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The Insulin-sensitive Glucose Transporter, GLUT4, Interacts Physically with Daxx

TWO PROTEINS WITH CAPACITY TO BIND Ubc9 AND CONJUGATED TO SUMO1*
  • Vassiliki S. Lalioti
    Affiliations
    Centro de Biologı́a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı́ficas, Universidad Autónoma de Madrid, Madrid 28049, Spain
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  • Silvia Vergarajauregui
    Footnotes
    Affiliations
    Centro de Biologı́a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı́ficas, Universidad Autónoma de Madrid, Madrid 28049, Spain
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  • Diego Pulido
    Affiliations
    Centro de Biologı́a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı́ficas, Universidad Autónoma de Madrid, Madrid 28049, Spain
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  • Ignacio V. Sandoval
    Correspondence
    To whom correspondence should be addressed: Centro de Biologı́a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı́ficas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain. Tel.: 34-91-397-8455; Fax: 34-91-397-4799
    Affiliations
    Centro de Biologı́a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı́ficas, Universidad Autónoma de Madrid, Madrid 28049, Spain
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  • Author Footnotes
    * This work was supported by Grant PB94-0035 from the Ministerio Español de Educación y Ciencia and the European Commission Grants ERB4061PL95-0924 and FMRX-CT96-0058. 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.
    ‡ Supported by Fellowship AP2000-3212 from the Ministerio Español de Educación, Cultura y Deporte.
Open AccessPublished:February 12, 2002DOI:https://doi.org/10.1074/jbc.M110294200
      In this study we have used the yeast two-hybrid system to identify proteins that interact with the carboxyl-cytoplasmic domain (residues 464–509) of the insulin-sensitive glucose transporter GLUT4 (C-GLUT4). Using as bait C-GLUT4, we have isolated the carboxyl domain of Daxx (C-Daxx), the adaptor protein associated with the Fas and the type II TGF-β (TβRII) receptors (
      • Yang X.
      • Khosravi-Far R.
      • Chang H.Y.
      • Baltimore D.
      ,
      • Perlman R.
      • Schiemann W.P.
      • Brooks M.W.
      • Lodish H.F.
      • Weinberg R.A.
      ). The two-hybrid interaction between C-GLUT4 and C-Daxx is validated by the ability of in vitro translated C-GLUT4 to interact with in vitro translated full-length Daxx and C-Daxx. C-Daxx does not interact with the C-cytoplasmic domain of GLUT1, the ubiquitous glucose transporter homologous to GLUT4. Replacement of alanine and serine for the dileucine pair (Leu489-Leu490) critical for targeting GLUT4 from the trans-Golgi network to the perinuclear intracellular store as well as for its surface internalization by endocytosis inhibits 2-fold the interaction of C-GLUT4 with Daxx. Daxx is pulled down with GLUT4 immunoprecipitated from lysates of 3T3-L1 fibroblasts stably transfected with GLUT4 and 3T3-L1 adipocytes expressing physiological levels of the two proteins. Similarly, GLUT4 is recovered with anti-Daxx immunoprecipitates. Using an established cell fractionation procedure we present evidence for the existence of two distinct intracellular Daxx pools in the nucleus and low density microsomes. Confocal immunofluorescence microscopy studies localize Daxx to promyelocytic leukemia nuclear bodies and punctate cytoplasmic structures, often organized in strings and underneath the plasma membrane. Daxx and GLUT4 are SUMOlated as shown by their reaction with an anti-SUMO1 antibody and by the ability of this antibody to pull down Daxx and GLUT4.
      The cytoplasmic domain of membrane proteins plays important roles in their transport, signal transduction, organization of protein scaffolds, and regulation of their turnover. Trafficking of GLUT4 in adipose and skeletal muscle cells is regulated by insulin and muscle contraction and is critical for the control of glucose levels in blood. Upon increase in insulin levels and muscle contraction the GLUT4 retained in intracellular stores is translocated to the plasma membrane, where it facilitates glucose transport (
      • James D.E.
      • Brown R.
      • Navarro J.
      • Pilch P.F.
      ). Trafficking of GLUT4 is mediated by motifs localized to the amino and carboxyl-cytoplasmic domains of the protein, though their characterization and the identification of the factors involved in their reading is incomplete.
