|
|
|
|
|
|
|
|
|||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
Journal of Cell Science, Vol 110, Issue 22 2883-2893, Copyright © 1997 by Company of Biologists
JOURNAL ARTICLES |
F Bachelerie, MS Rodriguez, C Dargemont, D Rousset, D Thomas, JL Virelizier and F Arenzana-Seisdedos
Unite d'Immunologie Virale, Institut Pasteur, Paris, France.
De novo synthesized IkappaBalpha accumulates transiently in the nucleus where it inhibits NF-kappaB-dependent transcription and reduces nuclear NF-kappaB content. A sequence present in the C-terminal domain of IkappaBalpha and homologous to the HIV-1 Rev nuclear export signal (NES) has been recently defined as a functional NES conferring on IkappaBalpha the ability to export IkappaBalpha/NF-kappaB complexes. Rev utilises its RNA-binding activity and NES sequence to promote specifically the transport of unspliced and monospliced viral RNAs to the cytoplasm. The object of this work was to determine if nuclear IkappaBalpha could interfere with Rev-dependent transport of viral RNA from the nucleus to the cytoplasm. We report that accumulation of IkappaBalpha in the cell nucleus blocks viral replication. This effect could be dissociated from the capacity of IkappaBalpha to inhibit NF-kappaB-DNA-binding activity and required a functional IkappaBalpha NES motif. Indeed, mutation of the NES abrogated the capacity of IkappaBalpha to inhibit Rev-dependent mechanisms involved in the replication of either wild-type or NF-kappaB-mutated HIV-1 molecular clones. Nuclear accumulation of a reporter protein tagged with a nuclear localization signal (NLS) and fused to the IkappaBalpha NES motif (NLS-PK-NES) was sufficient to inhibit HIV-1 replication at a post-transcriptional level by specifically blocking the expression of a Rev-dependent gene. Furthermore, in cells pulsed with TNF, a treatment which favors nuclear accumulation of newly synthesized IkappaBalpha, NLS-PK-NES expression promoted sustained accumulation of nuclear NF-kappaB lacking DNA-binding activity. This NES-mediated accumulation of inactive nuclear NF-kappaB is likely the consequence of interference in the IkappaBalpha-mediated export of NF-kappaB. These findings indicate that IkappaBalpha and Rev compete for the same nuclear export pathway and suggest that nuclear accumulation of IkappaBalpha, which would occur during normal physiological cell activation process, may interfere with the Rev-NES-mediated export pathway of viral RNAs, thus inhibiting HIV-1 replication.
This article has been cited by other articles:
|
|
 |
|
  A. Puca, G. Fiume, C. Palmieri, F. Trimboli, F. Olimpico, G. Scala, and I. Quinto I{kappa}B-{alpha} Represses the Transcriptional Activity of the HIV-1 Tat Transactivator by Promoting Its Nuclear Export J. Biol. Chem., December 21, 2007; 282(51): 37146 - 37157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Burton, C. D. Upadhyaya, B. Maier, T. J. Hope, and O. J. Semmes Human T-Cell Leukemia Virus Type 1 Tax Shuttles between Functionally Discrete Subcellular Targets J. Virol., March 1, 2000; 74(5): 2351 - 2364. [Abstract] [Full Text]
|
|
|
|
|
|
L. Chêne, M.-T. Nugeyre, F. Barré-Sinoussi, and N. Israël High-Level Replication of Human Immunodeficiency Virus in Thymocytes Requires NF-kappa B Activation through Interaction with Thymic Epithelial Cells J. Virol., March 1, 1999; 73(3): 2064 - 2073. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. Li, H. Tang, T.-M. Mullen, C. Westberg, T. R. Reddy, D. W. Rose, and F. Wong-Staal A role for RNA helicase A in post-transcriptional regulation of HIV type 1 PNAS, January 19, 1999; 96(2): 709 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Prigent, I. Barlat, H. Langen, and C. Dargemont Ikappa Balpha and Ikappa Balpha /NF-kappa B Complexes Are Retained in the Cytoplasm through Interaction with a Novel Partner, RasGAP SH3-binding Protein 2 J. Biol. Chem., November 10, 2000; 275(46): 36441 - 36449. [Abstract] [Full Text] [PDF]
|
|
