Robert M. Krug
Robert M. Krug is an American virologist. He is the Professor Emeritus at the Institute for Cellular and Molecular Biology, John Ring LaMontagne Center of Infectious Disease, and Department of Molecular Biosciences at the University of Texas at Austin. Krug’s research has focused on Avian flu, viral gene replication and expression, human influenza and infectious disease. His basic scientific research in the 1970’s, about how influenza hijacks a critical process inside cells early on, led to the development of the antiviral drug, Xofluza [(Baloxavir marboxil)]. Xofluza blocks flu from replicating, which makes it effective in reducing the spread of the flu. This discovery was highlighted at a March 8, 2018 hearing of the Committee on Energy and Commerce of the U.S. House of Representatives on treating flu with experts from the National Institutes of Health, Centers for Disease Control and Prevention among others. Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Disease, highlighted the importance of Krug's 1979 paper explaining the cap-snatching process, noting that the work was funded by the National Institutes of Health.
Contributions to Science
Discovery of the cap-snatching mechanism for the initiation of influenza viral mRNA synthesis Influenza viruses are unusual among negative sense RNA viruses in that they transcribe and replicate their genomes in the nucleus of infected cells. The viral polymerase that catalyzes the synthesis of both mRNAs and virion RNAs is comprised of three proteins, PB1, PB2 and PA, and is associated with viral ribonucleoproteins (vRNPs), each of which contains one of the eight virus gene segments and multiple copies of the viral nucleoprotein (NP). The viral polymerase lacks the ability to initiate the synthesis of viral mRNAs. It was not known how mRNA chains are initiated. My colleagues and I discovered this mechanism. We demonstrated that the intrinsic viral endonuclease of the viral polymerase cleaves short (10-13 bases in length), capped (5’ terminal m7GpppNm) RNA fragments from cellular pre-mRNAs in the nucleus, and the capped RNA fragments initiate viral mRNA synthesis This discovery led to the identification of a target for the development of antivirals, the endonuclease site on the PA subunit. In fact, a new oral antiviral, called Xofluza, which was approved in the United States for use in adults, and then in other countries, Xofluza inhibits the endonuclease, shutting down viral mRNA synthesis and virus production. Clinical studies showed that a single Xofluza treatment of infected patients almost totally inhibits virus production within 24 hours, thereby shortening virus shedding by 3-4 days. Consequently, virus spread within the household and in the general population is mitigated. Our modeling study predicts that Xofluza treatment of as few as 30% of infected patients would avert approximately 15-20 million infections and 5,000 deaths each year. Such mitigation of influenza spread is particularly important during the COVID-19 pandemic to substantially reduce the strain on health care systems. In addition, clinical studies showed that Xofluza is also effective for postexposure prevention of influenza. https://cns.utexas.edu/news/the-40-year-old-discovery-behind-a-promising-new-flu-drug
Education
Krug earned an A.B. from Harvard University, Magna Cum Laude with Highest Honors in Chemistry, Phi Beta Kappa, and earned a Ph.D. in Molecular Biology from Rockefeller University. While an undergraduate at Harvard, he worked in the molecular biology lab run by [D. Watson]James D. Watson, a Nobel Prize Laureate for co-discovering the structure of DNA.
Academic Career
After completing his Ph.D., Krug joined Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City as a Research Associate. He worked at both MSKCC and Cornell University Graduate School of Medical Sciences becoming a full Professor of Molecular Biology and Chairman of the Molecular Biology Program at MSKCC and a Professor of Molecular Biology at Cornell University Graduate School of Medical Sciences.
In 1990, Krug became the Director of the Joint Graduate Program in Biochemistry at Rutgers University-UMDNJ Robert Wood Johnson Medical School as well as the Professor and Chairman of the Department of Molecular Biology and Biochemistry at Rutgers University. From 1996 to 1999, he was a Member of the New Jersey Cancer Institute.
In 1999, Krug was appointed Professor, Institute for Cellular and Molecular Biology and Department of Molecular Genetics and Microbiology, University of Texas at Austin and served as Chair of the Department of Molecular Genetics and Microbiology from 2007 to 2013. In 2009, he became a Fellow, Mr. and Mrs. Corbin J. Robertson, Sr. Regents Chair in Molecular Biology, University of Texas at Austin. By 2015, Krug was selected as Professor, Institute for Cellular and Molecular Biology, John Ring LaMontagne Center of Infectious Disease, and Department of Molecular Biosciences, University of Texas at Austin.
Krug has served on the Editorial Boards of numerous journals, including Editor, of the Journal of Virology (from 1982 to 1987), Editorial Board of the Journal of Virology (from 1978 to 1982), Editorial Board of Virology (from 1979 to 2013) and Associate Editor of RNA (from 1994 to 2001).
Krug became a Fellow in the AAAS (American Association for the Advancement of Science) in 2012 and a Fellow of the American Academy of Microbiology in 2004. He also received the NIH Merit Grant Award (1987-1997).
In 2002, Krug was awarded the International [Latour Health Prize] (Belgium), for outstanding contributions to influenza virus research, specifically including the discovery of cap-snatching which is the basis for the new influenza antiviral Xofluza.