      SUMO (also called sentrin, PIC1, and GMP1), a 101-amino acid ubiquitin-like modifier protein that is highly conserved from yeast to human, appears to control protein turnover and compartmentalization (
      • Melchior F.
      ). Three members of the SUMO family have been described in vertebrates. They show major structural differences in the sequences of their N-extensions, which are absent in ubiquitin. It has been shown recently that Ubc9, the only E2-type SUMO1-conjugating enzyme described in vertebrates, interacts with the carboxyl-cytoplasmic domain of GLUT4 as part of a mechanism that slows its turnover (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ). Overexpression of Ubc9 increases GLUT4 abundance 8-fold, probably as result of the conjugation of SUMO1 to GLUT4 and the resistance of the conjugate to degradation (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ). Interestingly, overexpression of Ubc9 decreases the levels of GLUT1, the ubiquitous glucose transporter homologous to GLUT4, by 2-fold. Ubc9 binds to a highly conserved sequence of 11 amino acids contained in the C-cytoplasmic domains of GLUT4 (RVPETRGRTFD) and GLUT1 (KVPETKGRTFD) (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ).
      Here we report that Daxx,
      The abbreviations used are: Daxx
      death-associated protein
      PML
      promyelocytic leukemia
      JNK
      c-Jun NH2-terminal kinase
      X-gal
      5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside
      c
      carboxyl domain
      LDM
      low density membrane
      HDM
      high density membrane
      HA
      hemagglutinin
      PM
      plasma membrane
      TβRII
      type II TGF-β receptor
      GLUT
      glucose transporter
      1The abbreviations used are: Daxx
      death-associated protein
      PML
      promyelocytic leukemia
      JNK
      c-Jun NH2-terminal kinase
      X-gal
      5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside
      c
      carboxyl domain
      LDM
      low density membrane
      HDM
      high density membrane
      HA
      hemagglutinin
      PM
      plasma membrane
      TβRII
      type II TGF-β receptor
      GLUT
      glucose transporter
      an adaptor protein associated with the Fas receptor and TβRII that mediates activation of JNK and cell apoptosis (
      • Yang X.
      • Khosravi-Far R.
      • Chang H.Y.
      • Baltimore D.
      ,
      • Perlman R.
      • Schiemann W.P.
      • Brooks M.W.
      • Lodish H.F.
      • Weinberg R.A.
      ,
      • Chang H.Y.
      • Nishitoh H.
      • Yang X.
      • Ichijo H.
      • Baltimore D.
      ) and is distributed between the PD10 nuclear bodies enriched in SUMOlated proteins (
      • Pluta A.F.
      • Earnshaw W.C.
      • Goldberg I.G.
      ,
      • Everett R.D.
      • Earnshaw W.C.
      • Pluta A.F.
      • Sternsdorf T.
      • Ainsztein A.M.
      • Carmena M.
      • Ruchaud S.
      • Hsu W.L.
      • Orr A.
      ,
      • Ishov A.M.
      • Sotnikov A.G.
      • Negorev D.
      • Vladimirova O.V.
      • Neff N.
      • Kamitani T.
      • Yeh E.T.
      • Strauss 3rd, J.F.
      • Maul G.G.
      ,
      • Torii S.
      • Egan D.A.
      • Evans R.A.
      • Reed J.C.
      ,
      • Bell P.
      • Brazas R.
      • Ganem D.
      • Maul G.G.
      ,
      • Li H.
      • Leo C.
      • Zhu J., Wu, X.
      • O'Neil J.
      • Park E.J.
      • Chen J.D.
      ,
      • Maul G.G.
      • Negorev D.
      • Bell P.
      • Ishov A.M.
      ) and the cytoplasm (
      • Perlman R.
      • Schiemann W.P.
      • Brooks M.W.
      • Lodish H.F.
      • Weinberg R.A.
      ,
      • Zhong S.
      • Muller S.
      • Ronchetti S.
      • Freemont P.S.
      • Dejean A.
      • Pandolfi P.P.
      ,
      • Zhong S.
      • Salomoni P.
      • Ronchetti S.
      • Guo A.
      • Ruggero D.
      • Pandolfi P.P.
      ,
      • Ko Y.G.
      • Kang Y.S.
      • Park H.
