©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Interaction of the Transcriptional Activator Stat-2 with the Type I Interferon Receptor (*)

(Received for publication, July 11, 1995; and in revised form, August 25, 1995)

Shahab Uddin Aghiad Chamdin Leonidas C. Platanias (§)

From the Division of Hematology-Oncology, Department of Medicine, Loyola University Chicago, Maywood, Illinois 60153 and Hines Veterans Administration Hospital, Hines, Illinois 60141

ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES

ABSTRACT

Binding of interferon-alpha (IFNalpha) to the multisubunit type I IFN receptor (IFNR) induces activation of the Tyk-2 and Jak-1 kinases and tyrosine phosphorylation of multiple signaling elements, including the Stat proteins that form the ISGF3alpha complex. Although Jak kinases are required for IFNalpha-dependent activation of Stats, the mechanisms by which Stats interact with these kinases are not known. We report that Stat-2 associates with beta(s) subunit of the type I IFN receptor in an interferon-dependent manner. This association is rapid, occurring within 1 min of interferon treatment of cells, and is inducible by various type I (alpha, beta, ) but not type II () IFNs. The kinetics of Stat-2-IFNR association are similar to the kinetics of phosphorylation of Stat-2, suggesting that during its binding to the type I IFNR, Stat-2 acts as a substrate for interferon-dependent tyrosine kinase activity. These findings support the hypothesis that the type I IFNR acts as an adaptor, linking Stat proteins to Jak kinases. Interaction of Stat-2 with the beta(s) subunit of the type I IFNR may be a critical signaling event, required for the formation of the ISGF3alpha complex and downstream transcription of interferon-stimulated genes.


INTRODUCTION

In order for type I interferons to exert their pleiotropic biological effects on cells and tissues, binding to the type I IFN (^1)receptor (IFNR) is required (1) . Previous studies have established that the type I IFNR has a multisubunit structure(2, 3, 4, 5, 6) . In affinity cross-linking studies of I-IFNalpha to the type I IFNR, I-IFNalpha2-IFNR complexes with approximate molecular masses of 130-140 kDa (alpha subunit), 110-120 kDa (beta subunit), 210-230 kDa (that appears to result from an association of the alpha and beta subunits), and less prominent complexes of 75 and 180 kDa (most likely an association of the alpha subunit with the 75-kDa complex) are detected(2, 3, 4, 5, 6, 7) . The variant type I IFNR, expressed in some myelomonocytic cell lines, is characterized by lack of expression of the 110-120- and 210-kDa complexes and the presence of I-IFNalpha2-IFNR complexes of 130-140 kDa (alpha subunit), 75 kDa, and 180 kDa (association of the alpha subunit with the 75-kDa complex)(2, 6) . The cloning of the genes encoding two subunits of the type I IFNR has been reported(8, 9) . The subunit cloned by Uzéet al.(8) has been shown to correspond to the previously described alpha subunit of the receptor(10) . The relative molecular mass of the alpha subunit appears to exhibit slight variations in different cell lines, ranging from 110 to 135 kDa(2, 3, 4, 5, 6, 11, 12) , possibly due to differential glycosylation of the protein(4) . The subunit cloned by Novick et al.(9) has been reported to encode for a 51-kDa protein. Domanski et al.(7) have recently cloned a cDNA that encodes a 100-kDa form of the type I IFNR. This receptor form and the one cloned by Novick et al.(9) have identical extracellular and transmembrane domains and the first 15 amino acids of the cytoplasmic domain but differ in the rest of the cytoplasmic region(7) . In the current study, we used antibodies generated against the receptor subunits cloned by Uzéet al.(8) and by Novick et al.(9) to further characterize the structure of the type I IFNR and its interactions with other signaling molecules. To avoid confusion in the terminology of the different subunits and to be consistent with the terminology used by other groups(7) , we will refer to the product of the gene cloned by Uzéet al.(8) as the alpha subunit of the type I IFN receptor, the product of the gene cloned by Novick et al.(9) as the beta(s) subunit of the type I IFN receptor, and the product of the gene cloned by Domanski et al.(7) as the beta(L) subunit of the type I IFNR. Our findings demonstrate that during type I IFN stimulation, the transcriptional activator Stat-2 associates with the beta(s) subunit of the type I IFNR, providing direct evidence for an interaction of this member of the Stat family of proteins with a specific component of the type I IFNR.


