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The Journal of Neuroscience, July 30, 2008, 28(31):7788-7796; doi:10.1523/JNEUROSCI.0061-08.2008
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Neurobiology of Disease
Caveolin-1 Regulates Human Immunodeficiency Virus-1 Tat-Induced Alterations of Tight Junction Protein Expression via Modulation of the Ras Signaling
Yu Zhong,1 Eric J. Smart,2 Babette Weksler,4 Pierre-Olivier Couraud,5 Bernhard Hennig,3 andMichal Toborek1 1Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, 2Department of Pediatrics, and 3College of Agriculture, University of Kentucky, Lexington, Kentucky 40536, 4Weill Medical College of Cornell University, New York, New York 10021, and 5Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unité 567, 75014 Paris, France
Correspondence should be addressed to Dr. Michal Toborek, Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky Medical Center, 593 Wethington Building, 900 South Limestone, Lexington, KY 40536. Email: michal.toborek{at}uky.edu
The blood–brain barrier (BBB) is the critical structure for preventing human immunodeficiency virus (HIV) trafficking into the brain. Specific HIV proteins, such as Tat protein, can contribute to the dysfunction of tight junctions at the BBB and HIV entry into the brain. Tat is released by HIV-1-infected cells and can interact with a variety of cell surface receptors activating several signal transduction pathways, including those localized in caveolae. The present study focused on the mechanisms of Tat-induced caveolae-associated Ras signaling at the level of the BBB. Treatment with Tat activated the Ras pathway in human brain microvascular endothelial cells (HBMECs). However, caveolin-1 silencing markedly attenuated these effects. Because the integrity of the brain endothelium is regulated by intercellular tight junctions, these structural elements of the BBB were also evaluated in the present study. Exposure to Tat diminished the expression of several tight junction proteins, namely, occludin, zonula occludens (ZO)-1, and ZO-2 in the caveolar fraction of HBMECs. These effects were effectively protected by pharmacological inhibition of the Ras signaling and by silencing of caveolin-1. The present data indicate the importance of caveolae-associated signaling in the disruption of tight junctions on Tat exposure. They also demonstrate that caveolin-1 may constitute an early and critical modulator that controls signaling pathways leading to the disruption of tight junction proteins. Thus, caveolin-1 may provide an effective target to protect against Tat-induced HBMEC dysfunction and the disruption of the BBB in HIV-1-infected patients.
Key words: blood–brain barrier; HIV-1 Tat; Ras; caveolae; caveolin-1; tight junction proteins
Received Jan. 7, 2008; revised June 5, 2008; accepted June 17, 2008.
Correspondence should be addressed to Dr. Michal Toborek, Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky Medical Center, 593 Wethington Building, 900 South Limestone, Lexington, KY 40536. Email: michal.toborek{at}uky.edu
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[Abstract] [Full Text] [PDF]
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