Awards and Honors
2012 AAAS (American Association for the Advancement of Science) Fellow
2004 Fellow of the American Academy of Microbiology
2002 The International InBev-Baillet Latour Health Prize (Belgium)-for outstanding contributions to influenza virus research, specifically including the discovery of cap-snatching which is the basis for the new influenza antiviral Xofluza
1986 The Karl Meyer Lectureship, University of California at San Francisco Medical Center
1987-1997 NIH Merit Grant Award
1961 Magna Cum Laude with Highest Honors in Chemistry, Harvard University
Selected Publications and References
Books
Encyclopedic Entry
1. Primary contributor for the Encyclopedia Britannica entry for the term: virus.
Book Chapters
1. Krug, R.M. and Etkind, P.R. (1975). Influenza virus-specific products in the nucleus and cytoplasm of infected cells. In Negative Strand Viruses (B.W.J. Mahy and R.D. Barry, eds.) Academic Press, New York, and London, pp. 555-572.
2. Krug, R.M., Etkind, P.R. and Plotch, S.J. (1976). Influenza viral RNA transcripts synthesized in vivo and in vitro. In Animal Virology, ICN-UCLA Symposia on Molecular and Cellular Biology, Vol. 4. (D. Baltimore, A.S. Huang and C.F. Fox, eds.) Academic Press, New York, pp. 499-513.
3. Krug, R.M., Plotch, S.J. and Tomasz, J. (1978). Influenza viral RNA transcription in vivo and in vitro. In Negative Strand Viruses and the Host Cell (B.W.J. Mahy and R.D. Barry, eds.) Academic Press, London, pp. 301-311.
4. Mark, G.E., Taylor, J.M., Herring, L., Broni, B. and Krug, R.M. (1978). Transcription and replication of the influenza virus genome early after infection. In Negative Strand Viruses and the Host Cell (B.W.J. Mahy and R.D. Barry, eds.) Academic Press, London, pp. 333-340.
5. Krug, R.M., Bouloy, M. and Plotch, S.J. (1980). The 5' ends of influenza viral messenger RNAs are donated by capped cellular messenger RNAs. In Structure and Variation in Influenza Virus (G. Laver and G. Air, eds.) Elsevier/North-Holland, pp. 181-190.
6. Krug, R.M., Bouloy, M. and Plotch, S.J. (1980). Capped eukaryotic messenger RNAs are primers for influenza viral RNA transcription. In Mobilization and Reassembly of Genetic Information, Miami Winter Symposia, vol. 17 (W.A. Scott, ed.) Academic Press, New York, pp. 285-303.
7. Krug, R.M. (1981). Priming of influenza viral RNA transcription by capped heterologous RNAs. Current Topics in Microbiol. and Immunol., volume 93, entitled Initiation Signals in Viral Gene Expression (A.J. Shatkin, ed.) Springer/Verlag, Munich, pp. 125-150.
8. Krug, R.M., Ulmanen, I., Braam, J., Plotch, S.J., Beaton, A. and Broni, A. (1982). The unique interaction of influenza viral messenger RNA synthesis with the host cell transcriptional machinery. In The Origin of Pandemic Infuenza Viruses. (W.G. Laver, ed.), Elsevier Science Publishing Co., Inc., New York, p. 147-158.
9. Krug, R.M. (1983). Transcription and replication of influenza viruses. Chapter 3, In Genetics of Influenza Virus. (P. Palese and D.W. Kingsbury, eds.) Springer-Verlag, Wein, New York, p. 70-98.
10. Braam, J., Ulmanen, I. and Krug, R.M. (1983). Molecular topography of the influenza virus P protein complex during capped RNA-primed messenger RNA synthesis. In Segmented Negative Strand Viruses. (R.W. Compans and D.H.L. Bishop, eds.), Acadmic Press, Inc., p. 73-84.
11. Krug, R.M., Beaton, A., Braam, J. and Katze, M. (1984). Influenza viral RNA transcription. In Viral Messenger RNA (Y. Becker, ed.), Martinus Nijhoff, Boston/Dordresht, Lancaster pp. 225-255.
12. Katze, M.G., Detjen, B.M., Safer, B. and Krug, R.M. (1986). Translational control by influenza virus. In Translational Control (M.B. Mathews, ed.), Cold Spring Harbor Laboratory, New York, pp. 114-119.
13. Krug, R.M. (1988). Influenza viral RNA transcription and replication. In RNA Genetics, Volume 1 (E. Domingo, J.J. Holland, P. Ahlquist, eds.) CRC Press, Boca Raton, Florida, pp. 159-169.
14. Krug, R.M., Alonso-Caplen, F.V., Julkunen, I. and Katze, M.G. (1989). Expression and replication of the influenza virus genome. In The Influenza Viruses (R. Krug, ed.), Plenum Press, New York and London, Chapter 2, pp. 89-152.
15. Lamb, R.A. and Krug, R.M. (1996). Orthomyxoviridae: the viruses and their replication: In Virology, 3rd edition (R.N. Fields and D. M. Knipe, eds.) Lippincott-Raven Press, New York, pp. 1353-1395.
16. Krug, R. M. (1998). Unique functions of the NS1 protein. In Textbook of Influenza (K.G. Nicholson, R.G. Webster, and A. Hay, eds.). Blackwell Science Ltd., London, pp. 82-92.
17. Lamb, R.A. and Krug, R.M. (2001). Orthomyxoviridae: the viruses and their replication. Fields Virology, 4th edition (D. M. Knipe and P. W. Howley, eds.) Lippincott Williams & Wilkens, Philadelphia, pp.1487-1531.
18. Krug, R. M., Zhao, C. and Beaudenon, S. L. (2005). Properties of the ISG15 E1 enzyme UbE1L. Methods in Enzymology 398: 32-40.
19. Krug, R.M. and Fodor, E. (2013). The virus genome and its replication. Textbook of Influenza, 2nd edition (R.G. Webster, A.S. Monto, T.J. Braciale and R.A. Lamb, eds.) Wiley-Blackwell, pp. 57-66.