EXPERIMENTAL PROCEDURES

Cells and Reagents

The U-266 (human multiple myeloma), Daudi (lymphoblastoid), and Molt-4 (acute T cell lymphocytic leukemia) cell lines were grown in RPMI 1640 (Life Technologies, Inc.) supplemented with 10% (v/v) fetal bovine serum (Life Technologies, Inc.) or 10% (v/v) defined calf serum (Hyclone Laboratories, Logan, UT) and antibiotics. Human recombinant IFNalpha2 was provided by Dr. Michael Brunda (Hoffmann-La Roche) and Dr. Paul Trotta (Shering Plough). Human recombinant IFNbeta-1b (IFNbeta) was provided by Dr. Gary Williams (Berlex Laboratories, Richmond, CA). Human recombinant IFN was a gift (to Dr. M. O. Diaz) by Dr. G. Addolf (Ernst Boehringer Institute fur Arzneimittelforschung, Vienna, Austria). Human recombinant IFN was provided by Genentech Inc. (South San Francisco, CA). The anti-phosphotyrosine monoclonal antibody (4G-10) was obtained from Upstate Biotechnology (Lake Placid, NY). A rabbit polyclonal antibody (IFNalphaRC-1) against a synthetic peptide corresponding to the sequence DESESKTSEELQQDFV present in the C terminus of the alpha subunit was raised in rabbits. The rabbit polyclonal antibody (IFNalphaRC-2) against the subunit cloned by Novick et al.(9) (beta(s) subunit) was raised against a synthetic peptide corresponding to the sequence SSWDYKRASLCPSD present in the C terminus of this protein. This sequence is not present in the form of the beta subunit (beta(L) subunit) cloned by Domanski et al.(7) . A polyclonal antibody against Stat-2 (p113, 186-199) has been described elsewhere (6) and was used for immunoprecipitations. A polyclonal antibody raised against a peptide corresponding to amino acids 832-851 of Stat-2 was purchased from Santa Cruz Biotechnology and was used for immunoblotting. A monoclonal antibody against the tyrosine kinase Tyk-2 was purchased from Transduction Laboratories (Lexington, KY).

Immunoprecipitations and Immunoblotting

Cells were stimulated with the indicated amounts of different interferons for the indicated time periods. After stimulation, the cells were rapidly centrifuged in a microcentrifuge and lysed in a phosphorylation lysis buffer (0.5% Triton X-100, 150 mM NaCl, 200 µM sodium orthovanadate, 10 mM sodium pyrophosphate, 100 mM sodium fluoride, 1 mM EDTA, 50 mM Hepes, 1.5 mM magnesium chloride, 10% glycerol, 1 mM phenylmethylsulfonyl fluoride, and 10 µg/ml aprotinin) for 60 min at 4 °C. Insoluble material was removed by centrifugation, and cell lysates were immunoprecipitated with the indicated antibodies using protein G-Sepharose (Pharmacia Biotech Inc.). After five washes with phosphorylation lysis buffer containing 0.1% Triton X-100, proteins were analyzed by SDS-PAGE and transferred onto polyvinylidene difluoride filters (Immobilon, Millipore). The residual binding sites on the filters were blocked by incubating with TBST (10 mM Tris, pH 8.0, 150 mM NaCl, 0.05% Tween 20)/10% bovine serum albumin for 1-3 h at room temperature or overnight at 4 °C. The filters were subsequently incubated with the anti-phosphotyrosine monoclonal antibody and developed using an enhanced chemiluminescence (ECL) kit following the manufacturer's recommended procedure (Amersham Corp.).

Affinity Cross-linking of Iodinated IFNalpha to Its Receptor

Affinity cross-linking of I-IFNalpha2 to its receptor using the homobifunctional cross-linker disuccinimidyl suberate was performed essentially as described previously(4, 13) .


