From the Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN), Koyadai 3-1, Tsukuba, Ibaraki 305-0074, Japan
Received for publication, February 7, 2001, and in revised form, February 24, 2001
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ABSTRACT |
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We isolated a novel gene termed
interleukin (IL)-1-inducible nuclear ankyrin-repeat protein
(INAP), of which expression was specifically induced by IL-1 in OP9
stromal cells. The INAP has ankyrin-repeat motifs and shares weak amino
acid sequence homology with Bcl-3 and other I NF- I Unlike the other I Here we identified a novel I Isolation of INAP cDNA--
OP9 cells were cultured in
Northern Blot Analysis--
Total mRNAs from OP9 cells
stimulated with 10 ng/ml of mouse IL-1 Preparation of Glutathione S-Transferase (GST)-INAP and
Anti-INAP Antibody--
The INAP cDNA (amino acids 108 to 403) was
ligated into pGEX2T and expressed in Escherichia coli
BL21(DE3) pLysS cells. Rabbit antiserum was raised against GST-INAP,
and the polyclonal antibody was purified by GST-INAP affinity chromatography.
Indirect Immunofluorescence Staining of OP9 Cells--
Cells on
coverslips were fixed with 3% formaldehyde and 0.2% Triton X-100 for
15 min. The cells were blocked with 5% FCS in PBS and incubated with
purified anti-INAP-specific rabbit antibody. The cells were then
reacted with Cy3-conjugated F(ab')2 fragment donkey
anti-rabbit antibody (Jackson ImmunoResearch Laboratories) and 1 mg/ml
4,6-diamidino-2-phenylindole (DAPI). The coverslips were mounted in PBS
containing 90% glycerol and 0.1% 1,4-para-phenylene diamine and were
observed under a fluorescence microscope (Olympus BX60-34-FLBD1).
Immunoblot Analysis--
Cells were sonicated in 20 mM Hepes, pH 7.4, 1 mM EDTA, 0.1 mM
EGTA, 2 mM MgCl2, 1 mM
Na3VO4, 20 mM NaF, 150 mM NaCl, 5% glycerol, 0.2% Nonidet P-40, 1 µg/ml
pepstatin A, 1 µg/ml aprotinin, 5 µg/ml leupeptin, and 5 µg/ml
Pefabloc SC. Samples were fractionated by 10% SDS-PAGE and
electrotransferred to an ECL membrane. The membrane was blocked with
5% milk in 20 mM Tris-HCl, pH 7.5, 150 mM
NaCl, and 0.5% Tween 20, incubated with anti-INAP-specific rabbit
antibody for 2 h, and then incubated with horseradish
peroxidase-conjugated F(ab')2 fragment donkey
anti-rabbit antibody. The antibody complexes were visualized by an ECL
system (Amersham Pharmacia Biotech).
Isolation and Structure of INAP--
We attempted to isolate the
genes of which transcriptions were induced by IL-1 in mouse stromal OP9
cells. Subtraction of mRNAs of OP9 cells before and after IL-1
stimulation led to the isolation of a number of cDNA fragments
encoding factors related to the IL-1 response. Among them, we focused
on a novel gene, termed INAP. The isolated mouse full-length INAP
cDNA (2339 bp) contained an open reading frame, which encoded a
polypeptide of 728 amino acids with a calculated molecular mass of
79,007 daltons and a predicted pI of 6.45. A search in the NCBI data
base using the BLAST program revealed that a human genomic sequence
(map element NT_022504) of chromosome 3 contained the human INAP gene, which consists of 12 exons and is located at chromosome 3q13.11. Human
INAP constituted of 718 amino acids has a predicted molecular mass of
78,061 daltons. Human INAP has 82% amino acid identity and 85%
similarity with mouse INAP and has a 10-amino acid deletion at amino
acid 301-310 compared with mouse sequences.
Fig. 1A shows the schematic
drawings of the isolated mouse INAP cDNA and of the human genomic
INAP gene found in the NCBI data base. Mouse and human INAP were found
to be weakly homologous to the I
To examine the relationship of INAP to other members of the I INAP Expression Is Rapidly and Specifically Induced by IL-1
Stimulation--
Expression of INAP in various mouse tissues was
examined by Northern blot analyses, but no INAP mRNA was detectable
in any tissues examined because of its sparse expression (data not
shown). Therefore, we examined INAP expression in OP9 cells at various time points after IL-1
The expression of mouse INAP in the protein level was examined by
immunoblot analyses with a purified anti-INAP-specific rabbit antibody.
