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*
Department of Immunology, Berlex Biosciences, Richmond CA 94804;
Department of Pharmacology, University of Illinois, Chicago, IL 60612; and
Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Pushchino, Moscow Region, Russia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RßL) was used as bait in a yeast two-hybrid system
to identify novel proteins interacting with this region of the
receptor. We report here a specific interaction between the cytoplasmic
domain of IFN-RßL and a previously identified protein, RACK-1
(receptor for activated C kinase). Using GST fusion proteins encoding
different regions of the cytoplasmic domain of IFN-RßL, the
minimum site for RACK-1 binding was mapped to aa 300–346. RACK-1
binding to IFN-RßL did not require the first 91 aa of RACK-1,
which includes two WD domains, WD1 and WD2. The interaction between
RACK-1 and IFN-RßL, but not the human IFN receptor chain 1 (IFNAR1
or IFN-R), was also detected in human Daudi cells by
coimmunoprecipitation. RACK-1 was shown to be constitutively associated
with IFN-RßL, and this association was not effected by stimulation
of Daudi cells with type I IFNs (IFN-ß1b). RACK-1 itself did not
become tyrosine phosphorylated upon stimulation of Daudi cells with
IFN-ß1b. However, stimulation of cells with either IFN-ß1b or PMA
did result in an increase in detectable immunofluorescence and
intracellular redistribution of RACK-1. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß receptor heterodimerization leads to activation of two
members of the Janus kinase family, Tyk2 and JAK-1, that catalyze
receptor tyrosine phosphorylation. All STAT proteins contain Src
homology 2 (SH2)4 domains that
specifically recognize and bind to phosphorylated tyrosine residues
located within the cytoplasmic domain of cytokine receptor chains
(4, 5). After recruitment to the receptor complex, STAT
proteins become phosphorylated on a specific C-terminal tyrosine, homo-
or heterodimerize, translocate to the nucleus, and induce transcription
of specific genes. In addition to tyrosine phosphorylation,
serine/threonine phosphorylation has been shown to be important in
mediating signaling, regulation of biological responses, and STAT
activity (6). It is clear that a number of important protein-protein interactions involve the cytoplasmic domain of various receptors upon ligand binding. The precise regulation of these interactions leads to the formation of activated cytoplasmic transcription factors that are critical for mediating gene activation and subsequent biological effects. The regulation of such interactions is likely to involve proteins with different functional properties such as kinases and phosphatases (7), STATs (8), adapter proteins (9), chaparonins (10), and nuclear translocation factors (11).
RACKs (receptor for activated C kinases) (12, 13) are
members of a new group of proteins that may function as adaptors in
different systems. It has been suggested that RACKs may be responsible
for the intracellular localization of activated protein kinases C
(PKCs). RACK-1 specifically associates with the C2 domain of PKCß
(12, 13), while another RACK, the coantomer protein ß
(ßCOP) protein, associates with PKC
(14). A common
feature of RACK-1 and conantomer protein ß (ßCOP) is the presence
of tryptophan and aspartic acid (WD) repeats within these proteins,
which are thought to mediate protein-protein interactions. RACK-1 has a
molecular mass of 36,000 and is composed of seven WD repeats, thus
resembling the structure of the ß subunit of G proteins (Gß)
(15). The Gßs, and very likely RACK-1, form a rigid
seven-blade ß-propeller structure that has been proposed to function
as an adapter or scaffold motif (15). Recently, RACK-1 has
been reported to associate with other proteins, including Src kinase
where it inhibits kinase function (16). Also, RACK-1
appears to interact with ß integrin subunit cytoplasmic domain,
directly linking RACK-1 to integrin function (17). In
addition, RACK-1 has been shown to interact with the cAMP-specific
phosphodiesterase PDE4D5 isoform, where it is proposed to recruit other
proteins to a signaling complex (18).
Using the entire cytoplasmic domain of the long form of IFN-RßL as
bait in a yeast two-hybrid system screen, we identified RACK-1 as an
IFN receptor-associated protein. RACK-1 specifically binds to the
cytoplasmic domain of IFN-RßL in a ligand-independent manner as
demonstrated by coimmunoprecipitation and GST pull-down experiments.
Moreover, treatment of cells with type I IFN results in an increase in
detectable RACK-1, suggesting an active role of this WD
repeat-containing protein in IFN signaling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All cell lines were purchased from American Type Tissue Culture
(Manassas, VA) and grown at 37°C in 5% CO2.
