Caveolin-1 regulates human immunodeficiency virus-1 Tat-induced alterations of tight junction protein expression via modulation of the ras signaling

Yu Zhong, Eric J. Smart, Babette Weksler, Pierre Olivier Couraud, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7788-7796
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number31
DOIs
StatePublished - Jul 30 2008
Externally publishedYes

Keywords

  • Blood-brain barrier
  • Caveolae
  • Caveolin-1
  • HIV-1 Tat
  • Ras
  • Tight junction proteins

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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