Induction of HIV transcription by Nef involves Lck activation and protein kinase C theta raft recruitment leading to activation of ERK1/2 but not NF kappa B.
The Nef protein of HIV-1 is a key promoter of disease progression, owing to its dramatic yet ill-defined impact on viral replication. Previously, we have shown that Nef enhances Tat-mediated transcription in a manner depending on Lck and the cytoplasmic sequestration of the transcriptional repressor embryonic ectodermal development [corrected]. In this study, we report that Lck is activated by Nef and targets protein kinase Ctheta downstream, leading to the translocation of the kinase into membrane microdomains. Although microdomain-localized protein kinase Ctheta is thought to induce the transcription factor NFkappaB, we unexpectedly failed to correlate Nef-induced signaling events with enhanced NFkappaB activity. Instead, we observed an increase in ERK MAPK activity. We conclude that Nef-mediated signaling cooperates with Nef-induced derepression and supports HIV transcription through an ERK MAPK-dependent, but NFkappaB-independent, pathway.
Witte
Vanessa
V
Otto-von-Guericke University of Magdeburg, Institute of Molecular and Clinical Immunology, Magdeburg, Germany. vanessa.witte@med.ovgu.de
Laffert
Bernd
B
Gintschel
Patricia
P
Krautkrämer
Ellen
E
Blume
Katja
K
Fackler
Oliver T
OT
Baur
Andreas S
AS
D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D021962:Membrane Microdomains / Q000201:enzymology* / Q000821:virology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D021381:Protein Transport / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D015854:Up-Regulation / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
D007527:Isoenzymes; D016328:NF-kappa B; D054311:nef Gene Products, Human Immunodeficiency Virus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3