As shown in Fig. 3A, mouse
INAP of 79 and 82 kDa were clearly detected in IL-1
The double bands were clearly recognized by anti-INAP antibody, and
thus we speculated that the upper band might be the phosphorylated form
of the lower band. The INAP was therefore immunoprecipitated with its
specific antibody from the nuclear extracts, as well as the cytosolic
extracts, which were prepared from OP9 cells treated with or without
IL-1 INAP Is Rapidly Translocated into the Nucleus--
Subcellular
localization of INAP in OP9 cells with or without IL-1
To confirm these findings, FLAG-tagged INAP and HA-tagged INAP were
transiently expressed in mouse fibroblast NIH/3T3 cells. Fig.
4B shows that FLAG-tagged INAP was clearly detected only in
the nucleus of the transfected cells by anti-FLAG antibody (stained in
green; left panel). The chromosomes stained with
DAPI in blue (right panel) were completely
overlapped with INAP stained in green (left
panel) in transfectants. Similarly, HA-tagged INAP was also
localized in the nucleus (data not shown). Taken together, these
results clearly indicate that INAP was promptly translocated into the
nucleus after INAP protein synthesis was induced by IL-1 stimulation.
We isolated a novel IL-1-inducible nuclear factor, INAP, which is
related to the I INAP was found to be a novel nuclear factor related to the I A few potential NF-B family members. The
human genomic INAP gene found in the NCBI data base is located
at chromosome 3q3.11. Northern blot analyses revealed that INAP was not
expressed in any examined tissues without stimulation, but INAP
expression was rapidly and transiently induced by IL-1 although not by
tumor necrosis factor
nor by phorbol 12-myristate 13-acetate in OP9 cells. Immunoblots with anti-INAP-specific antibody demonstrated that
INAP was rapidly and specifically produced by IL-1 stimulation and was
predominantly localized in the nucleus. Immunofluorescence stainings
showed that the INAP newly synthesized by IL-1 stimulation was promptly
translocated into the nucleus, and FLAG-tagged INAP forcibly expressed
in NIH/3T3 cells was also specifically localized in the nucleus. The
possible interaction of INAP with RelA/p65, NF-
B1/p50, NF-
B2/p52,
C/EBP
, and retinoid X receptor was examined, but we could detect
none of these interactions in the nuclear extracts of IL-1-stimulated
cells. Unlike Bcl-3 and other I
B family members, INAP may play a
unique role in IL-1-induced specific gene expression and/or signal
transduction in the nucleus.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
B is a transcription factor that is known to play an
important role in regulating immune and inflammatory responses (1-3). There are presently five members of the mammalian NF-
B/Rel family, NF-
B1/p50, NF-
B2/p52, c-Rel, RelA/p65, and RelB (1-3). The classic form of NF-
B, the heterodimer of the NF-
B1/p50 and
RelA/p65, is normally retained in the cytoplasm through interactions
with inhibitor protein I
B. The I
B family of proteins includes
I
B
, I
B
, I
B
, Bcl-3, NF-
B1/p105, and NF-
B2/p100,
all of which possess 5-7 ankyrin-repeat motifs (1-3), which form a
functional unit able to interact with the Rel homology domain of
NF-
B. The cytoplasmic retention of the classic form of NF-
B is
primarily carried out by I
B
and I
B
(4-7). Inductive
stimuli, such as tumor necrosis factor
(TNF
),1 interleukin-1
(IL-1), and bacterial endotoxin, lead to the phosphorylation and
degradation of I
B, allowing NF-
B to translocate into the nucleus
and regulate specific gene expression (1-3).
B
is degraded in response to the NF-
B inducers TNF
, IL-1,
lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA), and
double-stranded RNA. In contrast, I
B
is degraded only when cells
are stimulated with IL-1 or LPS, both of which cause persistent long
term activation of NF-
B (4-7). Following degradation of the initial
pool of I
B
in response to IL-1 or LPS, newly synthesized I
B
accumulates as an unphosphorylated protein that forms a stable complex
with NF-
B and prevents it from binding to newly synthesized I
B
(4-7), resulting in the prolonged activation of NF-
B (4, 8). This
unphosphorylated I
B
cannot block the nuclear localization signal
of NF-
B, thus this NF-
B·I
B
complex translocates
into the nucleus. The function of this complex in the nucleus is yet to
be elucidated, and the mechanism by which only IL-1 and LPS can degrade
I
B
remains to be resolved.
B family members, Bcl-3 is a nuclear protein
(9-11). It does not bind to RelA/p65 but specifically binds to
NF-
B1/p50 or NF-
B2/p52 homodimers (10, 12-14) and takes them
into the nucleus where it exhibits transactivating activity (11, 15).
