Adenovirus Triggers Reorganization of Vimentin-Containing Intermediate Filaments Resulting in the Perinuclear Movement of cPLA2 and Suppression of Prostaglandin Production
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2008-11-20
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CULVER, CAROLYN ANNE. Adenovirus triggers reorganization of vimentin-containing intermediate filaments resulting in the perinuclear movement of cPLA2 and suppression of prostaglandin production. (Under the direction of Dr. Scott M. Laster)
Prostaglandins are important inflammatory mediators generated by the cleavage of arachidonic acid (AA) from phospholipid membranes by cytosolic phospholipase A2 (cPLA2). The AA is subsequently converted into prostaglandins (PGs) by the cyclooxygenase enzymes. In these experiments we examine the effects of adenovirus (Ad) 5 infection on the expression and activity of cPLA2, COX-2, and the production of PGs. Our experiments reveal multiple complex effects. Ad infection results in the rapid induction of cPLA2 specific AA release, COX-2 expression, and PG production. These effects are initiated before the onset of Ad gene expression, suggesting this is a receptor mediated host cell response. Later, as infection progresses, PG production stops and the cells become unable to produce PGs even in response to a broad range of external stimuli. UV inactivation experiments revealed that Ad gene expression is required for this later suppressive phase. While no effect was seen on cPLA2 activity, and COX-2 was still expressed, we found that infection with Ad causes cPLA2 to shift from its normal cytosolic location to the nuclear region of the cell where it is unable to translocate normally in response to ligand stimulation. We conclude, therefore, that Ad inhibits the production of PGs by causing the intracellular relocation of cPLA2 to a position that prevents its participation in inflammatory responses. These events are accompanied by an Ad induced reorganization of the vimentin containing intermediate filaments. Importantly, cPLA2 and vimentin were found to not only colocalize, but also to directly interact in our model system. These findings suggest that cPLA2 is relocated to the perinuclear region because of its association with vimentin. Importantly, these effects are seen in cells expressing E1A, the early transactivating protein of Ad, suggesting E1A is the viral protein responsible for these effects. As modulation of PGE2 production was also seen with Ad5 infected primary human lung fibroblasts, these effects may influence Ad pathogenesis and immune responsiveness to Ad and Ad derived vectors.
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cPLA2, vimentin, adenovirus
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Degree
PhD
Discipline
Microbiology