U-266 and Daudi cells were grown in RPMI 1640 (Life Technologies,
Gaithersburg, MD) containing 10% (v/v) bovine calf serum,
L-glutamine, 5% penicillin, and streptomycin (Life
Technologies) and were harvested at 1 x 106
cell/ml as previously described (19). Human dermal
microvascular endothelial cells (HMEC) were obtained from Dr. Ades
(Centers for Disease Control, Atlanta, GA). The cells were grown to
confluence in T75 flasks in MCDB 131 medium containing 0.7% FBS, 10 mM
glutamine, 0.5 mg/ml hydrocortisone, 10 ng/ml epidermal growth factor,
100 U/ml penicillin, and 100 mg/ml streptomycin (20), and
then subcultured on 12-mm diameter no. 1 glass coverslips in 24-well
plates for immunostaining. Human IFN-ß1b (sp. act., 2.5 x
107 U/mg) was produced as previously described
(21), and IFN-2 (sp. act., 3.0 x
108 U/mg) was purchased from PeproTech (Rocky
Hill, NJ). Anti-phosphotyrosine Abs Ab-2 and 4G10 were purchased from
Oncogen Sciences (Cambridge, MA) and Upstate Biotechnologies (Lake
Placid, NY). IFNAR1 (IFN-R) and IFNAR2c (IFN-RßL) antisera
were prepared as previously described (22). RACK-1 mAb was
purchased from Transduction Laboratories (Lexington, KY).
Yeast two-hybrid screen
The IFN-RßL cytoplasmic domain cDNA (aa 281–515) was
generated by PCR, subcloned into the Gal4 DNA
binding domain plasmid pAS2-1, and used as bait in a yeast two-hybrid
screen of a human B lymphocyte cDNA library constructed in pACT
(Clontech, Palo Alto, CA). Approximately 1.6 x
106 colonies were screened for activation of HIS3
and lacZ reporter genes using the host strain CG1945.
Primary screen positives were isolated by cycloheximide
counterselection against the bait and retested against the IFN-RßL
cytoplasmic domain (pßL281–515) and two other
unrelated bait plasmids pLAM 5'-1 (encodes DNA binding domain fusion
with human lamin C) and pVA3-1 (encodes DNA binding domain fusion with
murine p53). The inserts from positive library plasmids were then
amplified by PCR and mapped by AluI digests, and plasmids
were sequenced after isolation and bacterial transformation.
Immunoprecipitation and immunoblotting
U-266 or Daudi cells (1 x 107 cells) were lysed in lysis buffer (20 mM Tris-HCl, pH 6.6, containing 1% Nonidet P-40, 50 mM NaCl, 1 mM EDTA, 2.5% glycerol (v/v), 1.0 mM sodium fluoride, 1.0 mM sodium orthovanadate, 1.0 mM PMSF, 0.5 µg/ml leupeptin, and 5.0 µg/ml trypsin inhibitor) for 30 min at 4°C. For immunoprecipitation, the indicated Abs were added to each sample, incubated overnight, mixed with protein G-agarose (Roche, Indianapolis, IN), and resolved by SDS-PAGE (10% gels, Novex, San Diego, CA). Proteins were transferred to polyvinylidene difluoride membranes and then sequentially incubated with an anti-RACK-1 mAb (Transduction Laboratories) and anti-mouse IgM µ-chain coupled to HRP (Pierce, Rockford, IL) for 1 h. Filters were washed three times in blocking buffer and developed using a chemiluminescent detection method (Pierce).
GST fusion constructs
The different GST fusion proteins encoding different regions of
the cytoplasmic domain of IFN-RßL have been described previously
(23). Pull-down experiments and immunoblotting were
performed using the same procedure described above for
immunoprecipitations.
Immunofluorescence
Confluent HMEC on glass coverslips were washed twice and incubated for 2 h at 37°C in serum-free and phenol red-free DMEM containing 25 mM HEPES, pH 7.4. The cells were then stimulated at 37°C for 0–60 min with agonists (20,000 U/ml IFN-ß1b or 100 nM PMA) before fixation for 20 min in 4% paraformaldehyde in HBSS supplemented with 25 mM HEPES (HBSS). The coverslips were washed three times for 5 min each time in 100 mM glycine and three times for 10 min each time in HBSS to quench and remove the fixative. The cells were then preincubated in HBSS containing 5% goat serum, 0.2% BSA, 0.01% NaN3, and 0.1% Triton X-100 (blocking solution) for 30 min at room temperature, followed by incubation with anti-RACK-1 mouse monoclonal IgM overnight at 4°C in the same buffer. After washing three times for 10 min each time with HBSS, the coverslips were again preincubated in blocking solution for 30 min before exposure to Alexa 568 goat anti-mouse IgG F(ab')2 conjugate (Molecular Probes, Eugene, OR) for 2 h at room temperature. Primary and secondary Abs were centrifuged at 14,000 x g for 10 min through Spin-X filters (Amicon, Beverly, MA) and used at concentrations of 1 and 4 µg/ml, respectively. The coverslips were finally washed three times for 10 min each time in HBSS and mounted on a drop of ProLong Antifade mounting medium (Molecular Probes).
