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Research Summary:
The major focus of the Krug laboratory is the molecular biology of human influenza viruses (influenza A and B viruses), which cause widespread human disease. We are determining: (i) the molecular mechanisms of viral mRNA synthesis and viral RNA replication; (ii) how the viral nonstructural proteins of these two influenza viruses contribute to pathogenesis and overcome host defense by inhibiting crucial cellular functions, including the 3-prime end processing system used for the production of cellular pre-mRNAs, and the interferon-induced modification of proteins by the ISG15 ubiquitin-like protein; and (iii) identifying interactions between cellular and viral proteins that play important roles during virus replication.. Our research has already identified promising new targets for the development of antivirals, and one of these targets is now the subject of high-throughput screens.
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Publications:
2014 Aramini, J.M., Hamilton, K., Ma, L.-C., Swapna, G.V.T., Leonard, P.G., Ladbury, J.E., Krug, R.M., and Montelione, G.T. 19FNMR reveals multiple conformations at the dimer interface of the non-structural protein 1 effector domain from influenza A virus. Structure 32: 515-525.
2014 Chen, G., Liu, C.-H., Zhou, L., and Krug, R.M. Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein. Cell Host & Microbe 15: 484-493
2014 Krug, R.M. Viral proteins that bind double-stranded RNA: countermeasures against host antiviral responses. J Interferon Cytokine Res, in press.
2013 Seo, G.J., Kincaid, R.P., Phanaksri, T., Burke, J. M., Cox, J.E., Hsiang, T.-Y., Krug, R.M., and Sullivan, C.S. Antiviral signaling mediates inhibition of RNAi in mammalian cells. Cell Host & Microbe 14: 435-445.
2013 Zhao, C, Collins, M. N., Hsiang, T.-Y., and Krug, R. M. Interferon-induced ISG15 pathway: an ongoing virus-host battle. Trends in Microbiology 21: 181-186.
2012 Ye, Q., Guu, T. S. Y., Mata, D. A., Kuo, R.-L., Smith, B., Krug, R.M., and Tao, Y. T. Biochemical and structural evidence in support of a coherent model for the formation of the double-helical influenza A virus ribonucleoprotein. mBio 4: e00467-12.
2012 Malur, M., Gale, M., Jr., and Krug, R. M. LGP2 downregulates interferon production during infection by seasonal influenza A viruses that activate IRF3. J. Virol. 86: 10733-10738.
2012 Hsiang, T.-Y., Zhou, L., and Krug, R. M. Roles of the phosphorylation of specific serines and threonines in the NS1 protein of human influenza A viruses. J. Virol. 86: 10370-10376.
2012 Marklund, J. K., Ye, Q., Dong, J., Tao, Y. J. and Krug, R. M. Sequence in the influenza A virus nucleoprotein required for viral polymerase binding and RNA replication. J. Virol. 86: 7292-7927.
2011 Guan, R., Ma, L.-C., Leonard, P. G., Amer, B. R., Sridharan, H., Zhao, C., Krug, R. M., and Montelione, G.T. Structural basis for the sequence-specific recognition of human ISG15 by the NS1 protein of influenza B virus. Proc. Natl. Acad. Sci. USA 108: 13468-13473.
2011 Aramini, J. M., Ma, L. C., Zhou, L., Schauder, C. M., Hamilton, K., Amer, B. R., Mack, T. R., Lee, H.W., Ciccosanti, C. T., Zhao, L., Xiao, R., Krug, R.M., and Montelione, G. T. The dimer interface of the effector domain of non-structural protein 1 from influenza A virus: an interface with multiple functions. J. Biol. Chem. 286: 26050-26060.
2011 Spesock, A., Malur, M., Hossain, M. J., Chen, L. M., Njaa, B., Davis, C. T., Lipatov, A. S., York, I., Krug, R. M., and Donis, R. O. The virulence of 1997 H5N1 influenza viruses in the mouse model is increased by correcting a defect in their NS1 proteins. J. Virol. 85: 7048-7058.
2010 Kuo, R.-L., Zhao, C., Malur, M., and Krug, R. M. Influenza A virus strains that circulate in humans differ in the ability of their NS1 proteins to block the activation of IRF3 and interferon-b transcription. Virology 408: 146-158.
