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Zhong, Y, Zhang, B, Eum, SY and Toborek, M (2012) HIV-1 Tat triggers nuclear localization of ZO-1 via Rho signaling and cAMP response element-binding protein activation. J. Neurosci. 32:143-50


The human immunodeficiency virus (HIV)-specific protein trans-activator of transcription (Tat) can contribute to the dysfunction of brain endothelial cells and HIV trafficking 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 factor cAMP response 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.


PubMed PMC3566645 Online version:10.1523/JNEUROSCI.4266-11.2012


Animals; Blood-Brain Barrier/metabolism; Blood-Brain Barrier/virology; Cell Nucleus/metabolism; Cell Nucleus/virology; Cyclic AMP Response Element-Binding Protein/metabolism; Endothelial Cells/cytology; Endothelial Cells/metabolism; Endothelial Cells/virology; HEK293 Cells; HIV-1/physiology; Humans; Male; Membrane Proteins/metabolism; Mice; Mice, Inbred C57BL; Phosphoproteins/metabolism; Primary Cell Culture; Signal Transduction/physiology; Zonula Occludens-1 Protein; rho GTP-Binding Proteins/physiology; tat Gene Products, Human Immunodeficiency Virus/physiology



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:1900182: positive regulation of protein localization to nucleus



Figure 1C indicates that the tat protein triggers the ZO-1 protein localization to the nucleus. This is shown by significantly increased ZO-1 expression in the nucleus of adenovirus-infected hCMEC/D3 cells depicted in the bar graph in Figure 1C.

CACAO 6531



GO:1900182: positive regulation of protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion


Seeded From UniProt


See also


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