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J. Biol. Chem., Vol. 277, Issue 38, 35333-35340, September 20, 2002
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From The Burnham Institute, La Jolla, California 92037
PAAD domains are found in diverse proteins
of unknown function and are structurally related to a superfamily of
protein interaction modules that includes death domains, death
effector domains, and Caspase activation and recruitment domains. Using
bioinformatics strategies, cDNAs were identified that encode a
novel protein of 110 kDa containing a PAAD domain followed by a
putative nucleotide-binding (NACHT) domain and several
leucine-rich repeat domains. This protein thus resembles Cryopyrin, a
protein implicated in hereditary hyperinflammation syndromes, and was
termed PAN2 for PAAD and
NACHT-containing protein 2. When expressed in HEK293
cells, PAN2 suppressed NF- The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY072792.
A Novel PAAD-containing Protein That Modulates NF-
B Induction
by Cytokines Tumor Necrosis Factor-
and Interleukin-1
*
,,
B induction by the cytokines tumor
necrosis factor-
(TNF) and interleukin-1
(IL-1), suggesting
that this protein operates at a point of convergence in these two
cytokine signaling pathways. This PAN2-mediated suppression of NF-B
was evident both in reporter gene assays that measured NF-B
transcriptional activity and electromobility shift assays that measured
NF-B DNA binding activity. PAN2 also suppressed NF-B induction
resulting from overexpression of several adapter proteins and protein
kinases involved in the TNF or IL-1 receptor signal transduction,
including TRAF2, TRAF6, RIP, IRAK2, and NF-B-inducing kinase
as well as the IB kinases IKK and IKK. PAN2 also inhibited the
cytokine-mediated activation of IKK and IKK as measured by
in vitro kinase assays. Furthermore, PAN2 association with IKK was demonstrated by co-immunoprecipitation assays, suggesting a
direct effect on the IKK complex. These observations suggest a role for
PAN2 in modulating NF-B activity in cells, thus providing the
insights into the potential functions of PAAD family proteins and their
roles in controlling inflammatory responses.
*
This work was supported by the American-Italian Cancer
Foundation, the Austrian Science Foundation (Grant
J1809-Gen/J1990-Gen), the National Science Foundation (Grant
DBI-0078731), the Department of Defense Breast Cancer Research Program
(Grants DAMD17-00-1-0169 and BC001191), and the Gulbenkian Foundation
PGDBM (Program PRAXIS XXI A.T.T.).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.
Both authors contributed equally to this work.
§
To whom correspondence should be addressed: The Burnham Institute,
10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3132; Fax:
858-646-3194; jreed{at}burnham.org.
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