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Rho signaling is involved in HIV‐1 Tat‐induced dysfunction of brain endothelial cells and alterations of claudin‐5 expression
Author(s) -
Zhong Yu,
Couraud PierreOlivier,
Hennig Bernhard,
Toborek Michal
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.734.12
Subject(s) - rhoa , microbiology and biotechnology , cdc42 , rac1 , tight junction , signal transduction , blood–brain barrier , cytoskeleton , pak1 , gtpase , phosphorylation , small gtpase , rock1 , gtpase activating protein , claudin , chemistry , actin , biology , cell , g protein , neuroscience , central nervous system , biochemistry
The blood‐brain barrier (BBB) is the critical structure preventing HIV trafficking into the brain. Specific HIV proteins, such as Tat, can contribute to the dysfunction of brain microvascular endothelial cells (BMEC) and facilitate HIV entry into the brain. The Rho cascades of small GTPases (RhoA, Rac1 and Cdc42) have gained considerable recognition as powerful regulators of actin cytoskeletal organization. In addition, the Rho pathway is critical for the integrity of the BBB. Therefore, the present study was focused on the effects of Tat on the Rho signaling. Treatment with Tat markedly increased membrane RhoA levels in human BMEC, while the total level of RhoA was not changed. Tat also elevated GTP‐RhoA levels as assessed by the pull‐down assay. Moreover, we found that Tat increased ROCK phosphorylation. Because integrity of the brain endothelium is regulated by tight junctions, these structural elements of the BBB were also evaluated in the present study. Most interestingly, Tat induced a decrease in claudin‐5 expression by a Rho‐dependent mechanism. Indeed, inhibition of the Rho signaling by the C3 exoenzyme blocked Tat‐induced disruption of claudin‐5 expression in human BMEC. The present data indicate the importance of the Rho signaling in disruption of the integrity of the BBB in response to Tat exposure. Supported by NS39254, MH63022, and MH072567.