The intracellular localization of labeled RACK-1 was assessed in reference to nuclear 4'6'-diamidine-2-phenylindole dihydrochloride (DAPI) staining using a Zeiss 510 laser scanning confocal microscope (New York, NY). One-micron optical sections were scanned individually with 364- and 568-nm laser lines from Enterprise UV (Coherent, Palo Alto, CA) and OmniChrome Ar/Kr lasers (Melles Griot, Carlsbad, CA). The emission filters used to detect DAPI and Alexa 568 were BP385–470 nm and LP590 nm, respectively. Thus, nuclear DAPI staining appeared blue and RACK-1 red. Four frame averages of the brightest 1-µm thick focal plane observed with the x63 1.4 NA water immersion objective were acquired and later assembled using Adobe Photoshop and Macromedia Freehand image processing software (Adobe Systems, Mountainview, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A human B cell cDNA library was screened for cDNAs encoding
proteins that interact with the cytoplasmic domain of IFN-RßL.
Among a number of positive yeast clones, two different clones, C1-L and
C2-N1, encoded the C-terminal 216 aa of the previously described
receptor for activated C kinase, RACK-1 (Fig. 1
). The C1-L and C2-N1 clones strongly
bound the cytoplasmic domain of IFN-RßL, suggesting that amino
acids 91–317 contain the interaction site for IFN-RßL binding.
The first 91 aa of RACK-1 include two WD repeats (WD1 and WD2) that do
not appear to be required for IFN-RßL binding. The interaction
between RACK-1 and IFN-RßL detected in the two-hybrid system was
shown to be specific, because both the pACT-C1-L and pACT-C2-N1 clones
failed to produce ß-galactosidase-positive colonies when either was
reintroduced with one of two different control plasmids (pLAM 5'-1 or
pVA3-1) in CG1945 cells (Fig. 1). Cotransformation of the control (pLAM
5'-1 or pVA3-1) and bait plasmids (pACT-C1-L or pACT-C2-N1) was
confirmed by the observed growth of transformed yeast in tryptophan-
and leucine-deficient media (Fig. 1).
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RßL required for binding RACK-1
To confirm the interaction between IFN-RßL and RACK-1, we
performed "pull-down" experiments. GST constructs containing the
entire cytoplasmic domain of IFN-RßL bound RACK-1 in
IFN-stimulated or unstimulated cell lysates (Fig. 2A). No RACK-1 was observed
bound to GST alone. We next sought to determine which region of the
cytoplasmic domain of IFN-RßL was responsible for the interaction
with RACK-1. Fig. 2B shows that RACK-1 bound to GST-ßL
truncated at aa 462, 375, and 346, but not to a GST-ßL containing
only aa 265–299 or GST control. Therefore, the binding domain within
IFN-RßL required for RACK-1 binding was shown to be between aa 300
and 346 (Fig. 2B). No differences in the interaction between
RACK-1 and IFN-RßL were observed after type I IFN treatment (Fig. 2A). It is worth mentioning that truncations proximal to aa
375 bound less RACK-1 than truncation at aa 462 or full-length
IFN-RßL, raising the possibility that there may be more than one
RACK-1 binding site on IFN-RßL. These data strongly suggest that
RACK-1 is constitutively associated with the cytoplasmic domain of
IFN-RßL and probably binds via a mechanism independent of
ligand-induced receptor phosphorylation.
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RßL
To determine whether the interaction between RACK-1 and
IFN-Rß can be detected in vivo, we performed coimmunoprecipitation
experiments. RACK-1 could be detected directly in Daudi cell lysates by
immunoblotting as a 36-kDa protein (Fig. 3, lane 1). This molecular
mass corresponds to the previously reported m.w. of RACK-1 (12, 13). A protein that comigrated with RACK-1 could be shown to
coimmunoprecipitate with IFN-RßL in IFN-ß1b-stimulated and
unstimulated Daudi cells (Fig. 3, lanes 5 and 6).
We estimate that the fraction of cellular RACK-1 that
coimmunoprecipitates with IFN-RßL is within the range of 1–2%.
