Research

Innate Immune Signaling in Health and Disease

The Yan laboratory studies homeostatic functions of innate immunity. We use inborn-error diseases of innate immunity as well as infection, cancer and neurodegenerative disease models to elucidate mechanisms of innate immune pathways and to develop novel therapies. We are particularly interested in nucleic acid immunity and type I interferon signaling. Current research includes: 

1. Innate immune response to DNA. We investigate mechanisms of STING trafficking and degradation by lysosomes, the role of STING in lysosome biology and lysosomal diseases, and dynamics of STING expression in tissues and immune cells. We also study DNase TREX1 that degrades cytosolic DNA to avoid cGAS-STING activation.

2. Innate immune response to RNA. We study the physiological functions of OAS-2-5A-RNase L pathway in infection and cancer, including 2-5A as an immunotransmitter that spreads innate immunity. We also study the physiological functions of RNA exosome (degradation not secretion) in mammals, including maintaining skin tissue homeostasis and limiting the innate immune response to RNA via the OAS-RNase L pathway.

3. Neuroimmunology. We study the role of STING in neurodegenerative diseases, such as lysosomal storage disorders, NGLY1-deficiency, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

4. Cancer Immunology. We study the function of an innate immune checkpoint protein TREX1 and developing inhibitors. We study tumor-T cell interactions and mechanisms to enhance anti-tumor T cell immunity. We also study the role of immunotransmitters in cancer immunology.

Recent Publications:

Tang Z, Xing C, Araszkiewicz A, Yang K, Huai WW, Jeltema D, Dobbs N, Zhang Y, Sun LO, and Yan N. (2025) STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders. Mol. Cell. 2025 Mar 27:S1097-2765(25)00201-1. PMID: 40185098

Knox K, Jeltema D, Dobbs N, Tang Z, Xing C, Song K, Torres-Ramirez G, Wu T, Yao C, and Yan N. (2025) Dynamic STING expression orchestrates immune cell development and function. Sci. Immunol 2025 Mar 7;10(105):eado9933. PMID: 40053603

Huai WW, Yang K, Xing C, Song K, Lyu H, Williams NS, Wu JJ, and Yan N. (2025) OAS Cross-Activates RNase L Intercellularly Through Cell-to-Cell Transfer of 2-5A to Spread Innate Immunity. Immunity. 2025 Feb 19:S1074-7613(25)00065-2. PMID: 40010341

Jeltema D, Knox K, Dobbs N, Siordia IR, Matthews J, Cohen M, Yan N. (2025) PARP7 is a negative feedback regulator of type I interferon signaling that protects against autoimmunity by inhibiting IRF3 transcriptional activity. J. Exp. Med. 2025 May 5;222(5):e20241184. PMID: 39969510

    Our Research

    The cGAS-STING pathway

    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, Nat. Immunol. 2020). We identified NPC1 as a mediator of lysosomal degradation of STING that terminates STING signaling, and we showed that persistent STING signaling mediates Niemann-Pick disease type C (Nature 2021). We further identified GCC2-RAB14 in a Golgi-exit mechanism of STING (Nat. Comm. 2022). STING also regulates lysosomal quality control and recovery through its proton channel function and TFEB activation (Mol. Cell 2025). STING expression is dynamically regulated by epigenetic mechanisms in immune cells (Sci. Immunol. 2025)

    Related publications:

    sting biology
    The OAS-RNase L pathway and the RNA exosome

    The OAS-2-5A-RNase L pathway and the RNA Exosome

    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 (JCI 2022). 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 (Sci. Immunol. 2022 ). More recently, we also show that RNA exosome limits innate immune response to RNA via the OAS-RNase L pathway (EMBO J 2024).

    The 2’,5’-oligoadenylate synthetase (OAS)–RNase L pathway is a classical antiviral innate immune pathway. Upon sensing dsRNA, OAS produces 2’,5’-oligoadenylates (2-5A) as a second messenger to activate RNase L. We recently showed that 2-5A is transferred from cell to cell through gap junctions, importers and exporters, allowing OAS to remotely activate RNase L and protect neighboring cells from viral infection. Furthermore, OAShigh tumors such as MC38 naturally produce 2-5A in vivo, which is secreted via ABCC10 to activate host, not tumor, RNase L-mediated antitumor response. Therefore, 2-5A is an immunotransmitter that mediates short-range communication between cells in infection and cancer (Immunity 2025).

    Neuroimmunology

    STING in Neurodegenerative Diseases

    The STING pathway has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). We showed that the cGAS-STING pathway is activated in monogenic neurological disease in children called NGLY1-deficiency (JEM 2018). We found that tonic prime-boost of STING signaling mediates an early onset neurodegenerative disease called Niemann-Pick disease type C (NPC). STING also regulates lysosomal quality control and recovery through its proton channel function and TFEB activation (Mol. Cell 2025). 

    neurodegenerative diseases
    Cancer Immunology

    Nucleic Acid Immunity 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.

    The dsRNA sensing OAS-2-5A-RNase L pathway also plays an important role in antitumor immune response.

    cancer immunity
    Inborn Error Rare Disease

    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).

    We recently showed that PARP7 is a negative feedback regulator of type I interferon signaling that protects against autoimmunity by inhibiting IRF3 transcriptional activity (JEM 2025).