20. Krug, R.M. and Garcia-Sastre, A. (2013). The NS1 protein: a master regulator of host and viral functions. Textbook of Influenza, 2nd edition (R.G. Webster, A.S. Monto, T.J. Braciale and R.A. Lamb, eds.) Wiley-Blackwell, pp. 114-132.
Journal Articles
1. Furth, J.J., Hurwitz, J., Krug, R.M. and Alexander, M. (1961). The incorporation of adenylic and cytidylic acids into ribonucleic acid. J. Biol. Chem. 236: 3317-3322.
2. Cannon, M., Krug, R.M. and Gilbert, W. (1963). The binding of sRNA by E. coli ribosomes. J. Mol. Biol. 7: 360-383.
3. Krug, R.M. and Franklin, R.M. (1964). Studies on the time of synthesis of mengovirus ribonucleic acid. Virology 22: 48-58.
4. Gomatos, P.J., Krug, R.M. and Tamm, I. (1964). Enzymatic synthesis of RNA with reovirus RNA as template. I. Characteristics of the reaction catalyzed by the RNA polymerase from E. coli. J. Mol. Biol. 9: 193-207.
5. Krug, R.M., Gomatos, P.J. and Tamm, I. (1965). Enzymatic synthesis of RNA with reovirus RNA as template. II. Nearest neighbor analysis of the products of the reaction catalyzed by E. coli. RNA polymerase. J. Mol. Biol. 12: 872-880.
6. Gomatos, P.J., Krug, R.M. and Tamm, I. (1965). Reovirus RNA-directed synthesis of DNA. I. The reaction catalyzed by DNA polymerase from E. coli. J. Mol. Biol. 13: 802-816.
7. Krug, R.M. and Gomatos, P.J. (1969). Absence of adenine-rich ribonucleic acid from purified infectious reovirus 3. J. Virol 4: 642-650.
8. Krug, R.M. (1971). Influenza viral RNPs newly synthesized during the latent period of viral growth in MDCK cells. Virology 44: 125-136.
9. Krug, R.M. (1972). Cytoplasmic and nucleoplasmic viral RNPs in influenza virus-infected MDCK cells. Virology 50: 103-113.
10. Krug, R.M. and Etkind, P.R. (1973). Cytoplasmic and nuclear virus-specific proteins in influenza virus-infected MDCK cells. Virology 56: 334-348.
11. Etkind, P.R. and Krug, R.M. (1974). Influenza viral messenger RNA. Virology 62: 38-45.
12. Krug, R.M. and Soeiro, R. (1975). Studies on the intranuclear localization of influenza virus-specific proteins. Virology 64: 378-387.
13. Krug, R.M., Ueda, M. and Palese, P. (1975). Temperature-sensitive mutants of influenza WSN virus defective in virus-specific RNA synthesis. J. Virol. 16: 790-796.
14. Etkind, P.R. and Krug, R.M. (1975). Purification of influenza viral complementary RNA: its genetic content and activity in wheat germ cell-free extracts. J. Virol. 16: 1464-1475.
15. Krug, R.M., Morgan, M.M. and Shatkin, A.J. (1976). Influenza viral messenger RNA contains internal N6-methyladenosine and 5' terminal 7-methylguanosine in cap structures. J. Virol. 20: 45-53.
16. Plotch, S.J. and Krug, R.M. (1977). Influenza virion transcriptase: synthesis in vitro of large, polyadenylic acid-containing complementary RNA. J. Virol. 21: 24-34.
17. Taylor, J.M., Illmensee, R., Litwin, S., Herring, L., Broni, B. and Krug, R.M. (1977). Use of specific radioactive probes to study transcription and replication of the influenza virus genome. J. Virol. 21: 530-540.
18. Etkind, P.R., Buchhagen, D.L., Herz, C., Broni, B. and Krug, R.M. (1977). The segments of influenza viral mRNA. J. Virol. 22: 346-352.
19. Plotch, S.J. and Krug, R.M. (1978). The segments of influenza virus complementary RNA synthesized in vitro. J. Virol. 25: 579-586.
20. Tomasz, J., Simonscita, A., Kajtar, M., Krug, R.M. and Shatkin, A.J. (1978). Chemical synthesis of 5'-pyrophosphate and triphosphate derivatives of 3'-5' ApA, ApG, GpA and GpG. CD study of the effect of 5'-phosphate groups on the conformation of 3'-5' GpG. Nucl. Acids Res. 5: 2945-2957.
21. Plotch, S.J., Tomasz, J. and Krug, R.M. (1978). Absence of detectable capping and methylating enzymes in influenza virions. J. Virol. 28: 75-83.
22. Bouloy, M., Plotch, S.J. and Krug, R.M. (1978). Globin mRNAs are primers for the transcription of influenza viral RNA in vitro. Proc. Natl. Acad. Sci. USA 75: 4886-4890.
23. Mark, G.E., Taylor, J.M., Broni, B. and Krug, R.M. (1979). Nuclear accumulation of influenza viral RNA transcripts and the effects of cycloheximide, actinomycin D, and -amanitin, J. Virol. 29: 744-752.
24. Plotch, S.J., Bouloy, M. and Krug, R.M. (1979). Transfer of the 5' terminal cap of globin mRNA to influenza viral complementary RNA during transcription in vitro. Proc. Natl. Acad. Sci. USA 76: 1618-1622.
25. Krug, R.M., Broni, B. and Bouloy, M. (1979). Are the 5' ends of influenza viral mRNAs synthesized in vivo donated by host mRNAs? Cell 18: 329-334.
