Lingyin Li

Last updated
Lingyin Li
Born1981 (age 42–43)
Xi'an
Alma mater University of Wisconsin–Madison
University of Science and Technology of China
Scientific career
Institutions Stanford University
Thesis Synthetic surfaces to control cell fate  (2010)

Lingyin Li (born 1981) is a Chinese American chemical biologist who is an associate professor of biochemistry at Stanford University. Her research studies the chemical biology of innate immunity to design better therapeutics. She was named one of Chemical & Engineering News Talented 12 in 2020.

Contents

Early life and education

Li was born in Xi'an. [1] She was awarded a position on the competitive University of Science and Technology of China undergraduate program. [2] She was a doctoral researcher at the University of Wisconsin–Madison, where she worked with Laura L. Kiessling. She moved to Harvard Medical School as a postdoctoral researcher in the laboratory of Tim Mitchison.

Research and career

Li uses chemical biology to understand the mechanisms that underpin immunity, which she will use to develop new therapeutic pathways and targets. The activation of immunity can provide new therapeutic strategies for vaccines, cancer and viral infection.

At Harvard, she studied the drug Vadimezan (DMXAA), an activator of the stimulator of interferon genes (STING) pathway, and uncovered that DMXAA binds mouse but not human STING. [2] STING responds to inflammation and activates inflammatory proteins that trigger the adaptive immune system. [2] The combination of the innate and adaptive immune system eliminates pathogens and is predicted to fight cancer. Li also discovered ENPP1 as the first known hydrolase of cGAMP, the natural ligand and activator of STING. ENPP1 is an extracellular enzyme, which led her to propose that cGAMP is exported for degradation and thus must play an extracellular role in cancer. [3]

In 2015, Li set up her own lab at Stanford University [4] where she pioneered the study of the paracrine role of extracellular cGAMP in innate immunity and identified several transporters of cGAMP. These transporters include SLC19A1 [5] , SLC46A2 [6] , LRRC8A:C [7] , and SLC7A1 [8] . While many in the field have pursued STING agonists as a strategy for cancer immunotherapy, Li proposed an alternative strategy to sustain extracellular cancer signaling through the inhibition of the cGAMP hydrolases ENPP1 and ENPP3. [9] [10] She founded Angarus Therapeutics to develop ENPP1 inhibitors, which are now being tested in clinical trials.

In 2022, Li became one of the first core investigators at the Arc Institute, a nonprofit research organization founded by Silvana Konermann that operates in partnership with Stanford University, UCSF, and UC Berkeley.

Awards and honors

Selected publications

Related Research Articles

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light and during wound healing or tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans.

Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infected with viruses or bacteria. Granzymes also kill bacteria and inhibit viral replication. In NK cells and T cells, granzymes are packaged in cytotoxic granules along with perforin. Granzymes can also be detected in the rough endoplasmic reticulum, golgi complex, and the trans-golgi reticulum. The contents of the cytotoxic granules function to permit entry of the granzymes into the target cell cytosol. The granules are released into an immune synapse formed with a target cell, where perforin mediates the delivery of the granzymes into endosomes in the target cell, and finally into the target cell cytosol. Granzymes are part of the serine esterase family. They are closely related to other immune serine proteases expressed by innate immune cells, such as neutrophil elastase and cathepsin G.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

<span class="mw-page-title-main">NLRP3</span> Human protein and coding gene

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.

<span class="mw-page-title-main">Toll-like receptor 4</span> Cell surface receptor found in humans

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">RIG-I</span> Mammalian protein found in humans

RIG-I is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus. These viruses can include West Nile virus, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and coronaviruses.

<span class="mw-page-title-main">C5AR2</span> Protein-coding gene in the species Homo sapiens

Complement component 5a receptor 2 is a protein of the complement system that in humans is encoded by the C5AR2 gene. It is highly expressed in the blood and spleen, predominantly by myeloid cells.

<span class="mw-page-title-main">HAVCR2</span> Protein-coding gene in the species Homo sapiens

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmins because they serve as warning signs to alert the organism to any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern recognition receptor (PRR). Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns (PAMPs) initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

<span class="mw-page-title-main">Cyclic guanosine monophosphate–adenosine monophosphate</span> Chemical compound

Cyclic guanosine monophosphate–adenosine monophosphate is the first cyclic di-nucleotide found in metazoa. In mammalian cells, cGAMP is synthesized by cyclic GMP-AMP synthase (cGAS) from ATP and GTP upon cytosolic DNA stimulation. cGAMP produced by cGAS contains mixed phosphodiester linkages, with one between 2'-OH of GMP and 5'-phosphate of AMP and the other between 3'-OH of AMP and 5'-phosphate of GMP.

<span class="mw-page-title-main">Cyclic GMP-AMP synthase</span> Cytosolic DNA sensor

Cyclic GMP-AMP synthase, belonging to the nucleotidyltransferase family, is a cytosolic DNA sensor that activates a type-I interferon response. It is part of the cGAS-STING DNA sensing pathway. It binds to microbial DNA as well as self DNA that invades the cytoplasm, and catalyzes cGAMP synthesis. cGAMP then functions as a second messenger that binds to and activates the endoplasmic reticulum protein STING to trigger type-I IFNs production. Mice lacking cGAS are more vulnerable to lethal infection by DNA viruses and RNA viruses. In addition, cGAS has been shown to be an innate immune sensor of retroviruses including HIV. The human gene encoding cGAS is MB21D1 on chromosome 6.

