Department of Biological Chemistry and Molecular Pharmacology
Immune Disease Institute
Center for Life Science Building, Room 3095
3 Blackfan Circle
Boston, MA 02115
Tel: (617) 713-8250
Fax: (617) 713-8260
Elucidating the Principles of Self vs Non-self RNA Discrimination bythe Immune System
The innate immune system is the first line of defense against pathogen infection. Recognition of bacteria and viruses by the innate immune system immediately activates a series of downstream events that initiate antibacterial and antiviral responses and stimulate the adaptive immune system against the target pathogen. Several classes of pattern recognition receptors (PRRs) mediate the initial detection of non-self molecules such as bacteria-specific membrane components or viral nucleic acids. Correct recognition of non-self molecules is important for the efficient immune response against the target pathogen, whereas incorrect recognition of self molecules can trigger an inappropriate response resulting in autoimmune or inflammatory diseases such as type I diabetes, arthritis and inflammatory bowel disease.
Our lab focuses on the functions and mechanisms of several PRRs that specifically recognize viral nucleic acids, such as several Toll like receptors and RIG-I-like helicases. Understanding the function of the nucleic-acid specific PRRs (naPRRs) presents a new challenge compared to membrane specific PRRs because high concentrations of structurally diverse host nucleic acids are ubiquitous throughout the cellular environment. This raises the following questions:
1. What features of nucleic acids distinguish self from non-self?
2. How do naPRRs activate an immune response?
3. What role does the recognition of self nucleic acids play in autoimmune & inflammatory diseases?
To address these questions our lab uses a multidisciplinary approach including X-ray crystallography, computational simulation, biochemical and biophysical methods in conjunction with various cell biology techniques. Our short-term goal is to determine the structures, dynamics and functions of naPRRs 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 naPRRs resulting in activation of the immune response in tissues from patients with autoimmune or inflammatory diseases, with the long-term goal of determining the molecular mechanisms for disease pathogenesis.We believe that understanding the mechanisms of naPRR regulation will provide therapeutic strategies to treat inflammatory diseases as well as to improve the antiviral immune response. In addition, understanding the molecular mechanisms of nucleic acid specificity of naPRRs will help us design new therapeutic nucleic acids (such as siRNA) that do not evoke undesirable immune responses.
- Hur S, Stroud RM. How U38, 39 and 40 of Many tRNAs Become the Targets for Pseudouridylation by TruA. Mol. Cell 2007;26:189-203
- Hur S, Stroud RM, Finer-Moore J. Substrate Recognition by RNA 5-Methyluridine Methyltransferases and Pseudouridine Synthases: A Structural Perspective. J. Biol. Chem. 2006;281:38969-73
- Hur S, Newby ZE, Bruice TC. Transition State Stabilization by General Acid Catalysis, Water Expulsion and Enzyme Reorganization in Medicago savita Chalcone Isomerase Proc. Natl. Acad. Sci. U.S.A. 2004;101:2730-5
- Hur S, Bruice TC. The Near Attack Conformation Approach to the Study of the Chorismate to Prephenate Reaction. Proc. Natl. Acad. Sci. U.S.A. (2003);100:12015-20
BBS webpage updated 12/02/2009