Elucidating the Molecular Principles of Self vs Non-self RNA Discrimination by the Immune System

Correct discrimination of “self” vs “non-self” nucleic acids by the innate immune system is essential for host defense against viral infection. A failure to recognize viral nucleic acids can increase a susceptibility to viral infection whereas incorrect recognition of self nucleic acids can lead to autoimmune/inflammatory diseases. The Hur lab is interested in how the innate immune system, in particular germ-lined encoded pattern recognition receptors (PRR), can distinguish self from non-self nucleic acids at the level of molecular structures and functions. The general questions that we would like to address are

1. What features of nucleic acids distinguish self from non-self?

2. How do the nucleic-acid receptors activate an appropriate immune response or cellular stress response?

3. What are the roles of self nucleic acids and PRRs in autoimmune & inflammatory diseases?

The current focus of the lab is on the functions and mechanisms of viral double-stranded RNA receptors in the cytoplasm, such as RIG-I-like helicases, PKR and OAS. We are particularly interested in conformational changes in the receptors during viral RNA recognition that allow activation of specific antiviral immune response and/or cellular stress response. We have discovered that a RIG-I like receptor, MDA5, forms a cooperative filament along the length of dsRNA, and that this filament is highly dynamic in that it disassembles from filament termini upon ATP hydrolysis, much like actin and RecA filaments (Peisley et al, PNAS 2011 & 2012). We have recently solved the first crystal structure of MDA5 in complex with dsRNA (Wu et al, Cell 2013), providing a detailed mechanistic view of how MDA5 recognizes dsRNA and assembles higher-order oligomers for efficient signaling.

Our lab uses a multidisciplinary approach including X-ray crystallography, computational modeling, bioinformatics, biochemical and biophysical methods in conjunction with various cell biology techniques. Our short-term goal is to determine the structures, dynamics and functions of PRRs in isolation, in complex with nucleic acids, and in higher order complexes with functional partners involved in the signaling pathways. In parallel, we aim to identify & characterize cellular nucleic acids that trigger PRRs in pathologic conditions, with the long-term goal of understanding a potential involvement of cellular nucleic acid in autoimmune and inflammatory diseases. We believe that understanding the mechanisms of PRR functions and regulation will ultimately lead to novel therapeutic strategies for treatment or prevention of various immune disorders or viral infection.