Human immunodeficiency virus type 1 gp120-mediated disruption of tight junction proteins by induction of proteasome-mediated degradation of zonula occludens-1 and -2 in human brain microvascular endothelial cells
The infiltration of human immunodeficiency virus (HIV)-1, such as by HIV-infected leukocytes, across an injured blood-brain barrier (BBB) is a characteristic pathologic manifestation of HIV-1—associated dementia. HIV-1 gp120 has been implicated as a cause of breakdown of tight junctions between endothelial cells of the BBB, though the disrupting molecular mechanisms are unexplained. This study offers a new explanation for the increased BBB microvascular permeability, due to the degradation of tight junction proteins by the proteasome induced by gp120, and the negative regulation of this process by the scaffold protein, 14-3-3τ. gp120 reduced the amount of zonula occludens (ZO)-1 and ZO-2 in human brain microvascular endothelial cells (HBMECs). The treatment of HBMECs with the proteasome inhibitor, lactacystin, blocked the degradation of ZO-1 and ZO-2, suggesting that these proteins were targeted by gp120 for degradation by the proteasome. gp120 also specifically increased the expression of 14-3-3τ in HBMECs, and its down-regulation by RNAi facilitated the breakdown of tight junction proteins induced by gp120. Our results demonstrate the novel molecular mechanisms of the BBB breakdown by gp120.
Keywords14-3-3 protein HIV-1 gp120 HIV-1—associated dementia proteasome tight junction protein
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- Arese M, Ferrandi C, Primo L, Camussi G, Bussolino F (2000). HIV-1 Tat protein stimulates in vivo vascular permeability and lymphomononuclear cell recruitment. J Immunol 166: 1380–1388.Google Scholar
- Price RW, Perry SW (1994). HIV, AIDS, and brain. New York: Raven Press.Google Scholar
- Zerr I, Bodemer M, Gefeller O, Otto M, Poser S, Wiltfang J, Windl O, Kretzschmar HA, Weber T (2000). Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 43: 683–684.Google Scholar