RESULTS AND DISCUSSION

We initially sought to determine the specificity of the antibodies raised against the different type I IFN receptor subunits. We performed experiments in which I-IFNalpha2 was cross-linked to its receptor on human cells, and after cell lysis, the lysates were immunoprecipitated with the IFNalphaRC-1 or IFNalphaRC-2 antibodies and analyzed by SDS-PAGE. Fig. 1A shows such an experiment using the U-266 human myeloma cell line. The IFNalphaRC-1 antibody immunoprecipitates the alpha subunit of the receptor, which migrates as a doublet at 130-140 kDa (Fig. 1A). It also co-immunoprecipitates an associated high molecular weight complex (HMWC-1) migrating at approximately 210-230 kDa, which most likely results from an association of the alpha subunit with the 100-kDa form of the beta subunit (5, 6) (Fig. 1A). The IFNalphaRC-2 antibody immunoprecipitates a 70-75-kDa complex (Fig. 1A), corresponding to the beta(s) subunit of the type I IFNR (the expected M(r) of the beta(s) subunit in affinity cross-linking studies is approximately 71 kDa when the M(r) of the cross-linked IFNalpha2 molecule is taken into account). This antibody also co-immunoprecipitates a 130-140-kDa doublet corresponding to the alpha subunit, but it does not co-immunoprecipitate the HMWC-1 complex (Fig. 1A). HMWC-1, the 130-140-kDa (alpha subunit), and 70-75 kDa (beta(s) subunit) complexes were also detectable when total cell lysates from affinity cross-linked cells were analyzed in parallel (Fig. 1A). A 110-120-kDa complex seen in total lysates from affinity cross-linked cells, which corresponds to the 100-kDa beta subunit (beta(L) subunit)(5) , could not be detected by any of the anti-receptor antibodies studied here. A complex at approximately 180 kDa (HMWC-2) was also seen in total cell lysates and was weakly immunoprecipitated by both the IFNalphaRC-1 and IFNalphaRC-2 antibodies. Similar results were obtained when the Molt-4 human cell line was studied, except that the receptor complexes migrated slightly slower in these cells (approximately 15-20-kDa difference), a finding consistent with the reported variations in the mobility of type I IFNR components in different cell lines(11) . Taken altogether, the results of the affinity cross-linking experiments strongly suggested that two distinct forms of the type I IFN receptor are co-expressed on the surface of human cells. The form of the receptor immunoprecipitated by the IFNalphaRC-2 antibody is consistent with the previously described variant form of the type I IFNR(2, 6) . Further studies are required, however, to characterize the exact interactions between different receptor subunits and to establish that the form precipitated by the IFNalphaRC-2 antibody corresponds to the previously described variant receptor form(2, 6) .


Figure 1: Immunoprecipitation of two distinct type I IFN receptor complexes by the IFNalphaRC-1 and IFNalphaRC-2 antibodies. A,I-IFNalpha2 was affinity cross-linked to its receptor in U-266 cells, the cells were lysed, and cell lysates were either analyzed directly by SDS-PAGE (lane 1) or immunoprecipitated with IFNalphaRC-1 (lane 2) or IFNalphaRC-2 (lane 3) or preimmune rabbit serum (lane 4) prior to SDS-PAGE analysis. The gel was dried, and bands were visualized by autoradiography. A band at 110-120 kDa could be distinguished in lane 1 on shorter exposure of the autoradiogram (data not shown). B, Molt-4 cell lysates obtained after affinity cross-linking of I-IFNalpha2 to its receptor were immunoprecipitated with IFNalphaRC-1 (lane 1) or IFNalphaRC-2 (lane 2) or preimmune rabbit serum (lane 3) prior to SDS-PAGE analysis.



