Toxicity of extracellular cGAMP and its analogs to T cells is due to SLC7A1-mediated import
Valentino Sudaryo, Dayanne R. Carvalho, J. Michelle Lee, Jacqueline A. Carozza, Xujun Cao, Anthony F. Cordova, Lingyin Li
Welcome to the Li Lab
The Li lab combines chemistry, biochemistry, immunology, and physiology to uncover fundamental mechanisms of our first line of defense against pathogens and cancer: innate immunity. Activation of innate immunity is a proven therapeutic strategy for vaccination, viral infection, and cancer, while inhibition is a strategy for treating autoimmune diseases and neurodegeneration. We explore the novel chemistry of these pathways to understand and develop new therapeutic targets and drugs that can manipulate innate immune activation with precision.
Research Focus
Cell-specific Molecular Mechanisms
The innate immune STING pathway senses cytosolic dsDNA and generates the second messenger cGAMP, which activates STING to initiate downstream immune signaling. It exists in a delicate balance: it must detect and defend against viruses and cancer but not aberrantly respond to benign self dsDNA. We previously discovered that cGAMP is an immunotransmitter that is secreted by producing cells and detected by various immune cell types and stromal cells. We investigate cell type-specific cGAMP and STING regulation using chemical biology and genetic approaches, and discover new, potentially druggable checkpoints on the pathway.
Biochemical Mechanisms
We use classic biochemistry, structural biology, and medicinal chemistry to investigate at the atomic level how protein and small molecule immunomodulators of the STING pathway function effectively and how they fall into dysregulation and cause inflammation. In parallel, we develop and refine prototype drugs that bind to targets in the STING pathway and can be used to test therapeutic hypotheses in disease models.
Immunological Disease Models
Cancer and autoimmunity are two sides of the same coin of STING physiology. We have strong interest in the balancing act of the STING pathway in whole organisms. We rely heavily on mouse genetic models and are building cutting-edge genetic knock-in mouse strains that selectively perturb regulators that we have uncovered. We use these mouse strains coupled with cancer, infection, and autoimmune disease models to contextualize the roles of each regulator in different disease settings. We also use these disease models to test our therapeutic hypotheses and lead compounds.
Publications
PELI2 is a negative regulator of STING signaling that is dynamically repressed during viral infection
Christopher Ritchie, Lingyin Li
Molecular Cell • June 2024
Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint
Rachel Mardjuki, Songnan Wang, Jacqueline Carozza, Bahar Zirak, Vishvak Subramanyam, Gita Abhiraman, Xuchao Lyu, Hani Goodarzi, Lingyin Li
Cell Reports • May 2024
Stimulating STING for cancer therapy: Taking the extracellular route
Lingyin Li
Science Direct • May 2024
Galectin-1 mediates chronic STING activation in tumors to promote metastasis through MDSC recruitment.
Nambiar DK, Viswanathan V, Cao H, Zhang W, Guan L, Chamoli M, Holmes B, Kong C, Hildebrand R, Koong AJ, von Eyben R, Plevritis S, Li L, Giaccia A, Engleman E, Le QT
Cancer Research • Oct 2023
Blocking oligomerization is the most viable strategy to inhibit STING
Rebecca Chan, Xujun Cao, Sabrina L. Ergun, Evert Njomen, Stephen R. Lynch, Benjamin F. Cravatt.
bioRxiv • Aug 2023
Discovery of VH domains that allosterically inhibit ENPP1.
Solomon PE, Bracken CJ, Carozza JA, Wang H, Young EP, Wellner A, Liu CC, Sweet-Cordero EA, Li L, Wells JA
Nature Chemical Biology • Jul 2023
News
Welcome Tong Lan and Yu Li, who join the lab as postdoctoral researchers!
Welcome Dr. Yingjie Guo, who joins the lab as a postdoctoral researcher!
Welcome Gabriel Grenot, who joins the lab as our in vivo technician!
Welcome Michelle Lee, who joins the lab as a graduate student from the Chemistry Department!
Congratulations Dr. Rachel Mardjuki on a successful thesis defense!
Team
CORE INVESTIGATOR
Lingyin Li
Lingyin Li is an Associate Professor in the Biochemistry Department and the ChEM-H institute at Stanford. She received her Ph.D at the University of Wisconsin-Madison with Dr. Laura Kiessling and performed postdoctoral studies with Dr. Timothy Mitchison at Harvard Medical School. The Li Laboratory has pioneered the development of chemical tools to define and manipulate new modulators of the innate immune STING pathway. Dr. Li is the recipient of the NIH New Innovator Award in 2017, the Ono Pharma Foundation Breakthrough Science Initiative Award in 2017, and the 2022 Eli Lilly Award in Biological Chemistry.
Current Members
Lab Manager
Gemini Skariah
Before joining Li lab as lab manager/ LSRP, I was working at different Stanford labs since 2004. At Li lab I maintain all the mouse strains for different projects in the lab. Outside of the lab I enjoy spending time with family and friends.
Senior Scientist
Jackie Carozza
I trained in chemistry and biochemistry, completing my PhD at Stanford with Lingyin in 2021. Now, I work on identifying druggable proteins in innate immuno-oncology and developing molecules that target them. I really enjoy backpacking in the Sierra Nevada foothills and spending time with my family.
Staff Scientist
Daniel Fernandez
Before joining Stanford I worked at EMBL Grenoble, France, on X-ray structural characterization of plant hormone receptors and their ligands. At Li Lab I supervise protein structural work, training students. Outside of the lab, I enjoy biking and reading books.