26. Bouloy, M., Morgan, M.A., Shatkin, A.J. and Krug, R.M. (1979). Cap and internal nucleotides of reovirus mRNA primers are incorporated into influenza viral complementary RNA during transcription in vitro. J. Virol. 32: 895-904.
27. Krug, R.M., Bouloy, M. and Plotch, S.J. (1980). RNA primers and the role of host nuclear RNA polymerase II in influenza viral RNA transcription. Phil. Trans. Royal Soc. Lond. B 288: 359-370.
28. Robertson, H.D., Dickson, E., Plotch, S.J. and Krug, R.M. (1980). Identification of the RNA region transferred from a representative primer, -globin mRNA, to influenza mRNA during in vitro transcription. Nucl. Acids Res. 8: 925-942.
29. Bouloy, M., Plotch, S.J. and Krug, R.M. (1980). Both the 7-methyl and the 2'-0-methyl groups in the cap of mRNA strongly influence its ability to act as primer for influenza virus RNA transcription. Proc. Natl. Acad. Sci. USA 77: 3952-3956.
30. Krug, R.M., Broni, B., LaFiandra, A.J., Morgan, M.A. and Shatkin, A.J. (1980). Priming and inhibitory activities of RNAs for the influenza viral transcriptase do not require base-pairing with the virion template RNA. Proc. Natl. Acad. Sci. USA 77: 5874-5878.
31. Krug, R.M., Bouloy, M. and Plotch, S.J. (1981). The 5' ends of influenza viral messenger RNAs are donated by capped cellular RNAs. Trends Biochem. Sci. 6: 7-10.
32. Plotch, S.J. Bouloy, M., Ulmanen, I. and Krug, R.M. (1981). A unique cap (m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell 23: 847-858.
33. Beaton, A.R. and Krug, R.M. (1981). Selected host cell capped RNA fragments prime influenza viral RNA transcription in vivo. Nucl. Acids Res. 9: 4223-4236.
34. Ulmanen, I., Broni, B.A. and Krug, R.M. (1981). The role of two of the influenza virus core P proteins in recognizing cap 1 structures (m7GpppNm) on RNAs and in initiating viral RNA transcription. Proc. Natl. Acad. Sci. USA 78: 7355-7359.
35. Herz, C., Stavnezer, E., Krug, R.M. and Gurney, T., Jr. (1981). Influenza virus, an RNA virus, synthesizes its messenger RNA in the nucleus of infected cells. Cell 26: 391-400.
36. Heggeness, M.H., Smith, P.R., Ulmanen, I., Krug, R.M. and Choppin, P.W. (1982). Studies on the helical nucleocapsid of influenza virus. Virology 118: 466-470.
37. Ulmanen, I., Broni, B.A. and Krug, R.M. (1983). Influenza virus temperature-sensitive cap (m7GpppNm)-dependent endonuclease. J. Virol. 45: 27-35.
38. Braam, J., Ulmanen, I. and Krug, R.M. (1983). Molecular model of a eukaryotic transcription complex: functions and movements of influenza P proteins during capped RNA-primed transcription. Cell 34: 609-618.
39. Katze, M.G., Chen, Y.-T. and Krug, R.M. (1984). Nuclear-cytoplasmic transport and VAI RNA-independent translation of influenza viral messenger RNAs in late adenovirus-infected cells. Cell 34: 483-490.
40. Beaton, A.R. and Krug, R.M. (1984). Synthesis of the templates for influenza virion RNA replication in vitro. Proc. Natl. Acad. Sci. USA 81: 4682-4686.
41. Katze, M.G. and Krug, R.M. (1984). The metabolism of RNA polymerase II transcripts in influenza virus-infected cells. Mol. Cell. Biol. 4: 2198-2206.
42. Braam-Markson, J., Jaudon, C. and Krug, R.M. (1985). Expression of a functional influenza viral cap-recognizing protein using a bovine papillomavirus vector. Proc. Natl. Acad. Sci. USA 82: 4326-4330.
43. Krug, R.M. (1985). The role of RNA priming in viral and trypanosomal mRNA synthesis. Cell 41: 651-652.
44. Krug, R.M., Shaw, M., Broni, B., Shapiro, G. and Haller, O. (1985). Inhibition of influenza viral messenger RNA synthesis in cells expressing the interferon-induced Mx gene product. J. Virol. 56: 201-206.
45. Katze, M.G., DeCorato, D. and Krug, R.M. (1986). Cellular mRNA translation is blocked at both initiation and elongation following infection by influenza virus or adenovirus. J. Virol. 60: 1027-1039.
46. Beaton, A.R. and Krug, R.M. (1986). Transcription antitermination during influenza viral template RNA synthesis requires the nucleocapsid protein and the absence of a 5' capped end. Proc. Natl. Acad. Sci. USA 83: 6282-6286.
47. Plotch, S.J. and Krug, R.M. (1986). In vitro splicing of influenza viral NS1 mRNA and NS1--globin chimeras: possible mechanisms for the control of viral mRNA splicing. Proc. Natl. Acad. Sci. USA 83: 5444-5448.
48. Katze, M.G., Detjen, B.M., Safer, B. and Krug, R.M. (1986). Translational control by influenza virus: suppression of the kinase that phosphorylates the alpha subunit of initiation factor eIF-2 and selective translation of influenza viral mRNAs. Mol. Cell. Biol. 6: 1741-1750.
49. Detjen, B.M., St. Angelo, C., Katze, M.G. and Krug, R.M. (1987). The three influenza virus polymerase (P) proteins not associated with viral nucleocapsids in the infected cell are in the form of a complex. J. Virol. 61: 16-22.
