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J. Biol. Chem., Vol. 276, Issue 5, 3183-3187, February 2, 2001
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From the Center for Apoptosis Research and the Department of
Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson
University, Philadelphia, Pennsylvania 19107
vCLAP, the E10 gene product of equine
herpesvirus-2, is a caspase-recruitment domain (CARD)-containing
protein that has been shown to induce both apoptosis and NF-
vCLAP, a Caspase-recruitment Domain-containing Protein of Equine
Herpesvirus-2, Persistently Activates the I
B Kinases through
Oligomerization of IKK
*
,§, and
B
activation in mammalian cells. vCLAP has a cellular counterpart,
Bcl10/cCLAP, which is also an activator of apoptosis and
NF-B. Recent studies demonstrated that vCLAP activates NF-B
through an IB kinase (IKK)-dependent pathway, but
the underlying mechanism remains unknown. In this report, we
demonstrate that vCLAP associates stably with the IKK complex through
direct binding to the C-terminal region of IKK
. Consistent with this
finding, IKK was found to be essential for vCLAP-induced NF-B
activation, and the association between vCLAP and the IKK complex
induced persistent activation of the IKKs. Moreover, enforced
oligomerization of the isolated C-terminal region of vCLAP, which
interacts with IKK, can trigger NF-B activation. Finally,
substitution of the C-terminal region of IKK, which interacts with
vCLAP, with the CARD of vCLAP or Bcl10 produced a molecule that
was able to activate NF-B when ectopically expressed in
IKK-deficient cells. These data suggest that vCLAP-induced oligomerization of IKK, which is mediated by the CARD of vCLAP, could be the mechanism by which vCLAP induces activation of
NF-B.
*
This work was supported by National Institutes of Health
Grant CA85421 (to E. S. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Contributed equally to this work.
¶
Special fellow of the Leukemia and Lymphoma Society.
§
To whom correspondence should be addressed: Thomas Jefferson
University, Kimmel Cancer Inst., Bluemle Life Sciences Bldg., Rm. 904, 233 S. 10th St., Philadelphia, PA 19107. Tel.:
215-503-4632; Fax: 215-923-1098; E-mail:
E_Alnemri@lac.jci.tju.edu.
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