We subsequently performed studies in which cells were treated with IFNalpha and cell lysates were immunoprecipitated with the anti-receptor antibodies, analyzed by SDS-PAGE, and immunoblotted with anti-phosphotyrosine. Fig. 2, A and B, shows that the alpha subunit of the receptor is tyrosine-phosphorylated in response to IFNalpha treatment of cells, in agreement with our previous findings using a monoclonal antibody against this subunit(14, 15) . In addition, the IFNalphaRC-1 antibody co-immunoprecipitated an interferon-dependent tyrosine-phosphorylated protein with an M(r) of 135 kDa, corresponding to the phosphorylated form of the tyrosine kinase Tyk-2(16) . Immunoblotting of anti-IFNalphaRC-1 immunoprecipitates with a monoclonal anti-Tyk-2 antibody demonstrated that Tyk-2 is associated with the alpha subunit of the type I IFNR prior to and after IFNalpha stimulation (Fig. 2C), confirming the findings of a previous study (16) that had established an association of the alpha subunit with Tyk-2. Tyk-2 was not detectable in immunoprecipitates obtained with the anti-IFNalphaRC-2 antibody (Fig. 2C), suggesting that this kinase does not associate with the beta(s) subunit of the receptor. Fig. 3A shows an experiment in which cell lysates from IFNalpha-treated cells were immunoprecipitated with the IFNalphaRC-2 antibody and immunoblotted with anti-phosphotyrosine. A band corresponding to the 51-kDa beta(s) subunit could not be detected in such immunoblots, perhaps because it co-migrates with the heavy chain of rabbit immunoglobulin. Also no bands migrating at 102 kDa that would correspond to a phosphorylated receptor dimer were detectable. A 113-kDa tyrosine-phosphorylated protein, however, was clearly co-immunoprecipitated by this antibody upon treatment of cells with IFNalpha. As the M(r) of this protein was identical to the M(r) of the transcriptional activator Stat-2, we sought to determine whether it corresponds to Stat-2. Fig. 3B shows an anti-Stat-2 immunoblot on immunoprecipitates obtained with the IFNalphaRC-1 or IFNalphaRC-2 antibodies. Stat-2 is not present in IFNalphaRC-1 immunoprecipitates, but it is clearly detectable in IFNalphaRC-2 immunoprecipitates from IFNalpha-treated cells. Thus, Stat-2 appears to specifically associate with the beta(s) but not the alpha subunit of the type I IFNR. The kinetics of the association of Stat-2 with the beta(s) subunit were subsequently studied. Fig. 4A shows an experiment in which Daudi cells were treated for different times with IFNalpha, and after cell lysis, the lysates were immunoprecipitated with the IFNalphaRC-2 antibody and immunoblotted with alphaStat-2. IFNalpha-dependent association of Stat-2 with the beta(s) subunit was detectable within 1 min of treatment of cells; the signal peaked at 5-30 min and decreased, although it was still clearly detectable after 90 min of IFNalpha treatment. When the time course of phosphorylation of the beta(s) subunit-associated form of Stat-2 was studied, we noticed that the signal peaked at 5-30 min and diminished by 90 min of IFNalpha treatment (Fig. 4B). When the tyrosine phosphorylation of Stat-2 directly immunoprecipitated by an alphaStat-2 antibody was studied, the signal was more intense at all times but also declined at 90 min (Fig. 4B).


Figure 2: Association of the tyrosine kinase Tyk-2 with the alpha subunit of the type I IFNR. Molt-4 cells (5.4 times 10^7/lane) (A) or U-266 cells (1.3 times 10^7/lane) (B) were treated for 5 min at 37 °C with 10^4 units/ml IFNalpha as indicated, the cells were lysed, and cell lysates were immunoprecipitated with IFNalphaRC-1 (lanes 1 and 2) or normal rabbit serum (RS) (lane 3) and immunoblotted with anti-phosphotyrosine (alphaPTyr). C, anti-Tyk-2 immunoblot. Molt-4 cells (1.45 times 10^7/lane) were treated with 10^4 units/ml IFNalpha for 5 min at 37 °C as indicated, the cells were lysed, and lysates were precleared with non-immune rabbit immunoglobulin and immunoprecipitated with the IFNalphaRC-1 (lanes 1 and 2) or IFNalphaRC-2 (lanes 3 and 4) antibodies.