50. St. Angelo, C., Smith, G.E., Summers, M.D. and Krug, R.M. (1987). Two of the three influenza viral polymerase (P) proteins expressed using baculovirus vectors form a complex in insect cells. J. Virol. 61: 361-365.
51. Shapiro, G.I., Gurney, Jr., T. and Krug, R.M. (1987). Influenza viral gene expression: control mechanisms at early and late times of infection and nuclear-cytoplasmic transport of virus-specific RNAs. J. Virol. 61: 763-773.
52. Krug, R.M., St. Angelo, C., Broni, B. and Shapiro, G. (1987). Transcription and replication of influenza virion RNA in the nucleus of infected cells. Cold Spring Harbor Symp. Quant. Biol. LII, pp. 353-368.
53. Alonso-Caplen, F.V., Katze, M.G. and Krug, R.M. (1988). Efficient transcription, not translation, is dependent on adenovirus tripartite leader sequences at late times of infection. J. Virol. 62: 1606-1616.
54. Shapiro, G.I. and Krug, R.M. (1988). Influenza virus RNA replication in vitro: synthesis of viral template RNAs and virion RNAs in the absence of an added primer. J. Virol. 62: 2285-2290.
55. Katze, M.G., Tomita, J., Black, T., Krug, R.M., Safer, B. and Hovanessian, A. (1988). Influenza virus regulates protein synthesis during infection by repressing the autophosphorylation and activity of the cellular 68,000 Mr. protein kinase. J. Virol. 62: 3710-3717.
56. Agris, C.H., Nemeroff, M.E. and Krug, R.M. (1989). A block in mammalian splicing occurring after the formation of large complexes containing the U1, U2, U4, U5 and U6 small nuclear ribonucleoproteins. Mol. Cell. Biol. 9: 259-267.
57. Broni, B., Julkunen, I., Condra, J.J., Davies, M.-E., Berry, M.J. and Krug, R.M. (1990). Parental influenza virion nucleocapsids are efficiently transported into the nuclei of murine cells expressing the nuclear interferon-induced Mx protein. J. Virol. 64: 6335-6340.
58. Katze, M.G. and Krug, R.M. (1990). Translational control in influenza virus-infected cells. Enzyme 44: 265-277.
59. Alonso-Caplen, F.V. and Krug, R.M. (1991). Regulation of the extent of splicing of influenza virus NS1 mRNA: role of the rate of splicing and of the nucleocytoplasmic transport of NS1 mRNA. Mol. Cell Biol. 11: 1092-1098.
60. Nemeroff, M.E., Utans, U., Kramer, A. and Krug, R.M. (1992). Identification of the cis-acting intron and exon regions in influenza virus NS1 mRNA that inhibit splicing and cause the formation of aberrantly sedimenting pre-splicing complexes. Mol. Cell Biol. 12: 962-970.
61. Alonso-Caplen, F.V., Nemeroff, M.E., Yun, Q. and Krug, R.M. (1992). Nucleocytoplasmic transport: the influenza virus NS1 protein regulates the transport of spliced NS2 mRNA and its precursor NS1 mRNA. Genes Dev. 6: 255-267.
62. Melen, K., Ronni, T., Broni, B., Krug, R.M., von Bonsdorff, C-H., and Julkunen, I. (1992). Interferon-induced Mx proteins form oligomers and contain a putative leucine zipper. J. Biol. Chem. 267: 25898-25907.
63. Krug, R. M. (1993). The regulation of the export of mRNA from nucleus to cytoplasm. Current Opinion Cell Biol. 5: 944-949.
64. Qiu, Y. and Krug, R.M. (1994). The influenza virus NS1 protein is a poly A-binding protein that inhibits the nuclear export of mRNAs containing poly A. J. Virol. 68: 425-2432
65. Qian, X-Y, Alonso-Caplen, F., Qui, Y. and Krug, R.M. (1994). Two functional domains of the influenza NS1 protein are required for the regulation of the nuclear export of mRNA. J. Virol. 68: 2433-2441.
66. Lu, Y. Qian, X-Y., and Krug, R.M. (1994). The influenza virus NS1 protein: a novel inhibitor of pre-mRNA splicing. Genes Dev. 8: 1817-1828.
67. Qiu, Y., Nemeroff, M. and Krug, R.M. (1995). The influenza virus NS1 protein binds to a specific sequence in human U6 snRNA and inhibits U6-U2 and U6-U4 snRNA. RNA 1: 304-316
68. Shih, S-R., Nemeroff, M. and Krug, R.M. (1995). The choice of alternative 5' splice sites in influenza virus M1 mRNA is regulated by the viral polymerase complex. Proc. Natl. Acad. Sci. USA 92: 6324-6328.
69. Nemeroff, M.E., Qian, X.-Y. and Krug, R.M. (1995). The influenza virus NS1 protein forms multimers in vitro and in vivo. Virology 212: 422-428.
70. Lu, Y., Wambach, M., Katze, M. G. and Krug, R.M. (1995). Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the eIF-2 translation initiation factor. Virology 214: 222-228.
71. Qian, X.Y., Chien, C., Montelione, G. and Krug, R.M. (l995). An amino terminal polypeptide fragment of the influenza virus NS1 protein possesses specific RNA-binding activity and is largely alpha-helical. RNA 1: 948-956.
72. Qian, X.Y., Zhang, J., Rabson, A.B. and Krug, R.M. (1996). New approach for inhibiting rev function and HIV-1 production using the influenza virus NS1 protein. Proc. Natl. Acad. Sci. USA 93: 8873-8877.
