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Molecular and Cellular Biology, September 1999, p. 6345-6354, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Direct Association and Nuclear Import of the
Hepatitis B Virus X Protein with the NF-
B Inhibitor
I
B
Robert
Weil,1
Hüseyin
Sirma,2
Carlo
Giannini,2
Dina
Kremsdorf,2
Christine
Bessia,1
Catherine
Dargemont,3
Christian
Bréchot,2 and
Alain
Israël1,*
Unité de Biologie Moléculaire de
l'Expression Génique, URA 1773 Centre National de la Recherche
Scientifique, Institut Pasteur, 75724 Paris Cedex
15,1 INSERM U370,
Carcinogénèse Hépatique et Virologie
Moléculaire, Institut Necker, 75015 Paris,2 and Laboratoire de Transport
Nucléocytoplasmique, UMR 144 Institut Curie-CNRS, 75231 Paris
Cedex 05,3 France
Received 2 February 1999/Returned for modification 25 March
1999/Accepted 27 May 1999
The X protein of hepatitis B virus (HBV) is a transcriptional
activator which is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. It has been suggested that
X acts as a nuclear coactivator or stimulates several signal transduction pathways by acting in the cytoplasm. One of these pathways
leads to the nuclear translocation of NF-
B. A recent report
indicates that X activates NF-
B by acting on two cytoplasmic inhibitors of this family of transcription factors: I
B
and the precursor/inhibitor p105. We demonstrate here that X directly interacts
with I
B
, which is able to transport it to the nucleus by a
piggyback mechanism. This transport requires a region of I
B
(the
second ankyrin repeat) which has been demonstrated to be involved in
its nuclear import following NF-
B activation. Using deletion
mutants, we showed that amino acids 249 to 253 of I
B
(located in
the C-terminal part of the sixth ankyrin repeat) play a critical role
in the interaction with X. This small region overlaps one of the
domains of I
B
mediating the interaction with the p50 and p65
subunits of NF-
B and is also close to the nuclear export sequence of
I
B
, therefore providing a potential explanation for the nuclear
accumulation of I
B
with X. This association can also be observed
upon the induction of endogenous I
B
by tumor necrosis factor
alpha (TNF-
) treatment of Chang cells expressing X. In accordance
with this observation, band shift analysis indicates that X induces a
sustained NF-
B activation following TNF-
treatment, probably by
preventing the reassociation of newly synthesized nuclear I
B
with
DNA-bound NF-
B complexes.
*
Corresponding author. Mailing address: Unité de
Biologie Moléculaire de l'Expression Génique, URA 1773 CNRS, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33 1 45 68 85 53. Fax: 33 1 40 61 30 40. E-mail:
aisrael{at}pasteur.fr.
Molecular and Cellular Biology, September 1999, p. 6345-6354, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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