Innate Immune Signaling in Health and Disease

The Yan Lab studies molecular mechanisms of innate immunity in infection, autoimmune diseases, cancer immunology and neurodegenerative diseases.

We study the STING pathway, which is important for host defense against microbial infections as well as many other immune functions. Chronic activation of STING signaling drives autoimmune and autoinflammatory diseases, such as Aicardi-Goutieres Syndrome (AGS), Type I Interferonopathy. STING is implicated in several neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Niemann-Pick disease type C (NPC), and NGLY1-deficiency.

We are also interested in other inborn errors rare disease of innate immunity, mechanisms of disease, and preclinical testing of therapeutics that target innate immune signaling pathways.

    Our Research

    STING Trafficking and Signaling Mechanisms

    A unique feature of STING signaling is the obligatory trafficking of the STING protein through the secretory pathway. After ligand binding, STING undergoes a drastic conformational change that is believed to be the trigger for ER-exit. Then, STING translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi, where it recruits kinase TBK1 and transcription factor IRF3. TBK1 phosphorylates itself, STING and IRF3. Phosphorylated IRF3 translocates to the nucleus and activates expression of IFN and IFN-stimulated genes (ISG). Although STING activation occurs on the Golgi, it does not dwell on the Golgi. Instead, STING rapidly moves pass the Golgi to the lysosome where it is degraded. ER-exit is a critical checkpoint for turning on STING signaling, and lysosomal degradation turns off STING signaling.

    We showed that STING signaling can be activated by trafficking only, independently of ligand binding (Cell Host & Microbes 2015). We characterized STING gain-of-function SAVI mouse model and defined an IFN-independent function of STING (JEM 2017, 2019). We developed Sting-S365A mice to further define many other IFN-independent functions of STING (Immunity 2020). We uncovered cofactors of STING trafficking and signaling (PNAS 2017, Cell Report 2017, Nature Immunology 2020). We recently identified NPC1 as the lysosomal adaptor mediating STING protein degradation (Nature 2021).

    Related publications:

    sting biology

    STING in Neurodegenerative Diseases

    The STING pathway has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD) and and amyotrophic lateral sclerosis (ALS). We recently found that tonic prime-boost of STING signaling mediates an early onset neurovegetative disease called Niemann-Pick disease type C (NPC). We also study another monogenic neurological disease in children called NGLY1-deficiency. We are interested in understanding how the STING pathway impacts functions of neuronal cells and whether we can target this pathway to treat neurodegenerative diseases.

    neurodegenerative diseases

    STING in Cancer Immunology

    We are interested in understanding how innate immune signaling regulate cancer cell proliferation and tumorigenesis, and how can we harness innate immunity as novel cancer immunotherapy.

    STING-mediated anti-tumor immunity through activating DC:T cell cross priming is well recognized. STING also has an anti-proliferation activity intrinsic to cancer cells. We recently found that STING activation in T cells causes T cell death and loss of tumor control. We are investigating whether tumor evades immune control by targeting the STING pathway in T cells.

    cancer immunity

    Inborn Error Rare Disease

    We are broadly interested in mechanisms of in inborn error immune diseases. We establish mouse models, investigate disease mechanism, then test potential therapies in mice.

    In retinal vasculopathy with cerebral leukodystrophy (RVCL) associated with TREX1-frame—shift mutations, we identified the molecular defect in the glycotransferase OST enzyme complex (Immunity 2015), tested the FDA-approved drug ACM that inhibits the OST in mice in (J Autoimmunity 2017), and started a clinical trial using ACM to treat RVCL patients in 2017 (NCT02723448). We have since identified bioactive mammalian glycan species associated with autoimmune disease that are potent stimulators of innate immunity (Nat. Comm. 2019).

    RNA Exosome Biology

    The RNA exosome is an evolutionarily conserved intracellular RNA degradation machinery involved in RNA processing, maturation, surveillance and turnover. The super-killer (SKI) cytoplasmic RNA exosome is essential for survival in yeast but its physiological functions in mammals are unclear. Mutations in SKIV2L or TTC37 genes that encode key components of the SKI complex are associated with a rare inherited autosomal recessive disorder, trichohepatoenteric syndrome (THES). We recently showed that Skiv2l deficiency in mice disrupts skin epidermis and T-cell homeostasis. Skiv2l-deficient mice develop skin inflammation and hair abnormality that are also observed in a SKIV2L-deficient patient. Mechanistically, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease (Yang et al 2022 JCI). We also found that the RNA Exosome is important for early B cell development. Loss of function causes accumulation of ncRNA in the nucleus that impedes VDJ recombination during B cell development (Yang et al 2022 SI).