      • Seol W.
      • Kim J.
      • Kim T.
      • Park H.S.
      • Choi J.
      • Kim S.
      ), interacts physically with C-GLUT4 but not with C-GLUT1. As GLUT4, a small population of Daxx is conjugated to SUMO1. Microscopy studies localize Daxx to the nucleus and to punctate cytoplasmic structures identified as low density microsomes by cell fractionation studies. The binding of Daxx to GLUT4 is discussed in the framework of their demonstrated SUMOlation.

      DISCUSSION

      In this study we have shown that the insulin-sensitive glucose transporter GLUT4 interacts physically with Daxx, the adaptor protein whose function has been associated with apoptosis (
      • Yang X.
      • Khosravi-Far R.
      • Chang H.Y.
      • Baltimore D.
      ,
      • Perlman R.
      • Schiemann W.P.
      • Brooks M.W.
      • Lodish H.F.
      • Weinberg R.A.
      ,
      • Torii S.
      • Egan D.A.
      • Evans R.A.
      • Reed J.C.
      ,
      • Li R.
      • Pei H.
      • Watson D.K.
      • Papas T.S.
      ,
      • Michaelson J.S.
      ,
      • Hollenbach A.D.
      • Sublett J.E.
      • McPherson C.J.
      • Grosveld G.
      ). The co-immunoprecipitation of Daxx and GLUT4 from extracts of 3T3-L1 fibroblasts stably transfected with GLUT4 and from 3T3-L1 adipocytes expressing constitutive levels of the proteins assesses the physiological meaning of the two-hybrid interaction between Daxx and GLUT4. The small amount of Daxx/GLUT4 complexes detected in Daxx and GLUT4 immunoprecipitates suggests that the interaction implicates a small population of the proteins. This agrees with the limited colocalization of the two proteins observed in the microscopy studies
      The results of the study of Daxx in cellular fractions and by microscopy, indicate the existence of large amounts of Daxx outside the nucleus. This observation extends, therefore, recent results showing the presence of Daxx in the cytoplasm (
      • Perlman R.
      • Schiemann W.P.
      • Brooks M.W.
      • Lodish H.F.
      • Weinberg R.A.
      ,
      • Zhong S.
      • Muller S.
      • Ronchetti S.
      • Freemont P.S.
      • Dejean A.
      • Pandolfi P.P.
      ,
      • Zhong S.
      • Salomoni P.
      • Ronchetti S.
      • Guo A.
      • Ruggero D.
      • Pandolfi P.P.
      ,
      • Ko Y.G.
      • Kang Y.S.
      • Park H.
      • Seol W.
      • Kim J.
      • Kim T.
      • Park H.S.
      • Choi J.
      • Kim S.
      ). The punctate staining of the cytoplasm of 3T3-L1 fibroblasts and 3T3-L1 adipocytes incubated with antibodies against Daxx agrees with the localization of Daxx in LDM, the cellular fraction that enriched in endosomes contains a sizable part of GLUT4 (
      • Czech M.P.
      • Chawla A.
      • Woon C.W.
      • Buxton J.
      • Armoni M.
      • Tang W.
      • Joly M.
      • Corvera S.
      ). The localization of Daxx to endosomes and the identification of endosomes carrying ligand-receptor complexes as the sites where signal transduction is often initiated (
      • Haraguchi K.
      • Rodbell M.
      ) suggests that the interaction of Daxx with proteins such as Fas receptor TβRII could also occur at endosomes. The recovery of Daxx with the aqueous phase upon treatment of LDM with Triton X-114 indicates that its association with LDM membranes is peripheral, a result not unexpected since Daxx is soluble and interacts with the cytoplasmic domains of Fas receptor TβRII (
      • Yang X.
      • Khosravi-Far R.
      • Chang H.Y.
      • Baltimore D.
      ,
      • Perlman R.
      • Schiemann W.P.
      • Brooks M.W.
      • Lodish H.F.
      • Weinberg R.A.
      ) and GLUT4.