73. Shih,S.-R. and Krug, R. M. (1996). Novel exploitation of a nuclear function by influenza virus: the cellular SF2/ASF splicing factor controls the amount of the essential M2 ion channel protein in infected cells. EMBO J 15: 5415-5427.
74. Shih, S.R. and Krug, R.M. (1996). Surprising function of the three influenza viral polymerase proteins: selective protection of viral mRNAs against the cap-snatching reaction catalyzed by the same polymerase proteins. Virology 226: 430-435.
75. Chien, C., Tejero, R., Huang, Y., Zimmerman, D.E., Rios, C. B., Krug, R.M. and Montelione, G. T. (1997). A novel RNA-binding motif in influenza A virus non-structural protein 1. Nature Struct. Biol. 4: 891-895.
76. Liu, J., Lynch, P. A., Chien, C., Montelione, G. T., Krug, R. M. and Berman, H. M. (1997). Crystal structure of the unique multifunctional RNA-binding domain of the influenza virus NS1 protein. Nature Struct. Biol. 4: 896-899.
77. Wang, W. and Krug, R. M. (1998). U6atac snRNA, the highly divergent counterpart of U6 snRNA, is the specific target that mediates inhibition of AT-AC splicing by the influenza virus NS1 protein. RNA 4: 55-64.
78. Chen, Z., Li, Y. and Krug, R.M. (1998). Chimeras containing influenza NS1 and HIV-1 Rev protein sequences: mechanism of their inhibition of nuclear export of Rev protein-RNA complexes. Virology 241: 234-250.
79. Schultz-Cherry, S., Krug, R. M. and Hinshaw, V. S. (1998). Induction of apoptosis by influenza virus. Seminars in Virology 8: 491-495.
80. Nemeroff, M.E., Barabino, S.M.L., Li, Y., Keller, W. and Krug, R.M. (1998) Influenza virus NS1 protein interacts with the cellular 30kD subunit of CPSF and inhibits 3' end formation of cellular mRNAs. Molecular Cell 1: 991-1000.
81. Li, Y., Yamakita, Y. and Krug, R.M. (1998) Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein. Proc. Natl. Acad. Sci USA 95: 4864-4869.
82. Li, M.-L., Ramirez, C. and Krug, R.M. (1998) RNA-dependent activation of primer RNA production by the influenza virus polymerase: Different regions of the same protein subunit constitute the two required RNA-binding sites. EMBO J. 17: 5844-5852.
83. Wang, W., Riedel, K., Lynch, K., Chien, C., Montelione, G. T. and Krug, R. M. (1999). RNA-binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. RNA 5: 195-205.
84. Chen, Z., Li, Y. and Krug, R. M. (1999). Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3' end processing machinery. EMBO J. 18: 2273-2283.
85. Chen, Z. and Krug, R.M. (2000). Selective nuclear export of viral mRNAs in influenza-virus-infected cells. Trends in Microbiol. 8: 376-383.
86. Yuan, W. and Krug, R.M. (2001). Influenza B virus NS1 protein inhibits conjugation of the IFN-induced, ubiquitin-like ISG15 protein. EMBO J. 20: 362-371.
87. Li, M.-L. Rao, P. and Krug, R. M. (2001). The active sites of the influenza cap-dependent endonuclease are on different polymerase subunits. EMBO J. 20: 2078-2086.
88. Li, Y., Chen, Z.-Y., Wang, W., Baker, C. C. and Krug, R. M. (2001). The 3’ end processing factor CPSF is required for the splicing of single intron pre-mRNAs in vivo. RNA 7: 920-931.
89. Cassetti, M. C., Noah, D. L., Montelione, G. T. and Krug, R. M. (2001). Efficient translation of mRNAs in influenza A virus-infected cells is independent of the viral 5’ untranslated region. Virology 289: 180-185.
90. Kim, M.-J., Latham, A. G. and Krug, R. M. (2002). Human influenza viruses activate an interferon-independent transcription of cellular antiviral genes: the outcome with influenza A virus is unique. Proc. Natl. Acad. Sci. USA 99: 10096-10101.
91. Yuan, W., Aramini, J. M., Montelione, G. T. and Krug, R. M. (2002). Structural basis for ubiquitin-like ISG15 protein binding to the NS1 protein of influenza B virus: a protein-protein interaction function that is not shared by the corresponding N-terminal domain of the NS1 protein of influenza A virus. Virology 304: 291-301.
92. Krug, R. M. (2003). The potential use of influenza virus as an agent for bioterrorism. Antiviral Research 57: 147-150.
93. Noah, D. L., Twu, K. Y. and Krug, R. M. (2003). 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.
94. Rao, P., Yuan, W. and Krug, R. M. (2003). 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.
95. Krug, R, M., Yuan, W., Noah, D. L. and Latham, A. G. (2003). Intracellular warfare between human influenza viruses and human cells: the roles of the viral NS1 protein. Virology 309: 181-189.
96. Chien, C-Y., Xu, Y., Xiao, R., Aramini, J. M. , Sahasrabudhe, P. V., Krug, R. M., and Montelione, G. T. (2004). 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.
97. Zhao, C., Beaudenon, S. L., Kelley, M. L., Waddell, M. B., Yuan, W., Schulman, B. A., Huibregtse, J. M., and Krug, R. M. (2004). The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an interferon -induced ubiquitin-like protein. Proc. Natl. Acad. Sci. USA 101: 7578-7582.
98. Noah, D. L. and Krug, R. M. (2005). Influenza virus virulence and its molecular determinants. Advances in Virus Research 65: 121-146.
99. Zhao, C., Denison, C., Huibregtse, J. M., Gygi, S., and Krug, R. M. (2005). Human ISG15 targets both interferon-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc. Natl. Acad. Sci. USA 102:10200-10205.