Figure 3: IFNalpha-dependent association of Stat-2 with the beta(s) but not the alpha subunit of the type I IFNR. A, anti-phosphotyrosine (alphaPTyr) immunoblot. Daudi cells (2.9 times 10^7/lane) were treated with 2 times 10^4 units/ml IFNalpha for 5 min as indicated, and cell lysates were immunoprecipitated with the IFNalphaRC-2 antibody (lanes 1 and 2). B, alphaStat-2 immunoblot. U-266 cells (4.2 times 10^7/lane) were treated for 5 min with 10^4 units/ml IFNalpha as indicated, and cell lysates were immunoprecipitated with the IFNalphaRC-1 antibody (lanes 1 and 2) or the IFNalphaRC-2 antibody (lanes 3 and 4) or preimmune rabbit serum (PIRS) (lane 5).




Figure 4: Kinetics of the association of Stat-2 with the beta(s) subunit of the type I IFNR in Daudi cells. A, cells were treated with 10^4 units/ml IFNalpha for the indicated time periods at 37 °C, and cell lysates were immunoprecipitated with the IFNalphaRC-2 antibody (lanes 1-5) or preimmune rabbit serum (lane 6) or an antibody against Stat-2 (lane 7) and immunoblotted with an alphaStat-2 antibody. B, cells were treated with 10^4 units/ml IFNalpha for the indicated times at 37 °C, and cell lysates were immunoprecipitated with preimmune rabbit serum (PIRS, lane 1) or the IFNalphaRC-2 antibody (lanes 2-6) or an antibody against Stat-2 (lanes 7-11) and immunoblotted with anti-phosphotyrosine (alphaPTyr). A weak band corresponding to Stat-2 could be detected at 90 min in the IFNalphaRC-2 immunoprecipitates (lane 6) after longer exposure of the same blot (data not shown).



We have previously shown that different type I IFNs induce tyrosine phosphorylation of a common set of signaling proteins, including the alpha and beta (100 kDa) subunits of the type I IFNR(14, 15) , the Tyk-2 and Jak-1 kinases(15) , Stat-2 and Stat-1(15) , p95(17) , and insulin receptor substrate (IRS) proteins (18). (^2)These data have suggested that all type I IFNs activate common signaling cascades. However, differences among the signaling pathways of different type I IFNs also exist, as suggested by our finding that IFNbeta selectively phosphorylates p100, a protein that associates with the alpha subunit of the type I IFNR(15) . To determine whether different IFNs induce an association of Stat-2 with the beta(s) subunit, Daudi cell lysates were immunoprecipitated with the IFNalphaRC-2 antibody and immunoblotted with anti-phosphotyrosine or alphaStat-2. Association of the phosphorylated form of Stat-2 with the beta(s) subunit was clearly inducible during treatment of cells with IFNbeta or IFN (Fig. 5, A and B). In contrast, IFN failed to induce such an association (Fig. 5, A and B), a finding consistent with the lack of involvement of Stat-2 in IFN signaling(19) . Interestingly, no protein of the size of the IFNbeta-specific p100 protein was seen in IFNalphaRC-2 immunoprecipitates (Fig. 5A), suggesting that this protein specifically associates with the alpha but not the beta(s) subunit. On the other hand, p100 was clearly detectable in IFNalphaRC-1 immunoprecipitates from IFNbeta-treated cells, (^3)in agreement with our original observation(15) .


Figure 5: Association of Stat-2 with the beta(s) subunit of the type I IFNR during treatment with different interferons. A, Daudi cells were treated with 2 times 10^4 units/ml of the indicated interferons for 5 min at 37 °C, and cell lysates were immunoprecipitated with the IFNalphaRC-2 antibody (lanes 1-5) and immunoblotted with anti-phosphotyrosine (alphaPTyr). B, the blot shown in A was stripped and reblotted with an antibody against Stat-2.