2010 Sridharan, H., Zhao, C., and Krug, R. M., Species specificity of the NS1 protein of influenza B virus: NS1 binds only human and non-human primate ubiquitin-like proteins, J. Biol. Chem. 285: 7852-7856
2010 Zhao, C., Hsiang, T.-Y., Kuo, R.-L. and Krug, R. M., ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells, Proc. Natl. Acad. Sci. USA 107: 2253-2258
2009 Das, K., Aramini, J. M., Ma, L.-C., Krug, R. M. and Arnold, E. , Structures of influenza A proteins and insights into antiviral drug targets, Nat. Struct. Mol. Biol. 17: 530-538
2009 Krug, R.M. and Aramini, J.M. , Emerging antiviral targets for influenza A virus, Trends Pharmacol Sci. 30: 269-277
2009 Hsiang, T.-Y., Zhao, C. and Krug, R. M. , Interferon-induced ISG15 conjugation inhibits influenza A virus gene expression and replication in human cells, J. Virol 83: 5971-5979
2009 Newcomb, L.L., Kuo, R.L., Ye, Q., Jiang, Y., Tao, Y.T., and Krug, R.M., Interaction of the influenza A virus nucleocapsid protein with the viral RNA polymerase potentiates unprimed viral RNA replication., J. Virol. 83: 29-36
2009 Kuo RL, Krug RM., Influenza a virus polymerase is an integral component of the CPSF30-NS1A protein complex in infected cells., J. Virol. 83: 1611-1616
2008 Das K, Ma LC, Xiao R, Radvansky B, Aramini J, Zhao L, Marklund J, Kuo RL, Twu KY, Arnold E, Krug RM, Montelione GT., Structural basis for suppression of a host antiviral response by influenza A virus., Proc. Natl. Acad. Sci. USA 105: 13093-13098
2007 Yin, C., Khan J.A., Swapna G.V., Ertekin A., Krug R.M., Tong L and Montelione G.T., Conserved surface features form the double-stranded RNA binding site of non-structural protein 1 (NS1) from Influenza A and B viruses, J. Biol. Chem. 282: 20584-20592
2007 Melen, K., Kinnunen, L., Fagerlund, R., Ikonen, N., Twu, K.Y., Krug, R.M. and Julkunen, I., Nuclear and nucleolar targeting of influenza A virus NS1A protein: Striking differences between different virus subtypes, Journal of Virology 81: 5995-6006
2007 Min, .JY., Li, S., Sen, G.C. and Krug, R.M., A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis, Virology 363: 236-243
2007 Twu, K.Y., Kuo, RL., Marklund, J., and Krug, R. M., The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells, J Virol 81: 8112-8121
2006 Siren, J., Imaizumi, T., Sarkar, D., Pietila, T., Noah, D. L., Hiscott, J., Krug, R. M., Fisher, P. B., Julkunen, I., and Matikainen, S., Retinoic acid inducible gene-1 and mda-5 are involved in influenza A virus-induced expression of antiviral cytokines, Microbes Infect 8: 2013-2020
2006 Krug, R.M., Clues to the virulence of H5N1 viruses in humans, Science 311: 1562-1563
2006 , S., Min, J.-Y., Krug, R. M. and Sen, G. C. , Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA, Virology 349: 13-21
2006 Dastur, A., Beaudenon, S., Kelley, M., Krug, R. M. and Huibregtse, J. M., Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells, J. Biol. Chem. 281: 4334-4338
2006 Ye, Q., Krug, R.M. and Tao, Y.J., The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA, Nature 444: 1078-1082
2006 Min, J.-Y. and Krug, R. M., The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2'-5' oligo (A) synthetase / RNase L pathway, Proc. Natl. Acad. Sci. USA 103: 7100-7105
2006 Twu, K. Y., Noah, D. L., Rao, P., Kuo, R.-L., and Krug, R. M., The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target, Journal of Virology 80: 3957-3965
2005 Zhao, C., Denison, C., Huibregtse, J. M., Gygi, S., and Krug, R. M., Human ISG15 targets both interferon-induced and constitutively expressed proteins functioning in diverse cellular pathways, Proc. Natl. Acad. Sci. USA 102: 10200-10205
2005 Noah, D. L. and Krug, R. M., Influenza virus virulence and its molecular determinants, Advances in Virus Research 65: 121-146
2005 Zhao, C., Denison, C., Huibregtse, J. M., Gygi, S. and Krug, R.M., Human ISG15 targets both interferon-induced and constitutively expressed proteins functioning in diverse cellular pathways, Proc. Natl. Acad. Sci. USA 102: 10200-10205
2004 Chien, C-Y, Xu, Y., Xiao, R., Aramini, J.M., Sahasrabudge, P.V., Krug, R.M., and Montelieone, G.T., Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: evidence for a novel RNA-binding mode., Biochemistry 43: 1950-1962
2004 Zhao, C. Beaudenon, S.L., Kelley, M.L., Waddell, M.B., Yuan, W., Schulman, B.A., Huibregtse, J.M. and Krug, R.M., The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an interferon a/b-induced ubiquitin-like protein, Proc. Natl. Acad. Sci. U.S.A. 101: 7578-7582
2003 Rao, P., Yuan, W. and Krug, R. M., The crucial role of CA endonuclease cleavage sites in the cap-snatching mechanism for the initiation of viral messenger RNA synthesis, EMBO J 22: 1188-1198
2003 Noah, D. L., Twu, K. Y. and Krug, R. M., Cellular antiviral responses against influenza A virus are countered at the post-transcriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3’ end processing of cellular pre-mRNAs, Virology 307: 386-395
2003 Krug, R. M. , potential use of influenza virus as an agent for bioterrorism, Antiviral Research 57: 147-150
2003 Krug, R.M., Yuan, W., Noah, D.L. and Latham, A.G., Intracellular warfare between human influenza viruses and human cells: the roles of the viral NS1 protein, Virology 309: 181-189
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1961 Magna Cum Laude with Highest Honors in Chemistry, Harvard University
1986 The Karl Meyer Lectureship, University of California at San Francisco Medical Center
1987-1997 NIH Merit Grant Award
2002 The International Interbrew Baillet-Latour Health Prize (Belgium)-for outstanding contributions to influenza virus research
2004 Fellow of the American Academy of Microbiology
2012 Fellow of the American Association for the Advancement of Science (AAAS)
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