<span class="mw-page-title-main">Stimulator of interferon genes</span> Protein-coding gene in the species Homo sapiens

Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a protein that in humans is encoded by the STING1 gene.

Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death.

<span class="mw-page-title-main">Cyclic di-AMP</span> Chemical compound

Cyclic di-AMP is a second messenger used in signal transduction in bacteria and archaea. It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum Euryarchaeota.

The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms. DNA is normally found in the nucleus of the cell. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and invasion by some intracellular bacteria. The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response.

Daniel A. Portnoy is a microbiologist, the Edward E. Penhoet Distinguished Chair in Global Public Health and Infectious Diseases, and a professor of biochemistry, Biophysics and Structural Biology in the Department of Molecular and Cell Biology and in the Division of Microbiology in the Department of Plant and Microbial Biology at the University of California, Berkeley. He is one of the world's foremost experts on Listeria monocytogenes, the bacterium that causes the severe foodborne illness Listeriosis. He has made seminal contributions to multiple aspects of bacterial pathogenesis, cell biology, innate immunity, and cell mediated immunity using L. monocytogenes as a model system and has helped to push forward the use of attenuated L. monocytogenes as an immunotherapeutic tool in the treatment of cancer.

References

  1. ↑ "C&EN's Talented 12: Lingyin Li". Chemical & Engineering News. Retrieved 2024-01-20.
  2. 1 2 3 4 "C&EN's Talented 12". Chemical & Engineering News. Retrieved 2024-01-20.
  3. ↑ Li, Lingyin; Yin, Qian; Kuss, Pia; Maliga, Zoltan; Millán, José L; Wu, Hao; Mitchison, Timothy J (December 2014). "Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs". Nature Chemical Biology. 10 (12): 1043–1048. doi:10.1038/nchembio.1661. ISSN   1552-4450. PMC   4232468 . PMID   25344812.
  4. ↑ "Lingyin Li's Profile | Stanford Profiles". profiles.stanford.edu. Retrieved 2024-01-20.
  5. ↑ Ritchie, Christopher; Cordova, Anthony F.; Hess, Gaelen T.; Bassik, Michael C.; Li, Lingyin (2019-07-25). "SLC19A1 Is an Importer of the Immunotransmitter cGAMP". Molecular Cell. 75 (2): 372–381.e5. doi:10.1016/j.molcel.2019.05.006. ISSN   1097-4164. PMC   6711396 . PMID   31126740.
  6. ↑ Cordova, Anthony F.; Ritchie, Christopher; Böhnert, Volker; Li, Lingyin (2021-06-23). "Human SLC46A2 Is the Dominant cGAMP Importer in Extracellular cGAMP-Sensing Macrophages and Monocytes". ACS Central Science. 7 (6): 1073–1088. doi:10.1021/acscentsci.1c00440. ISSN   2374-7943. PMC   8228594 . PMID   34235268.
  7. ↑ Lahey, Lauren J.; Mardjuki, Rachel E.; Wen, Xianlan; Hess, Gaelen T.; Ritchie, Christopher; Carozza, Jacqueline A.; Böhnert, Volker; Maduke, Merritt; Bassik, Michael C.; Li, Lingyin (2020-11-19). "LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP". Molecular Cell. 80 (4): 578–591.e5. doi:10.1016/j.molcel.2020.10.021. ISSN   1097-4164. PMID   33171122.
  8. ↑ Sudaryo, Valentino; Carvalho, Dayanne R.; Lee, J. Michelle; Carozza, Jacqueline A.; Cao, Xujun; Cordova, Anthony F.; Li, Lingyin (2024-09-24). "Toxicity of extracellular cGAMP and its analogs to T cells is due to SLC7A1-mediated import". BioRxiv: The Preprint Server for Biology: 2024.09.21.614248. doi:10.1101/2024.09.21.614248. ISSN   2692-8205. PMC   11463533 . PMID   39386698.
  9. ↑ Li, Lingyin (2024-05-16). "Stimulating STING for cancer therapy: Taking the extracellular route". Cell Chemical Biology. 31 (5): 851–861. doi:10.1016/j.chembiol.2024.04.004. ISSN   2451-9448. PMID   38723635.
  10. ↑ Carozza, Jacqueline A.; Brown, Jenifer A.; Böhnert, Volker; Fernandez, Daniel; AlSaif, Yasmeen; Mardjuki, Rachel E.; Smith, Mark; Li, Lingyin (2020-11-19). "Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP". Cell Chemical Biology. 27 (11): 1347–1358.e5. doi:10.1016/j.chembiol.2020.07.007. ISSN   2451-9448. PMC   7680421 . PMID   32726585.
  11. ↑ "NIH Director's New Innovator Award Program - 2017 Award Recipients | NIH Common Fund". commonfund.nih.gov. Retrieved 2024-01-20.
  12. ↑ "Awardees List". www.onofound.org. Retrieved 2024-10-25.
  13. ↑ "Eli Lilly Award in Biological Chemistry". Division of Biological Chemistry. Retrieved 2024-01-20.
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