100 Dastur, A., Beaudenon, S., Kelley, M., Krug, R. M. and Huibregtse, J. M. (2006). Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells. J. Biol. Chem. 281: 4334-4338.
101 Li, S., Min, J.-Y., Krug, R. M. and Sen, G. C. (2006). 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.
102. Krug, R. M. (2006). Clues to the virulence of H5N1 viruses in humans. Science 311: 1562-1563.
103 Twu, K. Y., Noah, D. L., Rao, P., Kuo, R.-L, and Krug, R. M. (2006). The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target. J. Virol. 80: 3957-3965.
104. Min, J.-Y. and Krug, R. M. (2006). 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.
105. Siren, J., Imaizumi, T., Sarkar, D., Pietila, T., Noah, D. L., Hiscott, J., Krug, R. M., Fisher, P. B., Julkunen, I., and Matikainen, S. (2006). Retinoic acid inducible gene-1 and mda-5 are involved in influenza A virus-induced expression of antiviral cytokines. Microbes Infect 8: 2013-2020.
106. Ye, Q., Krug, R. M. and Tao, Y. J. (2006) The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444: 1078-1082.
107. Melén, K., Kinnunen, L., Fagerlund, R., Ikonen, N., Twu, K. Y., Krug, R. M.,and Julkunen, I. (2007). Nuclear and nucleolar targeting of influenza A virus NS1A protein: Striking differences between different virus subtypes. J. Virol. 81; 5995-6006.
108. Min, J.-Y., Li, S., Sen, G. C. and Krug, R. M. (2007). 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.
109. Yin C., Khan J.A, ,Swapna G.V., Ertekin A., Krug R.M, Tong L, .and Montelione G.T. (2007). 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.
110. Twu, K.Y., Kuo. R.-L., Marklund, J. and Krug, R. M. (2007), The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in human cells. J. Virol. 81: 8112-8121.
111. Das, K., Ma, L.-C., Xiao, R., Radvansky, B., Aramini, J., Zhao, L., Marklund, J., Kuo, R.-L., Tw, K. Y., Arnold, E., Krug, R.M. and Montelione, G. T. (2008). Structural basis for suppression of a host antiviral response by influenza A virus. Proc. Natl. Acad. Sci. USA 105: 13093-13098.
112. Newcomb, L. L., Kuo, R.-L., Ye, Q., Tao, Y. J. and Krug, R. M. (2009). Interaction of the influenza A virus nucleocapsid protein with the viral RNA polymerase potentiates unprimed viral RNA replication. J. Virol. 83: 29-36.
113. Kuo, R.-L. and Krug, R. M. (2009). Influenza A virus polymerase is an integral component of the CPSF30-NS1A complex in infected cells. J. Virol. 83: 1611-1616.
114. Hsiang, T.-Y., Zhao, C. and Krug, R. M. (2009). Interferon-induced ISG15 conjugation inhibits influenza A virus gene expression and replication in human cells. J. Virol. 83: 5971-5979.
115. Krug, R.M. and Aramini, J.M. (2009). Emerging antiviral targets for influenza A virus. Trends Pharmacol Sci. 30: 269-277.
116. Das, K., Aramini, J. M., Ma, L.-C., Krug, R. M. and Arnold, E. (2009). Structures of influenza A proteins and insights into antiviral drug targets. Nat. Struct. Mol. Biol. 17: 530-538.
117. Zhao, C., Hsiang, T.-Y., Kuo, R.-L. and Krug, R. M. (2010) ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells. Proc. Natl. Acad. Sci. USA 107: 2253-2258.
118. Sridharan, H., Zhao, C., and Krug, R. M. (2010). 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.
119. Liu, H., Golebiewski, L., Dow, E.C., Krug, R.M., Javier, R.T. and Rice, A.P. (2010). The ESEV PDZ-binding motif of the avian influenza A virus NS1 protein protects infected cells from apoptosis through directly targeting Scribble. J. Virol. 84: 11164-11174.
120. Kuo, R.-L., Zhao, C., Malur, M., and Krug, R. M. (2010). Influenza A virus strains that circulate in humans differ in the ability of their NS1 proteins to block the activation of IRF3 and interferon- transcription. Virology 408: 146-158.
121. You, L., Cho, E. J., Leavitt, J., Ma, L. C., Montelione, G. T., Anslyn, E. V., Krug, R. M., Ellington, A., and Robertus, J. D. (2010). Synthesis and evaluation of quinoxaline derivatives as potential influenza NS1A protein inhibitors. Bioorg. Med. Chem. Lett. 21: 3007-3011.
122. Schauder, C., Ma, L. C., Krug, R. M., Montelione, G. T. and Guan, R. (2010). Structure of the iSH2 domain of human phosphatidylinositol 3-kinase p85 subunit reveals conformational plasticity in the interhelical turn region. Acta Crystallogr Sect F Struct Biol Cryst Commun 66: 1567-1571.
123. Yin. C., Aramini, J. M., Ma, L. C., Cort, J. R., Swapna, G. V., Krug, R. M., and Montelione, G. T. (2011). Backbone and Ile-1, Leu, Val Methyl (1)H, (13)C and (15)N NMR chemical shift assignments for human interferon-stimulated gene 15 protein. Biomol NMR Assign 5: 215-219.
124. 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. (2011). 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.
125. 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. (2011). 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.
126. Guan, R., Ma, L.-C., Leonard, P. G., Amer, B. R., Sridharan, H., Zhao, C., Krug, R. M., and Montelione, G. T. (2011). 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.