The formation of Bcl-3·(NF-
B1/p50)2·
B
complex or Bcl-3·(NF-
B2/p52)2·
B complex is
regulated by the phosphorylation status of Bcl-3 (14, 16). Bcl-3 also
interacts with retinoid X receptor (RXR) or activating protein-1 (AP-1)
and functions as their transcription coactivator (17, 18). However, the detailed characters of this unique I
B family member remain mysterious.
B family member, termed IL-1-inducible
nuclear ankyrin-repeat protein (INAP), of which expression is
specifically induced by IL-1. INAP was found to be weakly homologous to
Bcl-3 and localized in the nucleus like Bcl-3. We discuss here the
possible function of this novel I
B family member.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-minimum Eagle's medium supplemented with 20% fetal calf
serum (FCS) with or without 10 ng/ml of mouse IL-1
(Genzyme/Techne)
in the presence of 10 µg/ml of cycloheximide for 1 h, and total
mRNA was isolated. The PCR-Select cDNA subtraction kit
(CLONTECH) was used for cDNA synthesis and suppressive subtractive hybridization, according to the manufacturer's instructions. The cDNA from OP9 cells incubated with IL-1
was used as the tester sample, and that from untreated cells was used as
the driver sample. The 5' end of INAP cDNA was confirmed by the
rapid amplification of the cDNA ends (5' RACE) method.
, 20 ng/ml of mouse TNF
(Genzyme/Techne), or 100 ng/ml of PMA (Sigma) for the indicated period
of time were isolated. Total mRNA (20 µg/lane) was resolved on a
1% agarose gel and transferred to a Hybond-N+ membrane.
The filters were hybridized with the digoxigenin (DIG)-labeled INAP
cDNA probe (nucleotides 838-1368) at 42 °C for 16 h in DIG Easy Hyb solution (Roche Diagnostics). After washing at 68 °C for 30 min in 1 × SSC containing 0.2% SDS, the hybridized bands were
detected by chemiluminescent detection using CDP-StarTM
substrate (Roche Diagnostics).
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
B family and the Rel family. The
most striking feature of mouse and human INAP is that both INAP contain
five highly conserved ankyrin-repeat motifs in carboxyl-terminal
regions. Using PESTFIND software, it was also found that both INAP have PEST (P, E, D, S, and T
residue-rich)-like sequences, which are implicated in the rapid
turnover of proteins (19). Although I
B
and I
B
have PEST
sequences in carboxyl-terminal ends, both mouse and human INAP have
them at amino-terminal regions (amino acids 11-84 and 185-203 in
mouse and 184-204 in human). A serine-rich region was also found in
amino-terminal regions (amino acids 53-77 in mouse and 51-86 in
human), and a glutamine-rich region was found in the middle regions
(amino acids 245-308 in mouse and 247-299 in human). However, the
glycine-rich region, Rel homology domain, or obvious nuclear
localization signal, which commonly exist in the Rel family, was not
found in INAP. Reinhardt's method (20) for cytoplasmic or nuclear
discrimination predicted that there is a 94% possibility that INAP is
localized in the nucleus.
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Fig. 1.
Structure of INAP. A,
schematic drawings of mouse full-length INAP cDNA
(mINAP) and of the human genomic INAP gene
(hINAP). The locations of the serine-rich region,
glutamine-rich region, PEST-like sequences, and ankyrin-repeat motifs
are indicated. B, phylogenetic tree of INAP and its related
proteins. The phylogenetic tree was constructed by the neighbor-joining
method using ClustalX 1.8 based on the alignment and visualized with
the Treeview program 1.6.1. Species abbreviations are as follows:
h, Homo sapiens; m, Mus
musculus; r, Rattus norvegicus;
b, Bos taurus; and s, Sus
scrofa.
B and
Rel families, a phylogenetic tree was constructed using the amino acid
sequences of all known mammalian I
B and Rel families (Fig.
1B). The closest protein of INAP turned out to be Bcl-3, and
the second closest was I
B
. Mouse INAP has 30-33% identity and
36-38% similarity with human Bcl-3 and mouse Bcl-3. Mouse INAP has
26-29% identity and 33-36% similarity with those of the other I
B
family members and has 22-35% identity and 22-41% similarity with
those of Rel family members.
stimulation (Fig.