      Whereas Daxx and partly GLUT4 are localized to punctate structures distributed throughout the cytoplasm, it is interesting that in adipocytes double-immunostained for GLUT4 and Daxx the colocalization of the two proteins is confined to a few punctate structures localized in the vicinity of the PC-GSC that stores the bulk of GLUT4. The meaning of this is not clear. While the lack of extensive overlapping between the distributions of Daxx and GLUT4 could be an artifact and reflect the masking of their C-domains (involved in their interaction and containing the epitopes recognized by the antibodies), the small amount of Daxx/GLUT4 complexes found in the GLUT4 and Daxx-immunoprecipitates is in agreement with the results of the microscopy studies. Daxx could interact quickly and reversibly with GLUT4 to regulated its trafficking as it moves through one or more intracellular compartments. The contrast between the translocation of GLUT4 from intracellular stores to the plasma membrane and the staying of Daxx in LDM after stimulation of adipocytes with insulin discards that Daxx moves shoulder to shoulder with GLUT4 and reaffirms that their interaction is transient and occurs intracellularly.
      The ability of the anti-SUMO1 antibody to immunoprecipitate the 90-kDa GLUT4 species detected in crude cell lysates confirms the previous detection of SUMO1 in anti-GLUT4 immunoprecipitates (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ) and assesses the SUMOlation of GLUT4. GLUT4, therefore, may belong to the group of SUMOlated proteins whose ability to bind to Daxx has been separately documented by methods that include the yeast two-hybrid-based trap, immunoprecipitations, analysis of cellular fractions, and microscopy. The interaction of Daxx with in vitro translated C-GLUT4 and with SUMO1 (
      • Ryu S.W.
      • Chae S.K.
      • Kim E.
      ) suggest that Daxx may bind simultaneously to both. On the other hand, the lack of reactivity of GLUT1 with Daxx and its probable conjugation to SUMO1 (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ) suggests that Daxx does not interact with all the SUMOlated proteins and that additional binding determinants are involved in the binding of Daxx. Nevertheless the demonstration of the SUMOlation of Fas (
      • Okura T.
      • Gong L.
      • Kamitani T.
      • Wada T.
      • Okura I.
      • Wei C.F.
      • Chang H.M.
      • Yeh E.T.
      ) and the interaction of this with Daxx suggests that SUMO is an important determinant in the binding of Daxx to other proteins.
      The immunoprecipitation of Daxx by the anti-SUMO1 antibody and the detection of SUMO1 in Daxx-immunoprecipitates indicates that Daxx is conjugated to SUMO1. Once again, the amount of Daxx immunoprecipitated by the anti-SUMO1 antibody was small. It is not clear if the low levels of SUMOlated Daxx reflects the rapid turnover of conjugated SUMO1 in the cell or the loss of conjugated SUMO during the manipulation of the cell extracts (
      • Melchior F.
      ). Daxx has been shown to be sequestered in PML bodies, the nuclear stores of SUMOlated proteins, and its release from these results in repression of specific transcription factors (
      • Li R.
      • Pei H.
      • Watson D.K.
      • Papas T.S.
      ). We do not know if the recruitment of Daxx by PML nuclear bodies requires its prior SUMOlation. The recent demonstration that SUMO inhibits the interaction between Daxx and protein targets (
      • Li H.
      • Leo C.
      • Zhu J., Wu, X.
      • O'Neil J.
      • Park E.J.
      • Chen J.D.
      ,
      • Muller S.
      • Hoege C.
      • Pyrowolakis G.
      • Jentsch S.
      ), raises the possibility that SUMOlation may regulate the interaction between Daxx and GLUT4. With regard to this, it is interesting that SUMOlated-Daxx and SUMOlated-GLUT4 are segregated in LDM and HDM, respectively. It would be interesting, therefore, to know whether the conjugation of GLUT4 to SUMO occurs in LDM and provokes its dissociation from Daxx and its rapid transfer to HDM. The coupling between SUMOlation and trafficking could explain the localization of the 79- and 100-kDa GLUT4 species in LDM and of the SUMOlated 90-kDa GLUT4 in HDM.
      The reported interaction of GLUT4, GLUT1, and Daxx with Ubc9, the SUMO-conjugating enzyme, is likely to reflect the involvement of Ubc9 in their conjugation to SUMO1. Overexpression of Ubc9, the SUMO-conjugating enzyme, has been shown to increase dramatically the levels of GLUT4 and to decrease the levels of GLUT1 (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ). It is not known if this difference reflects their different abilities to interact with Daxx. With regard to this it would be interesting to know if the interaction of the Daxx contained in LDM blocks the targeting of GLUT4 to lysosomes in a manner regulated by SUMO.