No RACK-1 coimmunoprecipitation was observed using a nonspecific Ab as
a negative control (Fig. 3, lane 2) or anti-IFN-R
Abs before or after IFN-ß1b stimulation (Fig. 3, lanes 3
and 4). However, it should be pointed out that we cannot
completely rule out the presence of low affinity interactions between
RACK-1 and IFN-R that cannot be detected by
coimmunoprecipitation.
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shows that RACK-1 was not tyrosine
phosphorylated either before (lanes 2 and
4) or after (lanes 1 and 3)
stimulation of Daudi cells with IFN-ß1b, demonstrating that RACK-1 is
not regulated by this mechanism.
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HMEC were used to localize the distribution of RACK-1 within the
cell before and after treatment with either PMA (Fig. 5, c, e, and
g) or IFN-ß (Fig. 5, b, d, and
f). In unstimulated cells (Fig. 5a) RACK-1 was
detected throughout the cytoplasm. Interestingly, upon treatment of
HMEC with IFN-ß1b, a dramatic increase in RACK-1 immunostaining
became evident (Fig. 5, c, e, and g).
This increase was maximal at 60 min after stimulation with IFN (Fig. 5g) and was similar to the increase in immunostaining
induced by PMA (Fig. 5, b, d, and f).
Treatment with IFN-ß1b and PMA also appeared to induce intracellular
redistribution of RACK-1 toward the perinuclear area (Fig. 5, d and e). This observation is consistent with the
idea that RACK-1 distribution within the cell is influenced by
ligand-induced activation of the type I IFN receptor. However, it is
not clear whether IFN stimulation of cells results in the release of
sequestered RACK-1 or induces a conformational change in the protein
resulting in the observed increase in immunostaining. Furthermore, it
is important to note that the increase in RACK-1 immunostaining is
observable within 15 min after stimulation of cells with IFN-ß1b,
suggesting that this increase is probably not dependent on new protein
synthesis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study we found an additional protein, RACK-1, (12, 13), associated with a region of the cytoplasmic domain of
IFN-RßL that was previously reported in murine cells to be
required for signaling by type I IFNs (29). This
association is not dependent on ligand-induced assembly of the receptor
or tyrosine phosphorylation (30). RACK-1 is therefore
constitutively associated with IFN-RßL. In addition, the minimum
binding site of RACK-1 on IFN-RßL was mapped using GST-ßL
constructs to aa 300–346, close to the proposed JAK1 binding
site.
RACK-1 was originally identified and cloned from a rat brain cDNA expression library as a protein that specifically bound activated Ca2+/phospholipid-dependent PKCß (12). Among other functions, RACK-1 is believed to be a member of a family of receptors for PKC, where it is proposed to direct and localize activated PKCs to their respective sites of action (31). RACK-1 is a 317-aa-long protein containing seven WD motifs present in the cytoplasm of a variety of cells. The WD motif has previously been identified as playing a role in mediating protein-protein interactions and is defined as a motif present in intracellular adaptor proteins (32). The WD repeats in RACK-1 are conserved from Chlamydomonas ssp. to humans, suggesting an important function through evolution (32).
Recent observations have demonstrated that overexpression of RACK-1 in
NIH-3T3 cells suppresses cell proliferation and demonstrated the direct
interaction between RACK-1 and the SH2 domain of Src (16).
Such an interaction suggests the possibility that RACK-1 may act not
only as a receptor for activated PKC, but also as an adapter protein
for proteins containing SH2 domains. Furthermore, it has been shown
that RACK-1 binds directly to the integrin ß subunit and that this
interaction is dependent on the prior treatment of cells with phorbol
esters such as PMA (12, 13). Such an interaction links
RACK-1 directly to integrins and perhaps regulation of integrin
function. In addition, RACK-1 was recently demonstrated to associate
with the cAMP-dependent phosphodiesterase isoform, PDE4D5
(18), in a PMA-independent manner, where it is proposed to
bring regulatory proteins to the enzyme complex. This further supports
the suggestion that RACK-1 may play a more general role in
intracellular signaling by mediating important protein-protein
interactions. Therefore, RACK-1 is likely to play a role in regulating
signaling different from that simply involving PKC (31).
In light of this, RACK-1/PKC interactions appear to first require the
activation of PKC, by PMA, before its association with RACK-1; however,
interaction of RACK-1 with IFN-RßL, Src kinase, and integrin ß
subunit is constitutive and does not appear to require any activation
step. Therefore, different mechanisms of RACK-1 interactions exist.