2, right panel). Although no
INAP mRNA was detected in unstimulated OP9 cells (Fig. 2,
right panel, lane 1), a single hybridized band
was weakly detected 15 min after IL-1
stimulation (lane
2). The level of INAP mRNA increased and reached the
maximum at 1 h after IL-1
stimulation (lane 4) and
then decreased thereafter (lanes 5, 6), indicating that the INAP gene was rapidly and transiently transcribed after IL-1
stimulation in OP9 cells. IL-1
also exhibited the same effect on
INAP expression (data not shown). Similarly, INAP expression after
TNF
or PMA stimulation was examined, but no transcript was detected
(Fig. 2, left and middle panels) although OP9
cells are responsive to TNF
and PMA, indicating that INAP
transcription was specifically induced by IL-1 stimulation.
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Fig. 2.
INAP transcripts were specifically induced by
IL-1. Northern blot analysis of INAP mRNA expression in OP9
cells is shown. OP9 cells were treated with TNF (left
panel), PMA (middle panel), or IL-1
(right
panel) for the indicated time period, and total mRNA (20 µg/lane) blotted on the filters was hybridized with
DIG-labeled INAP cDNA probe.
(right
panel)- but not TNF
(left panel)- or PMA
(middle panel)-stimulated OP9 cells, confirming that INAP expression was specifically induced by IL-1
. The double bands were
clearly detected within 30 min after IL-1
stimulation (Fig. 3A, right panel, lane 2), although
they were not seen in the cells without stimulation (lane
1). Although INAP transcripts were transiently expressed, the
protein level increased until 1 h after IL-1
stimulation and
retained its level even 24 h after stimulation (lanes
3-5), suggesting that the newly synthesized INAP is relatively
stable and accumulates in the cells. We also detected human INAP in
IL-1
-stimulated HeLa cell extracts by the same antibody (data not
shown).
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Fig. 3.
Immunoblot analyses of INAP.
A, INAP protein was specifically produced by IL-1
stimulation. OP9 cells were treated with TNF (left
panel), PMA (middle panel), or IL-1
(right
panel) for the indicated time period, and total cell extract (100 µg/lane) blotted on the filters was reacted with purified
anti-INAP-specific rabbit antibody. Arrows indicate double
bands of INAP. Location and size (in kDa) of protein standards are
shown at the left. B, INAP was not phosphorylated
and was localized in the nucleus. OP9 cells were treated with (+) or
without (
) IL-1, and nuclear extracts and cytosolic extracts were
prepared. The INAP was immunoprecipitated with purified
anti-INAP-specific rabbit antibody, treated (+) or untreated (
) with
CIP, and separated by SDS-PAGE. The blotted proteins were reacted with
anti-INAP rabbit antibody. Arrows indicate double bands of
INAP.
. The immunoprecipitates were treated with calf intestine
alkaline phosphatase (CIP), separated by SDS-PAGE, and immunoblotted
with anti-INAP antibody. The results demonstrated that INAP was
predominantly detected in the nuclear extracts and that the double
bands were not affected by phosphatase treatment (Fig. 3B),
indicating that INAP was not phosphorylated and that subcellular
localization of INAP was not affected by its phosphorylation status. We
therefore concluded that the upper band was not the phosphorylated form
of the lower band. We further noticed that the INAP has a second Met
codon at amino acid 26, and thus the lower band may be the protein
product translated from this second Met codon.
stimulation
for 1 h was examined by indirect immunofluorescence microscopic
analysis, and the fluorescent images were overlaid on difference
interference contrast images (Fig.
4A). The INAP stained
with purified anti-INAP-specific antibody in red were predominantly detected in the nuclei of OP9 cells treated with IL-1
for 1 h (Fig. 4A, left lower panel), whereas
it was rarely seen in the cells prior to IL-1
stimulation
(left upper panel). The chromosomes stained with DAPI in
blue (right lower panel) were completely
overlapped with INAP stained in red (left lower panel). These results clearly demonstrated that newly synthesized INAP was promptly translocated into the nucleus by IL-1
stimulation in OP9 cells. Furthermore, we found that IL-1 stimulated the production of INAP in various mouse organs including spleen, small intestine, lung, liver, heart, and kidney and that INAP was always localized in
nucleus in these IL-1-stimulated tissues (data not shown). Thus,
IL-1-specific INAP expression and its nuclear localization are not
specific events observed only in OP9 cells.
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Fig. 4.
Newly synthesized INAP was translocated into
the nucleus. A, OP9 cells stimulated
(lower panels) or unstimulated (upper panels)
with IL-1 for 1 h were stained with anti-INAP-specific rabbit
antibody followed by Cy3-conjugated F(ab')2 fragment donkey
anti-rabbit antibody (left panels). The nuclei (chromosomes)
of the same cells were also stained with DAPI (right
panels). Fluorescent images are overlaid on difference
interference contrast images. The INAP in the nucleus is shown in
red, and chromosomes are shown in blue.
