Lentivirus-associated MAPK/ERK2 phosphorylates EMD and regulates infectivity.
Infection of a cell by lentiviruses, such as human immunodeficiency virus type 1 or feline immunodeficiency virus, results in the formation of a reverse transcription complex, the pre-integration complex (PIC), where viral DNA is synthesized. In non-dividing cells, efficient nuclear translocation of the PIC requires the presence of the inner nuclear lamina protein emerin (EMD). Here, we demonstrate that EMD phosphorylation is induced early after infection in primary non-dividing cells. Furthermore, we demonstrate that EMD phosphorylation is dependent on virion-associated mitogen-activated protein kinase (MAPK). Specific inhibition of MAPK activity with kinase inhibitors markedly reduced EMD phosphorylation and resulted in decreased integration of the proviral DNA into chromatin. Similarly, when a MEK1 kinase-inactive mutant was expressed in virus-producer cells, virus-induced phosphorylation of EMD was impaired and viral integration reduced during the subsequent infection. Expression of constitutively active MEK1 kinase in producer cells did not result in modulation of EMD phosphorylation or viral integration during subsequent infection. These studies demonstrate that, in addition to phosphorylating components of the PICs at an early step of infection, virion-associated MAPK plays a role in facilitating cDNA integration after nuclear translocation through phosphorylation of target-cell EMD.
Bukong
Terence N
TN
University College Dublin, Centre for Research in Infectious Diseases, Belfield, Dublin 4, Ireland.
Hall
William W
WW
Jacqué
Jean-Marc
JM
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology; D002415:Cats; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D066298:In Vitro Techniques; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000821:virology; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D014774:Virulence / Q000235:genetics / Q000502:physiology; D016662:Virus Integration / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D004279:DNA, Viral; D008565:Membrane Proteins; D009687:Nuclear Proteins; C092710:emerin; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1