However, both PMA and IFN stimulation of HMECs can similarly influence
RACK-1 levels, in that both treatments resulted in a dramatic increase
in the levels of RACK-1 within the cell as measured by
immunofluorescence. Such a rapid increase in immunofluorescent signal
for RACK-1 suggests a change in conformation of RACK-1 after type I IFN
treatment rather than an increase in steady state level.
It is interesting to note that RACK-1 is constitutively associated with
IFN-RßL in the absence of ligand. Such an observation suggests
that the role of RACK-1 in type I IFN signaling is different from that
resulting from the direct activation of PKC by type I IFNs themselves.
However, it is possible that PKC activated by other receptors may
sequester, via RACK-1, to the IFN receptor. Such a process may lead to
sensitive cross-talk between different receptors and stimuli.
Currently, there are only a few reports suggesting a role for PKC
(33) and serine/threonine phosphorylation
(34) in cytokine signaling and STAT regulation
(6). However, recent efforts have demonstrated a direct
effect of IFN-ß in reversing the rapid nuclear translocation of
protein kinase C-
in human T cells (35). Such an effect
demonstrates a link between type I IFNs and upstream signaling events
surrounding T cell apoptosis (35). It is possible,
however, that RACK-1 is acting not only as a receptor for activated PKC
but also as a general adaptor protein, helping to bring proteins
involved in signaling to the receptor (36). In this role,
RACK-1 may function as an adapter protein recognizing other kinases or
transcription factors with SH2 domain motifs, as suggested by the
observation that RACK-1 binds to the SH2 domain of Src
(16). Because many adapter proteins interact with several
different proteins (36), it is also tempting to speculate
that the association of RACK-1 with IFN-RßL is not unique to the
type I IFN receptor and that RACK-1 may link other cytokine receptors
with different downstream signaling molecules. Indeed, recent evidence
has demonstrated an interaction of RACK-1 with another cytokine
receptor subunit, the common ß-chain of the IL-5/IL-3 and GM-CSF
receptor (37). Finally, the involvement of PKC- in the
regulation of STAT3 function has been recently linked to IL-6
stimulation. In this case, PKC- was shown to bind to and
phosphorylate STAT3 on Ser727
(38).
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Acknowledgments |
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Footnotes |
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2 The laboratories of E.C. and O.C. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ed Croze, Department of Immunology, Berlex Biosciences, 15049 San Pablo Avenue, Richmond, CA 94806.
4 Abbreviations used in this paper: SH2, Src homology 2; HMEC, human dermal microvascular endothelial cells; IFNAR1, human type I IFN receptor chain 1; IFNAR2c, full-length human type I IFN receptor chain 2; RACK-1, receptor for activated protein kinase C; PKC, protein kinase C; DAPI, 4'6'- diamidine-2-phenylindole dihydrocholoride.
Received for publication March 24, 2000. Accepted for publication August 9, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor different from box 1 interacts with JAK1 and is sufficient to activate the JAK-STAT pathway and induce an antiviral state. J. Biol. Chem. 272:26388.- and interferon ß-stimulated gene expression. Science 269:1721.-receptor-1 (IFNAR1) but not for activation of phosphoinositol 3-kinase. J. Biol. Chem. 274:32507.. Proc. Natl. Acad. Sci. USA 87:8761. requires components of T-cell-receptor signaling. Nature 390:629.[Medline]
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H. Chen, J. Huang, F. Y. Wu, G. Liao, L. Hutt-Fletcher, and S. D. Hayward Regulation of Expression of the Epstein-Barr Virus BamHI-A Rightward Transcripts J. Virol., February 1, 2005; 79(3): 1724 - 1733. [Abstract] [Full Text] [PDF]
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A. Usacheva, X. Tian, R. Sandoval, D. Salvi, D. Levy, and O. R. Colamonici The WD Motif-Containing Protein RACK-1 Functions as a Scaffold Protein Within the Type I IFN Receptor-Signaling Complex J. Immunol., September 15, 2003; 171(6): 2989 - 2994. [Abstract] [Full Text] [PDF]
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A. Usacheva, R. Smith, R. Minshall, G. Baida, S. Seng, E. Croze, and O. Colamonici The WD Motif-containing Protein Receptor for Activated Protein Kinase C (RACK1) Is Required for Recruitment and Activation of Signal Transducer and Activator of Transcription 1 through the Type I Interferon Receptor J. Biol. Chem., June 15, 2001; 276(25): 22948 - 22953. [Abstract] [Full Text] [PDF]
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) using IFN-
