Rho signaling is involved in HIV‐1 Tat‐induced tight junction protein ZO‐1 translocation and alterations of claudin‐5 expression in brain endothelial cells

The blood‐brain barrier (BBB) is the critical structure preventing HIV trafficking into the brain. HIV Tat protein can contribute to the dysfunction of brain microvascular endothelial cells (BMEC) and facilitate HIV entry into the brain. Rho signaling plays an essential role in HIV‐1‐mediated disruption of the BBB integrity. Our data shows that Tat activated RhoA signaling pathway, leading to a decrease in claudin‐5 and ZO‐1 expression. ZO‐1 is known to link the trans‐membrane proteins occudin, claudins, and JAMs to many cytoplasmic proteins and to the actin cytoskeleton. The Rho cascades of small GTPases have gained considerable recognition as powerful regulators of actin cytoskeletal organization. However, the mechanism of Rho signaling, which regulates tight junction assembly, remains unclear. We hypothesize that ZO‐1 serves as a scaffold for signal transduction and organizing Rho signaling molecules with a transmembrane tight junction protein regulates Tat‐mediated tight junction dysfunction. Indeed, we found that Tat increased MLC and ZO‐1 translocation into nuclear as assessed by western blotting, and activate activator protein 1 (AP‐1) transcription factor JunD, resulting in a decrease in membrane tight junction protein claudin‐5 expression in BMEC. Moreover, inhibition of the Rho activation by the C3 exoenzyme blocks Tat‐induced ZO‐1 translocation and claudin‐5 disruption in BMEC. The present data indicates the importance of Rho signaling in regulation of ZO‐1activation modulating the integrity of the BBB in response to Tat exposure.