      In addition to GLUT4, Daxx has been reported to interact with a broad array of proteins (
      • Michaelson J.S.
      ). A 139-amino acid region from the N-end of ETS1 has been shown to contain a PLL TPSSK motif (Daxx interacting domain) conserved as P SVLL DAK in the CENP-C sequence (
      • Li R.
      • Pei H.
      • Watson D.K.
      • Papas T.S.
      ) and contained asP SLL EQEVK in C-GLUT4. It is interesting that substitution of AS for LL in C-GLUT4 inhibited the two-hybrid interaction between Daxx and GLUT4. Because the inhibition was not complete it is likely that other determinants in C-GLUT4 may mediate its interaction with Daxx.
      Computer-aided alignment of the human C-GLUT4 sequence and the sequences of another six Daxx-binding proteins, including H-CENP, H-ASK1, H-PML, H-ETS1, H-Pax3, and H-Fas receptor, reveals a three-block consensus within a domain of less than 73 residues (see Fig. 10). While the domain of C-GLUT4 that binds to Ubc9 has been identified (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ) and C-GLUT4 contains sequences that could be involved in the regulation of SUMO conjugation (
      • Melchior F.
      ), the only putative SUMO1 acceptor sequences in the GLUT4 molecule (KXD or E, and P or G residues two to five sites upstream or downstream of the acceptor lysine) are localized to its large cytoplasmic loop (K DE KRK LE RERP).
      Figure thumbnail gr10
      Figure 10Binding domains in Daxx protein targets. The C-domain of GLUT4 was aligned with the sequences of six other Daxx-binding proteins. Putative Daxx binding domains are divided into three subdomains: A, B, and C. Identical and conserved residues are black and gray boxed, respectively.
      While the almost exclusive association of Daxx with cytoplasmic and nuclear mechanisms that control apoptosis may reflect the current areas of interest, it is interesting that in addition to the interaction with GLUT4 described here Daxx interacts with the centromeric protein CENP-C during interphase (
      • Pluta A.F.
      • Earnshaw W.C.
      • Goldberg I.G.
      ). In fact, the interaction between CENP-C and Daxx and the recently demonstrated binding of Daxx to SUMO makes it more comprehensible that the first reported member of the SUMO family, the Saccharomyces cerevisiae SMT3, was cloned in a screen for suppressors of a temperature-sensitive allele of MIF2, a gene encoding an homologue of the mammalian CENP-C (
      • Meluh P.B.
      • Koshland D.
      ). One of the most relevant findings of the recent analysis of functional protein complexes in S. cerevisiae (
      • Ho Y.
      • Gruhler A.
      • Meffbut A.
      • Bader G.D.
      • Moore L.
      • Adams S.-L.
      • Millar A.
      • Taylor P.
      • Bennett K.
      • Boutillier K.
      • et al.
      ,
      • Gavin A.-C.
      • Bösche M.
      • Krause R.
      • Grandi P.
      • Marzioch M.
      • Bauer A.
      • Schultz J.
      • Rick J.M.
      • Michon A.-M.
      • Cruciat C.-M.
      • et al.
      ) is that the same protein is often integrated in different complexes, a finding that suggests that the activity of a protein may depend on the protein complex in which it is incorporated.
      In summary, we have shown here that Daxx interacts specifically with GLUT4 both in vitro and in vivo and that both proteins are conjugated to SUMO1. SUMO1 is known to enhance protein stability and to be an address for protein targeting. While SUMO 1 enhances GLUT4 stability (
      • Giorgino F.
      • de Robertis O.
      • Laviola L.
      • Montrone C.
      • Perrini S.
      • McCowen K.C.
      • Smith R.J.
      ) it is not known if this effect is produced through the regulation of GLUT4 trafficking. The ability of GLUT4 to interact with Daxx appears to be transient. This ability extends the number of SUMO targets that interact with Daxx.

      ACKNOWLEDGEMENTS

      We thank Dr. Carlos Sanchez and Maria Angeles Muñoz for help with the confocal microscopy. The institutional support of the Fundación Ramón Areces is acknowledged.

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