HMS Virology

Virology Faculty Member - Sun Hur

Sun Hur

Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
Program in Cellular & Molecular Medicine
Boston Children's Hospital

Center for Life Science Building, Rm 3095
3 Blackfan Circle
Boston, MA 02115

Tel: 617-713-8250
Fax: 617-713-8260
Email: Sun.Hur@childrens.harvard.edu



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 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 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 could 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




Last Update: 7/14/2014



Publications

1. Wu B, Peisley A, Tetrault D, Li Z, Egelman EH, Magor, KE, Walz T, Penczek PA and Hur S, Molecular imprinting as a signal activation mechanism of the viral RNA sensor RIG-I. Molecular Cell, (2014) In press.
2. Rice GI*, del Toro Duany Y*, Jenkinson EM, Forte GMA, Anderson BH, Ariaudo G, Bader-Meunier B, Baildam EM, Battini R, Beresford MW, Casarano M, Chouchane M, Cimaz R, Collins AE, Cordeiro NJV, Dale RC, Davidson JE, De Waele L, Desguerre I, Faivre L, Fazzi E, Isidor B, Lagae L, Latchman AR, Lebon P, Li C, Livingston JH, Lourenco CM, Mancardi MM, Masurel-Paulet A, McInnes IB, Menezes MP, Mignot C, O’Sullivan J, Orcesi S, Picco PP, Riva E, Robinson RA, Rodrigues D, Salvatici E, Scott C, Szybowska M, Tolmie JL, Vanderver A, Vanhulle C, Vieira JP, Webb K, Whitney RN, Williams SG, Wolfe LA, Zuberi SM, Hur S**, Crow YJ**. Gain of function mutations in IFIH1 (MDA5) cause a spectrum of human disease phenotypes associated with an upregulation of type I interferon signaling. Nature Genetics, (2014), 46:503-9, (* co-first authors, ** co-corresponding authors).
3. Peisley A, Wu B, Xu H, Chen ZJ & Hur S. Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I. Nature, (2014), 509:110-4
4. Peisley A*, Wu B*, Yao H, Walz T & Hur S. RIG-I forms signaling-competent filaments in an ATP-dependent and ubiquitin-independent manner. Molecular Cell, (2013), 51, 573-83, PMID: 23993742 (* equal contribution)
5. Wu B, Peisley A, Richards C, Yao H, Zeng Z, Lin C, Chu F, Walz T & Hur S. Structural Basis for dsRNA recognition, filament formation and antiviral signaling by MDA5. Cell, (2013) 152, 276-89, PMID: 23273991
6. Peisley A*, Jo MH*, Lin C, Wu B, Orme-Johnson M, Walz T, Hohng S & Hur S. Kinetic Mechanism for Viral dsRNA Length Discrimination by MDA5 filament. Proc. Natl. Acad. Sci. U.S.A. (2012), 109, E3340-9, PMID:23129641 (* equal contribution)
7. Peisley A, Lin C, Wu B, Orme-Johnson M, Liu M, Walz T & Hur S. Cooperative Assembly and Dynamic Disassembly of MDA5 Filaments for Viral dsRNA Recognition.Proc. Natl. Acad. Sci. U.S.A. (2011), 108, 21010-5.



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