Significant progress has been made recently on our understanding of the mechanisms of activation of the ISGF3 transcriptional activator during IFNalpha treatment of target cells. During IFNalpha stimulation, three Stat proteins (Stat-2, Stat-1alpha, and Stat-1beta) are phosphorylated on tyrosine and associate with a 48-kDa protein (ISGF3) to form an active complex(19, 20, 21, 22) . This complex translocates to the nucleus and activates gene transcription during binding to interferon-stimulated response elements(19) . The exact mechanisms, however, by which Stat proteins interact with IFN-dependent Jak kinases to act as substrates for their kinase activity remain unknown.

In the current report we present evidence that Stat-2 specifically associates with the subunit of the type I IFN receptor cloned by Novick et al.(9) (beta(s) subunit). This association is rapid, is induced by various type I but not type II IFNs, and has similar kinetics with the IFNalpha-induced phosphorylation of Stat-2. A previous study (10) had suggested that Stat-2 may associate with the the type I IFN receptor, as evidenced by the weak co-precipitation of I-IFNalpha2 cross-linked complexes by an alphaStat-2 antibody. By using this methodology (affinity cross-linking), however, it is not possible to distinguish the specific receptor component that interacts with Stat-2 nor is it possible determine whether such an association is IFNalpha-dependent. The results of our studies demonstrate that the association of Stat-2 with the type I IFNR is IFNalpha-dependent, occurs specifically with the beta(s) but not the alpha subunit, and appears to be of relatively high stoichiometry as evidenced by the intensity of the detected signal.

Our findings also provide some hints on the kinase activity responsible for Stat-2 phosphorylation. Colamonici et al.(10, 16) have reported that the alpha subunit of the receptor forms a complex with the tyrosine kinase Tyk-2, a finding confirmed by us using the IFNalphaRC-1 antibody. Novick et al.(9) used an antibody that apparently detects both forms of the beta subunit (51 and 102 kDa) and were able to demonstrate an association with the tyrosine kinase Jak-1. As Stat-2 appears to interact specifically with the beta(s) but not the alpha subunit of the receptor, it is tempting to hypothesize that Stat-2 acts as a specific substrate for Jak-1 but not Tyk-2. Furthermore, as the Stat-2-IFNR association is IFNalpha-dependent, it is possible that it involves binding of the SH2 domain of Stat-2 to the beta(s) subunit of the type I IFNR. Such a model for an interaction of Stat-2 with the type I IFNR would be also consistent with the findings of a recent study that demonstrated that the SH2 domain of Stat-2 is the determinant of signaling specificity, while Tyk-2 is not specifically required for Stat-2 phosphorylation(23) . It remains to be determined whether Stat-1 also utilizes components of the type I IFNR for its interaction with Jaks. Interestingly, a recent study has demonstrated that phosphorylation of Stat-2 is required for activation of Stat-1, but not vice versa, suggesting that one binding site necessary for activation of Stat-1 may be the phosphotyrosine of Stat-2 itself(24) . Taken together with our data, these findings raise the possibility that binding of Stat-2 to the beta(s) subunit of the type I IFNR is the critical event required for the formation of the ISGF3alpha complex and downstream transcription of ISGs.


FOOTNOTES

*
This work was supported by a grant from the Department of Veterans Affairs (to L. C. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§
Recipient of a Career Development Award from the American Cancer Society. To whom correspondence should be addressed: Division of Hematology-Oncology, Loyola University Chicago, Bldg. 112, 2160 South First Ave., Maywood, IL 60153. Tel.: 708-327-3304; Fax: 708-216-2319.

(^1)
The abbreviations used are: IFN, interferon; ISG, interferon-stimulated gene; PAGE, polyacrylamide gel electrophoresis; IFNR, interferon receptor; Stat, signal transducer and activator of transcription; HMWC, high molecular weight complex.

(^2)
L. C. Platanias, S. Uddin, A. Yetter, X-J. Sun, and M. F. White, manuscript in preparation.

(^3)
S. Uddin, A. Chamdin, and L. C. Platanias, unpublished data.


ACKNOWLEDGEMENTS

We thank Dr. Oscar R. Colamonici for sharing with us data from his laboratory prior to publication.


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