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, 14-3-3tau. 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 14-3-3tau 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.
Nakamuta
Shinichi
S
The Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
Endo
Hiroshi
H
Higashi
Youichiro
Y
Kousaka
Aoi
A
Yamada
Hiroshi
H
Yano
Mihiro
M
Kido
Hiroshi
H
D048948:14-3-3 Proteins / Q000378:metabolism; D015526:AIDS Dementia Complex / Q000378:metabolism / Q000821:virology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply; D002199:Capillary Permeability; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation; D015699:HIV Envelope Protein gp120 / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein
D048948:14-3-3 Proteins; D015699:HIV Envelope Protein gp120; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569046:TJP2 protein, human; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D046988:Proteasome Endopeptidase Complex