127. Marklund, J. K., Ye, Q., Dong, J., Tao, Y. J. and Krug, R. M. (2012) Sequence in the influenza A virus nucleoprotein required for viral polymerase binding and RNA replication. J. Virol. 86: 7292-7297.
128. Sundquist, W. I. and Krug, R.M. (2012). Assemble, replicate, remodel and evade. Curr Opin Virol 2: 111-114.
129. Hsiang, T.-Y., Zhou, L., and Krug, R.M. (2012). Roles of the phosphorylation of specific serines and threonines in the NS1 protein of human influenza A viruses. J. Virol. 86: 10370-10376.
130. Malur, M., Gale Jr., M., and Krug, R.M. (2012). LGP2 downregulates interferon production during infection with seasonal human influenza A viruses that activate interferon regulatory factor 3. J. Virol. 86: 10733-10738.
131. Ye, Q., Guu, T. S. Y., Mata, D. A., Kuo, R.-L., Smith, B., Krug, R.M., and Tao, Y. T. (2012). 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.
132. Zhao, C, Collins, M. N., Hsiang, T.-Y., and Krug, R. M. (2013). Interferon-induced ISG15 pathway: an ongoing virus-host battle. Trends in Microbiology 21: 181-186.
133. Seo, G.J., Kincaid, R.P., Phanaksri, T., Burke, J. M., Cox, J.E., Hsiang, T.-Y., Krug, R.M., and Sullivan, C.S. (2013). Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells. Cell Host & Microbe 14: 435-445.
134. Barman ,S., You, L., Chen. R., Codrea, V., Kago, G., Edupuganti, R., Robertus, J., Krug, R.M., and Anslyn, E.V. (2013). Exploring naphthyl-carbohydrazides as inhibitors of influenza A viruses. Eur J Med Chem 71C: 81-90.
135. 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. (2014). 19FNMR reveals multiple conformations at the dimer interface of the non-structural protein 1 effector domain from influenza A virus. Structure 32: 515-525.
136. Chen, G., Liu, C.-H., Zhou, L., and Krug, R.M. (2014). Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein. Cell Host & Microbe 15: 484-493.
137. Krug, R.M. (2014). Viral proteins that bind double-stranded RNA: countermeasures against host antiviral responses. J Interferon Cytokine Res, 34: 464-468.
138. Krug, R.M. (2014). Influenza: An RNA-synthesizing machine. Nature 516: 388-389.
140. Liu, C.H., Zhou, L., Chen, G, and Krug, R.M. (2015). Battle between influenza A virus and a newly identified antiviral activity of the PARP-containing ZAPL protein. Proc.Natl.Acad.Sci USA 112: 14048-14053.
141. Kuo, R.-L., Li, L.H., Lin, S.J., Li ,Z.H., Chen, G.W., Chang, C.K., Wang, Y.R., Tam, E.H., Gong, Y.N,, Krug, R.M., and Shih, S.R. (2016). Role of N Terminus-Truncated NS1 Proteins of Influenza A Virus in Inhibiting IRF3 Activation. J.Virol. 90: 4696-4705.
142. Ma, L.C., Guan, R., Hamilton, K., Aramini, J.M., Mao, L., Wang, S., Krug, R.M., and Montelione, G.T. (2016). A Second RNA-Binding Site in the NS1 Protein of Influenza B Virus. Structure 24: 1562-1572.
143. Zhao, C., Sridharan, H., Chen, R., Baker, D.P., Wang, S., and Krug, R.M. (2016). Influenza B virus non-structural protein 1 counteracts ISG15 antiviral activity by sequestering ISGylated viral proteins. Nat.Commun. 7: 12754
144. Smelkinson, M.G., Guichard, A., Teijaro, J. R., Malur, M., Maria Eugenia Loureiro, M. E., Jain, P., Ganesan, S., Z, El, Z., Krug, R. M., Oldstone, M.B.,Bier, E. (2017). Influenza NS1 directly modulates Hedgehog signaling during infection. PLoS Pathog.13: e1006588
145. Meyerson, N. R., Zhou, L. Guo, Y. R., Zhao, C., Tao, Y.J., Krug, R. M., and Sawyer, S. L. (2017). Nuclear TRIM25 specifically targets influenza virus ribonucleoproteins to block the onset of RNA chain elongation. Cell Host Microbe 22: 627-638.
146. Smith, B. L., Chen, G., Wilke, C. O. and Krug, R. M. (2018). Avian Influenza PB1 gene in H3N2 viruses evolved in humans to reduce interferon inhibition by skewing codon usage toward interfereon-altered tRNA pools. mBio 9: e01222-18.
147. Chen, G., Ma, L. C., Wang, S., Woltz, R. L., Grasso, E. M., Montelione, G. T. and Krug, R. M. (2020). A double-stranded RNA platform is required for the interaction between a host restriction factor and the NS1 protein of influenza A virus. Nucleic Acid Res. 48: 304-315.
148. Du, Z., Nugent, C., Galvani, A., Krug, R. M. and Meyers, L. A. (2020). Modeling mitigation of influenza epidemics by baloxavir. Nature Commun. 11:750.
Interviews and News Articles
"Is There a 'Baloxavir' for Coronavirus?" Precisionvaccinations.com, June 2, 2020
"Texas Researcher Behind New Flu Drug Approved by FDA" kxan, November 2, 2018
"University of Texas professor’s research lead to new anti-flu drug Xofluza" Austin360, November 5, 2018.
Interview about influenza virus and microRNAs, October 20, 2013: https://www.microbe.tv/twiv/twiv-255-longhorns-go-viral/