Poxvirus infection rapidly activates tyrosine kinase signal transduction.
Viruses have evolved a number of strategies to gain entry and replicate in host target cells that, for human immunodeficiency virus (HIV) and the poxvirus, myxoma virus, involve appropriating chemokine receptors. In this report we demonstrate that activation of multiple intracellular tyrosine phosphorylation events rapidly ensues following virus adsorption to NIH 3T3.CD4.CCR5 cells and affects the ultimate level of myxoma virus replication. UV-inactivated myxoma virus induces the rapid phosphorylation of CCR5 on tyrosine residues, the association of CCR5 with Jaks and p56(lck), and their phosphorylation-activation within minutes of virus adsorption. Additionally, we provide evidence for myxoma virus-inducible signal transducers and activators of transcription (Stat) and insulin receptor substrate (IRS) activation. In contrast to CCR5 activation effected by HIV Env protein, these myxoma virus-inducible phosphorylation events are not sensitive to pertussis toxin treatment. Moreover, in cells that are non-permissive for myxoma virus infection, we provide evidence that myxoma virus fails to invoke this tyrosine phosphorylation cascade. Consistent with the observation that infection of CCR5-expressing cells is blocked by herbimycin A and the Jak 2 inhibitor, tyrophostin AG490, we infer that viral infectivity may be dependent on non-G-protein-coupled signal transduction pathways triggered by the infecting myxoma virus particle. This provides a novel post-binding mechanism by which viruses can co-opt a cellular receptor to permit productive virus infection.
Masters
J
J
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Canadian Blood Services Building, Toronto, Ontario M5G 2M1, Canada.
Hinek
A A
AA
Uddin
S
S
Platanias
L C
LC
Zeng
W
W
McFadden
G
G
Fish
E N
EN
D016475:3T3 Cells; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation; D005434:Flow Cytometry; D008561:Membrane Fusion; D051379:Mice; D010766:Phosphorylation; D011212:Poxviridae / Q000472:pathogenicity / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D015704:CD4 Antigens; D019713:Receptors, CCR5; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases