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Molecular and Cellular Biology, September 1999, p. 6345-6354, Vol. 19, No. 9
Unité de Biologie Moléculaire de
l'Expression Génique,
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-
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
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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