Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade

Influenza A viruses are important worldwide pathogens in humans and different animal species. The functions of most of the ten different viral proteins of this negative-strand RNA virus have been well elucidated. However, little is known about the virus-induced intracellular signalling events that support viral replication. The Raf/MEK/ERK cascade is the prototype of mitogen-activated protein (MAP) kinase cascades and has an important role in cell growth, differentiation and survival. Investigation of the function of this pathway has been facilitated by the identification of specific inhibitors such as U0126, which blocks the cascade at the level of MAPK/ERK kinase (MEK). Here we show that infection of cells with influenza A virus leads to biphasic activation of the Raf/MEK/ERK cascade. Inhibition of Raf signalling results in nuclear retention of viral ribonucleoprotein complexes (RNPs), impaired function of the nuclear-export protein (NEP/NS2) and concomitant inhibition of virus production. Thus, signalling through the mitogenic cascade seems to be essential for virus production and RNP export from the nucleus during the viral life cycle.

[1]  F. Hobbs,et al.  Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase* , 1998, The Journal of Biological Chemistry.

[2]  P. Palese,et al.  The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins , 1998, The EMBO journal.

[3]  Utz Fischer,et al.  The HIV-1 Rev Activation Domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs , 1995, Cell.

[4]  F. Su,et al.  Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases , 1996, Journal of virology.

[5]  Alan R. Saltiel,et al.  Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo , 1999, Nature Medicine.

[6]  D. McDonald,et al.  Steroid-receptor fusion of the human immunodeficiency virus type 1 Rev transactivator: mapping cryptic functions of the arginine-rich motif. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Gaestel,et al.  3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways , 1996, Molecular and cellular biology.

[8]  A Helenius,et al.  Nuclear trafficking of influenza virus ribonuleoproteins in heterokaryons , 1996, Journal of virology.

[9]  B. Jaffee,et al.  Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy. , 1998, Journal of immunology.

[10]  E. Paoletti,et al.  The phosphorylation of the integral membrane (M1) protein of influenza virus. , 1990, Virus research.

[11]  L. Mahadevan,et al.  Parallel signal processing among mammalian MAPKs. , 1995, Trends in biochemical sciences.

[12]  P. Cohen,et al.  The search for physiological substrates of MAP and SAP kinases in mammalian cells. , 1997, Trends in cell biology.

[13]  M. Cobb,et al.  Mitogen-activated protein kinase pathways. , 1997, Current opinion in cell biology.

[14]  J. Troppmair,et al.  The ins and outs of Raf kinases. , 1994, Trends in biochemical sciences.

[15]  J. Wityak,et al.  MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. , 1998, Bioorganic & medicinal chemistry letters.

[16]  D. Spector,et al.  Extracellular Signal-Regulated Kinase Activity Is Sustained Early during Human Cytomegalovirus Infection , 1998, Journal of Virology.

[17]  I. Kovesdi,et al.  Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression , 1997, Journal of virology.

[18]  C. Scholtissek,et al.  Differential Phosphorylation of the Nucleoprotein of Influenza A Viruses , 1989 .

[19]  P. Pitha,et al.  Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 receptor. , 1998, Virology.