open positions for Tsinghua and Xiangya Scholars in studying cellular quality control mechanisms in aging, immunity, and disease. We have multiple active research projects on these topics and will provide top-quality training in cell biology, molecular biology, biochemistry, advanced biochemistry, genetics, and mouse models.
Multiple undergraduate research positions are available for our exciting, ongoing projects. Undergraduate researchers are expected to apply for Ph.D. or M.D. programs when moving forward to the next stage of their careers.
Department of Cell Biology
University of Pittsburgh School of Medicine/UPMC
Bridgeside Point I, Suite 564
100 Technology Dr.
Pittsburgh, PA 15219
Email: Jay.Tan at Pitt.edu
100 Technology Drive, Room 457, Pittsburgh, Pennsylvania 15219, United States