B, NIH/3T3 cells expressing FLAG-tagged INAP were stained
with anti-FLAG mouse monoclonal antibody followed by fluorescein
isothiocyanate-labeled F(ab')2 fragment goat anti-mouse
antibody. The FLAG-INAP in the nucleus is shown in green,
and chromosomes are shown in blue.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
B family and the Rel family. It is well known that
I
B family members bind to the RelA/p65·NF-
B1/p50 complex and
prevents the complex from activating and translocating into the
nucleus. Therefore, possible interaction of INAP with the
RelA/p65·NF-
B1/p50 complex was examined by immunoprecipitation followed by immunoblot analysis. However, we failed to detect the
direct and/or indirect binding of INAP to RelA/p65 (data not shown).
Furthermore, one of the most important factors induced by IL-1
stimulation is IL6, of which gene expression is regulated by C/EBP
(NF-IL6), AP-1, and NF-
B (21, 22). Therefore, we also examined the
possible interactions of INAP with C/EBP
and c-Fos/c-Jun in nuclear
extracts prepared from IL-1
-stimulated OP9 cells. Once again, we
could not detect the interactions of INAP with C/EBP
or with
c-Fos/c-Jun (data not shown). Moreover, the fact that Bcl-3, the
protein most closely related to INAP, associates NF-
B1/p50 or
NF-
B2/p52 homodimers and modulates their transactivation activities
(11, 16) motivated us to examine whether INAP associates with
NF-
B1/p50 or NF-
B2/p52 in IL-1-stimulated nucleus. None of these
interactions, however, was detected by immunoprecipitation followed by
immunoblot analysis (data not shown). It has also been reported that
Bcl-3 binds to RXR (17) or to AP-1 (18) and regulate specific gene
expression, and thus we also examined the possible interactions of INAP
with RXR or with AP-1 but failed to detect the bindings (data not
shown). We concluded that INAP could not bind to any of the binding
partners with which Bcl-3 has been reported to interact and that INAP
is a very unique protein in the I
B family and is clearly distinct even from the most closely related I
B family member, Bcl-3. To determine the biological function of INAP on IL-1 signalings it is very
important to identify the INAP-binding proteins in the IL-1-stimulated
nucleus by other means such as yeast two-hybrid screening, pull-down
experiments, and far-Western screening.
B
family, but by IL-1 stimulation INAP was newly produced and accumulated
in the nucleus, rather than being degraded as were other I
B family
members. From a gene expression point of view, INAP is quite a distinct
protein from these family members. There exists no obvious nuclear
localization signal in INAP, but it does exist in the nucleus.
Furthermore, INAP was not phosphorylated no matter whether it
was localized in the cytoplasm or nucleus, indicating that the
phosphorylation status of INAP does not affect its subcellular localization.
B binding sites were found around
340 bp
upstream from the initiation codon in human INAP gene promoter regions.
However, we demonstrated that INAP gene expression was rapidly induced
by IL-1 but not by TNF
nor by PMA, all of which are known to
activate the NF-
B signaling pathway. Thus, INAP gene expression is
not simply regulated by NF-
B signaling. IL-1- and LPS-specific
persistent activation of NF-
B has been reported (4, 5), but rapid
IL-1- (and LPS-) specific INAP gene expression cannot be explained by
this mechanism. The mechanism is thus obscure at this moment, and
further analyses are required.
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FOOTNOTES |
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* 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.
The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBankTM/EBI Data Bank with accession number(s) AB026551.
Present address: Dept. of Biological Sciences, Tokyo Inst. of
Technology, Yokohama, Japan.
§ To whom correspondence should be addressed. Tel.: 81-298-36-9075; Fax: 81-298-36-9090; E-mail: todokoro@rtc.riken.go.jp.
Published, JBC Papers in Press, March 2, 2001, DOI 10.1074/jbc.C100075200
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ABBREVIATIONS |
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The abbreviations used are:
TNF, tumor
necrosis factor
;
IL-1, interleukin-1;
PMA, phorbol 12-myristate
13-acetate;
DAPI, 4,6-diamidino-2-phenylindole;
LPS, lipopolysaccharide;
RXR, retinoid X receptor;
GST, glutathione
S-transferase;
PAGE, polyacrylamide gel electrophoresis;
PBS, phosphate-buffered saline;
AP-1, activating protein-1;
INAP, IL-1-inducible nuclear ankyrin-repeat protein;
FCS, fetal calf serum;
DIG, digoxigenin;
ECL, enhanced chemiluminescence;
bp, base pair;
CIP, calf intestine alkaline phosphatase;
HA, hemagglutinin.
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