(Division of Rheumatology, Department of Medicine)
Type I interferons regulate a wide array of biological effects. These include the induction of an antiviral state, regulation of apoptosis, inhibition of cell growth, and modulation of both the innate and adaptive immune responses. Interferons mediate these activities through the induction of hundreds of gene products known as interferon stimulated genes. While several of these genes, such as PKR and RNAseL, have previously been defined as important antiviral molecules, many of these genes have no known function ascribed to them. Utilizing an in vivo screen, we identified interferon stimulated gene 15 (ISG15) as a novel antiviral molecule. ISG15 is an ubiquitin-like molecule with two biological activities. It forms conjugates with intracellular proteins, with over 150 host proteins having been identified as ISG15 targets. It can also be released from cells to function as an immunostimulatory cytokine. Mice deficient in ISG15 exhibit increased susceptibility to multiple viruses including Influenza A and B viruses, herpes simplex virus, Sindbis virus and Chikungunya virus. Ongoing work in our lab is aimed at elucidating the mechanism by which ISG15 exerts its antiviral activity by exploring the function of the innate immune system in the absence of ISG15; determining the fate of proteins conjugated to ISG15; and investigating the cytokine activity of ISG15.
A second area of interest in the lab is to understand the relationship between type I interferons and autoimmunity. Through collaborations with several investigators at Washington University, we are exploring the role of various interferon stimulated genes in the pathogenesis of autoimmune diseases, including SLE.
- Lenschow, D.J., N. Giannakopoulos, L.J. Gunn, C. Johnston, A.K. O’Guin, R.E. Schmidt, B. Levine, and H.W. Virgin. 2005. Identification of ISG15 as an antiviral molecule during Sindbis virus infection in vivo. Journal of Virology. 79:13974-13983.
- Giannakopoulos, N.V., J. Luo, V. Papov, W. Zou, D.J. Lenschow, B.S. Jacobs, E.C. Borden, J.Li, H.W. Virgin, D. Zhang. 2005. Proteomic identification of ISGylated proteins in mouse and human cells. Biochemical and Biophysical Research Communications. 336(2):496-506.
- Lenschow, D.J., C. Lai, N. Frias-Staheli, N.V. Giannakopoulos, A. Lutz, T. Wolff, A. Osiak, B. Levine, R.E. Schmidt, A. Garcia-Sastre, D.A. Leib, A. Pekosz, K.P. Knobeloch, I. Horak, and H.W. Virgin. 2007. ISG15 functions as a critical antiviral molecule against both influenza and herpes viruses. Proceedings of the National Academy of Sciences, USA . 104(4):1371-1376.
- Frias-Staheli N, Giannakopoulos NV, Kikkert M, Taylor SL, Bridgen A, Paragas JJ, Richt JA, Rowland RR, Schmaljohn CS, Lenschow DJ, Snijder EJ, Garcia-Sastre A, and Virgin HW. 2007. Ovarian Tumor (OTU)-domain containing viral proteases evade ubiquitin- and ISG15- dependent innate immune responses. Cell Host and Microbe. 2:404-416.
- Okumura F, Lenschow DJ, and Zhang DE. 2008. Nitrosylation of ISG15 prevents the disulfide bond mediated dimerization of ISG15 and contributes to effective ISGylation. Journal of Biological Chemistry. 283:24484-24488.
- Giannakopoulos NV, Arutyunova E, Lai C, Lenschow DJ, Haas, AL, and Virgin HW. 2009. ISG15 Arg151 and the ISG15 conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. Journal of Virology. 83:1602-1610.
- Lai C, Struckhoff JJ, Schneider J, Martinez-Sobrido L, Wolff T, García-Sastre A, Zhang DE, and Lenschow DJ. 2009. Mice lacking the ISG15 E1 enzyme, Ube1L, demonstrate increased susceptibility to both mouse adapted and non-adapted influenza virus infection. Journal of Virology. 83:1147-1151.
- Versteeg GA, Hale BG, van Boheemen S, Wolff T, Lenschow DJ, and Garcia-Sastre A. 2010. Species-specific antagonism of host ISGylation by the influenza B virus NS1 protein. Journal of Virology, 84:5423-5430.
- Nakka VP, Lang BT, Lenschow DJ, Zhang DE, Dempsey RJ, and Vemuganti R. 2011. Increased cerebral protein ISGylation after focal ischemia is neuroprotective. Journal of Cerebral Blood Flow and Metabolism. Epub: August 17. 10:1038.
- Werneke S, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Fontanet A, Albert MA, and Lenschow DJ. 2011. ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathogens, 10:e1002322.
- Swiecki M, Wang Y, Gilfillan S, Lenschow DJ, and Colonna M. 2012. Cutting Edge: Paradoxical roles of BST-2/Tetherin in host antiviral responses. Journal of Immunology. 188(6):2488-92.
- Joubert PE, Werneke S, de la Calle C, Guivel-Benhassine F, Giodini A, Peduto L, Levine B, Schwartz O, Lenschow DJ, and Albert, MA. 2012. Chikungunya virus-induced autophagy delays apoptosis via the induction of ER stress and generation of reactive oxygen species. Journal of Experimental Medicine. 209:1029-1047.
- S Shoji-Kawata, Sumpter Jr. R, Leveno M, Zou Z, Kinch L, Wilkins A, Sun Q, Pallauf L, MacDuff D, Huerta C, Virgin HW, Helms B, Eerland R, Tooze SA, Xavier R, Lenschow DJ, Yamamoto A, King D, Lichtarge O, Grishin NV, Spector S, Kaloyanova DV, and Levine B. 2013. Identification of a candidate therapeutic autophagy-inducing peptide. Nature. 494(7436):201-206.
- Lubman OY, Marina C, Xinxin W, Kristen M, Lenschow DJ, Huang Y, and Fremont DH. 2014. Rodent herpesvirus Peru encodes a secreted chemokine decoy receptor. Journal of Virology, 88(1):538-546.
- Rohatgi A, Monte KK, Kardon G, Corbo JC, Higgs S, and Lenschow DJ. 2014. Infection of myofibers contributes to the increased pathogenicity during neonatal infection with an epidemic strain of Chikungunya virus. Journal of Virology, 88(5):2414-2425.
- Rodriguez M, Monte K., Thackray L, and Lenschow DJ. 2014. ISG15 functions as an interferon-mediated antiviral effector early in the murine norovirus life cycle. Journal of Virology, In press.