Postdoctoral Researcher
Chris Ritchie
I have a PhD in Biochemistry from Stanford. In lieu of a traditional bio, I commissioned members of my lab space to write a descriptive haiku for me:
In my PhD
I found cGAMP transporters
I enjoy biking.
Postdoctoral Researcher
Rachel Mardjuki
Prior to Stanford, I worked in epigenetics and organic synthesis. At Arc, I work on understanding the regulation of extracellular cGAMP. Outside of lab I enjoy swimming and music.
Graduate student, Dept of Chemistry
Xujun Cao
Prior to Stanford, I majored in Chemistry at the National University of Singapore, where I worked on the organic synthesis of carbohydrate probes and imprinted polymers. At Arc, I use tools in biochemistry, computation and cell and structural biology to study molecular mechanisms of innate immune activation. Outside of the lab I enjoy mahjong, board games and mind games, eating and running so I can keep eating.
MD-PhD Student, Dept of Biochemistry
Songnan Wang
I studied Chemical Engineering at Johns Hopkins and spent two years doing stem cell research at USCF before starting medical school at Stanford. I’m currently pursuing a joint master degree where I study ENPP1's role as an innate immune checkpoint in cancer. In my free time I like to cook/eat good food with friends and families.
Graduate student, Dept of Immunology
Valentino Sudaryo
Prior to Stanford, I did my undergrad at MIT, where I worked on a joint project between the labs of Harvey Lodish and Hidde Ploegh to engineer red blood cells and nanobodies for various therapeutic purposes. At Arc, I work on how extracellular cGAMP signals in T cells. Outside of lab I enjoy doing photography, watching basketball games and trying out different food.
Graduate student, Dept of Chemical & System Biology
Rebecca Chan
Prior to Stanford, I completed my BS in Chemical Biology from UC Berkeley followed by two years of research in Judith Frydman’s lab studying chaperone-huntingtin interactions. At Arc, I work on understanding the cellular and biochemical factors that regulate STING activation. Outside of lab, I enjoy being active outdoors, trying new foods, and bingeing true crime shows.
Graduate student, Dept of Chemistry
Dayanne Carvalho
Prior to Stanford, I received my B.S. in Chemistry and Biology from the Massachusetts Institute of Technology (MIT), where I worked in Prof. Laura Kiessling's lab studying structure-fuction relationships of mucins by designing mucin-mimetic polymers with antivirulence properties against cholera toxin. At Arc, I work on STING signaling and regulation in T cells. Outside of lab I enjoy going on road trips, hiking, and attempting to cook Brazilian dishes.
Graduate Student, Dept of Chemistry
Michelle Lee
I'm originally from Seoul, Korea. I did my undergrad at MIT, where I received a B.S. in chemistry. At Arc, I work on elucidating the role of cGAS-STING pathway in metabolic dysfunction and insulin resistance, hoping to guide effective therapeutic strategies that can benefit patients. Outside of the lab, I spend a lot of time being active — I love practicing yoga and training for aerial arts. I also love live music; I am a classical pianist and love playing with other musicians!
In Vivo Technician
Gabriel Grenot
I have a BS focused in Pharmacy Technician from the Polytechnic Institute of Health. Today, I'm an In Vivo Technician in the Li Lab at Arc.
Postdoctoral Researcher
Yingjie Guo
I have completed my PhD in regenerative medicine from the Chinese Academy of Sciences. Then I spent a short period as a postdoc at Harvard Medical School/Dana-Farber Cancer Institute. My previous research targeted mitochondria as a therapeutic approach for various diseases. At Arc, I work on how to regulate ENPP1 and explore the important role of cGAS-STING pathway in GBM. Outside of the lab, I enjoy road trips, singing, and eating great food.
Executive Assistant
Rebeca Trabachini
I assist Lingyin Li with day to day administrative tasks; and work with the lab on event planning, meeting scheduling, ad-hoc projects, and more. In my free time, I love exercising, especially running and playing beach tennis during the summer and snowboarding during the winter. I also enjoy exploring new restaurants in the Bay Area over the weekends.
Postdoctoral Researcher
Yu Li
I completed my PhD training at Westlake University, focusing on mucosal immunology before joining Li lab. My current research explores the role of extracellular cGAMP in regulating immune cells across various mouse models. Outside of work, I enjoy crafting with natural materials like shells, stones, and tree seeds. I also enjoy going to the gym and playing badminton.
Postdoctoral Researcher
Tong Lan
I received my PhD in Chemistry at University of Chicago. At UChicago, I worked on covalent inhibitor development with peptides, and at the same time worked on novel user-friendly assay for biomarker. At Arc, I am exploring how extracellular cGAMP regulates STING signaling and activation. Outside of the lab I enjoy exploring national parks, reading, and trying new foods.
Alumni
Volker BöhnertLaronde Therapeutics
Anthony CordovaMSTP student, Stanford University
Jenifer BrownMicrosoft
Sabrina ErgunPost Doc, Jonikas lab, Princeton University
Lauren LaheyInzen Therapeutics, Scientist
Yasmeen AlsaifStanford Undergrad
Kelsey ShawGraduate School of Emory University
Phil ThomsonCY Partners
Out and about
Contact Us
We are accepting post-docs and students! Please email lingyin@arcinstitute.org with your CV and a description of your background and research interests.
We would love to hear from trainees from any scientific discipline and background. In the past, students have joined the Li lab from the Departments of Biochemistry, Chemistry, Chemical & Systems Biology, Biology, Immunology, and Biophysics.
We would love to hear from trainees from any scientific discipline and background. In the past, students have joined the Li lab from the Departments of Biochemistry, Chemistry, Chemical & Systems Biology, Biology, Immunology, and Biophysics.
