HIV-1 Tat triggers nuclear localization of ZO-1 via Rho signaling and cAMP response element-binding protein activation

Yu Zhong, Bei Zhang, Sung Yong Eum, Michal J Toborek

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

The human immunodeficiency virus (HIV)-specific protein trans-activator of transcription (Tat) can contribute to the dysfunction of brain endothelial cells andHIVtrafficking into the brain by disrupting tight junction (TJ) integrity at the blood-brain barrier (BBB) level. Specific TJ proteins, such as zonula occludens (ZO) proteins, localize not only at the cell-cell borders but are also present in the nuclei. The objective of the present study was to evaluate the mechanisms and significance of Tat-induced nuclear localization of ZO-1. Treatment of a brain endothelial cell line (hCMEC/D3 cells) with Tat resulted in a decrease in total levels of ZO-1 but significantly upregulated ZO-1 protein expression in the nuclei. In addition, exposure to Tat stimulated Rho signaling and induced phosphorylation and activity of transcription factorcAMPresponse element-binding protein (CREB), binding sites that have been identified in the proximal region of the ZO-1 promoter. Interestingly, inhibition of the Rho cascade protected against Tat-induced upregulation of ZO-1 in the nuclei and activation of CREB. Depletion of CREB by infection of cells with specific shRNA lentiviral particles attenuated both Tat-induced Rho signaling and nuclear targeting of ZO-1. A decrease in CREB levels also attenuated Tat-induced endothelial and BBB hyperpermeability as well as transendothelial migration of monocytic cells. The role of CREB in Tat-mediated alterations of ZO-1 was confirmed in brain microvessels in mice with CREB shRNA lentiviral particles injected into the cerebral circulation. The present results indicate the crucial role of Rho signaling and CREB in modulation of nuclear localization of ZO-1 and maintaining the integrity of endothelial monolayers.

Original languageEnglish
Pages (from-to)143-150
Number of pages8
JournalJournal of Neuroscience
Volume32
Issue number1
DOIs
StatePublished - Jan 4 2012

Fingerprint

Cyclic AMP Response Element-Binding Protein
Trans-Activators
Tight Junctions
HIV-1
Brain
Blood-Brain Barrier
Zonula Occludens Proteins
Small Interfering RNA
Cerebrovascular Circulation
Endothelial Cells
Zonula Occludens-1 Protein
CREB-Binding Protein
Human Immunodeficiency Virus Proteins
Tight Junction Proteins
Transendothelial and Transepithelial Migration
Microvessels
Up-Regulation
Binding Sites
Phosphorylation
Cell Line

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

HIV-1 Tat triggers nuclear localization of ZO-1 via Rho signaling and cAMP response element-binding protein activation. / Zhong, Yu; Zhang, Bei; Eum, Sung Yong; Toborek, Michal J.

In: Journal of Neuroscience, Vol. 32, No. 1, 04.01.2012, p. 143-150.

Research output: Contribution to journalArticle

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