Our lab investigates how the vertebrate immune system discriminates between self and non-self on the basis of RNA structure and modifications. Using structural and biochemical approaches, our team focuses its attention on immune receptors and modulators involved in antiviral innate immune response. Our lab is also interested in other biological processes involving nucleic acids, such as transcriptional reprogramming and post-transcriptional regulation during development and maturation of the vertebrate immune system. Our work has implications for better understanding and treating viral infections and other diseases, such as autoimmune-based inflammatory disorders and cancer.
Antiviral Innate Immunity
Pattern recognition receptors (PRRs) in the innate immune system are responsible for the early detection of pathogen invasion and activation of appropriate immunological responses. We are particularly interested in how a subset of PRRs (RIG-I-like receptors) robustly and accurately discriminate between cellular and viral RNAs during infection. It was traditionally thought that the dsRNA structure, which is often present in viral RNAs, provides sufficient means for PRRs to selectively recognize viral RNAs against the background of cellular RNAs. However, accumulating evidence suggests that the mechanism for viral RNA detection is more complex than a simple duplex binding, and the rules that separate self from non-self may not be as rigid as previously thought.
Colocalization of RIG-I and MAVS with stress granules marker (biomolecular condensates that form in response to various stresses including viral dsRNA).
Our mechanistic studies on the RIG-I-like receptors, in particular the discovery of their oligomerization and signaling mechanisms, have provided a new framework for understanding how these receptors detect viral RNAs during infection, how this recognition is coupled to antiviral signal activation, and how certain mutations lead to inappropriate recognition of self RNAs.
Our current research focuses on
(1) identities of self RNAs that trigger these receptors during pathologic conditions,
(2) mechanisms by which these signaling complexes are resolved during the negative regulation of antiviral signaling, and
(3) mechanisms of other antiviral RNA binding proteins, such as PKR, ZAP and TRIM25.
Nucleic acid biology of the immune system
Unlike the innate immune system, the adaptive immune system establishes its ability to discriminate between self vs. non-self through a series of positive and negative selections of T- and B-cells. In establishing immunological tolerance of T-cells against self antigens, a transcriptional regulator, Aire, plays a central role by up-regulating thousands of peripheral tissue antigens in the thymus medulla, the site of negative selection of self-reactive T-cells. Mutations that impair proper functioning of AIRE result in development of multiorgan autoimmune disease, known as APECED. Aire functions through formation of a large complex with proteins involved in transcriptional control and mRNA processing. However, the precise molecular composition of these complexes, their assembly pathways and the mechanism by which they regulate promiscuous gene expression are poorly understood. Adding to this challenge is AIRE's poor biochemical behavior, which has thus far defied rigorous analyses of its function. We are currently investigating the structural assemblies underlying the apparent aggregation behavior, and how the assembly structure and process play a role in target site recognition and transcriptional regulation.
Aire CARD multimerization has both gene activation and regulatory functions
Crystal structure of Foxp3∆N in complex with IR-FKHM4g DNA.
Nucleic acid biology of the immune system
FoxP3 is a forkhead transcriptional factor, pivotal in immune homeostasis, playing a critical role in development of regulatory T cells. Mutations in FoxP3 lead to the multi-organ autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in human.
Despite its importance in immune homeostasis, the biochemical and structural properties and molecular functions of FoxP3 remain poorly understood.
Our lab has focused its efforts on defining the overall architecture of FoxP3. Our functional data provide new insights into the pathogenic mechanism for IPEX mutations and a new framework of understanding for FoxP3 functions.