Dr. Yan studies mechanisms of microbial immune evasion, monogenic and complex immune disorders, glycol-immunology and cancer immunology.Innate immune signaling pathways are essential for detecting pathogens, but mutations in key molecules of these pathways often cause immune disorders such as autoimmune disease and immunodeficiency. My lab was the first to report and characterize HIV-1 immune evasion mechanism involving the function of host DNase TREX1 and host cytosolic DNA sensing cGAS-STING pathway. We also elucidated molecular mechanisms of several monogenic autoimmune diseases associated with TREX1, RNaseH2and STING. These studies have substantially improved our understanding of an increasing group of monogenic diseases that are collective called type I interferonopathy. We reported the first mouse model with active disease for RNaseH2-associated autoimmune disease, the first mouse model and an interferon-independent disease mechanism for STING gain-of-function autoinflammatory disease. More recently, we begin to characterize innate immune signaling mechanisms that underlie several monogenic diseases that present concurrent features of autoimmunity and immunodeficiency.

We are also actively translating our findings into actionable therapy. For example, we identified the molecular defect of retinal vasculopathy with cerebral leukodystrophy (RVCL) as the glycotransferase OST enzyme complex in 2015, tested the FDA-approved drug ACM that inhibits the OST in mice in 2017, and started a clinical trial using ACM to treat RVCL patients in 2017 (NCT02723448). 

We take a multidisciplinary approach from immunology, glycobiology, protein biochemistry, live-cell/electron microscopy imaging, and mouse models. Our overarching goal is to gain key molecular insights in innate immunity that will enhance our understanding of the underlying biology and accelerate therapeutic development for treating immune disorders.