S J Burakoff

Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States

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Publications (371)2787.89 Total impact

  • No preview · Article · Apr 2014 · Cancer Research
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    ABSTRACT: Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin fixed and paraffin embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53 immune gene panel predictive of non-progression (AUC=0.920) defined. The signature predicted disease specific survival (DSS P<0.001) and relapse free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a co-expression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001) and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger dataset annotated based on prospectively gathered data.Journal of Investigative Dermatology accepted article preview online, 12 February 2014; doi:10.1038/jid.2014.85.
    Full-text · Article · Feb 2014 · Journal of Investigative Dermatology
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    ABSTRACT: HIV-1 Nef is an accessory protein necessary for HIV-1 virulence and rapid AIDS development. Nef promotes viral replication and infection by connecting CD4 and several other cell surface receptors to the clathrin adaptor protein AP2, resulting in the internalization and degradation of the receptors interacting with Nef. We investigated how Nef can mediate constitutive receptor endocytosis through the interaction of the dileucine motif in its C-terminal flexible loop (C-loop) with AP2, whereas AP2 binding of the transmembrane receptors usually results in an equilibrated (recycled) endocytosis. Our results indicated that besides the dileucine motif, there is a second motif in the Nef C-loop involved in the Nef-AP2 interaction. Nef-mediated CD4 downregulation was impaired when the residue in the hydrophobic region in the Nef C-loop (LL165HPMSLHGM173) was mutated to a basic residue K/R or an acidic residue E/D or to the rigid residue P, or when M168L170, L170H171 or G172M173 were mutated to AA. A pull-down assay indicated that AP2 was not co-precipitated with Nef mutants that did not downregulate CD4. Computer modeling of the Nef C-terminal flexible loop in complex with AP2 suggests that M168L170 occupies a pocket in the AP2 s2 subunit. Our data suggest a new model in the Nef-AP2 interaction -where the hydrophobic region in the Nef C-loop with the dileucine (L164L165) motif and M168L170 motif bind to AP2(s2), while the acidic motif E174 and D175 binds to AP2(α), which explains how Nef through the flexible loop connects CD4 to AP2 for the constitutive CD4 downregulation.
    No preview · Article · Nov 2012 · AIDS research and human retroviruses
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    ABSTRACT: HPK1 is a negative regulator of TCR-initiated signal transduction. HPK1-/- mice are more susceptible to experimental autoimmune encephalomyelitis, suggesting that the ability to enforce peripheral tolerance may have been compromised. Paradoxically, we observed that more natural regulatory T cells were found in the periphery of HPK1-/- mice than in wild type C57BL/6. We determined whether HPK1-/- Foxp3+ Tregs retained their ability to suppress TCR-induced effector T cell proliferation and found that they lack the ability to suppress. Because the ability to suppress T cell proliferation is a function conferred to Tregs by Foxp3-dependent suppression of IL-2 transcription, we assessed whether HPK1-/- Foxp3+ Tregs retain the ability to repress TCR-induced IL-2 production. We found that HPK1-/- Tregs produce a significant amount of IL-2 in response to TCR engagement, suggesting that Foxp3 is unable to carry out transcriptional repression. This aberrant phenotype implicates HPK1 as an important regulator of Treg functions.
    No preview · Conference Paper · May 2012
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    Sansana Sawasdikosol · Renyuan Zha · Boyu Yang · Steven Burakoff
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    ABSTRACT: Identifying the appropriate drug targets for the development of a novel anti-tumor immunotherapy is one of the most risky steps in the drug development cycle. We have identified a hematopoietic cell-restricted serine/threonine kinase, hematopoietic progenitor kinase 1 (HPK1), as a possible target for therapeutic intervention. Targeted disruption of HPK1 alleles confers T cells with an elevated Th1 cytokine production in response to TCR engagement. HPK1 −/− T cells proliferate more rapidly than the haplotype-matched wild-type counterpart and are resistant to prostaglandin E2 (PGE2)-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1 −/− T cells became resistant to lung tumor growth. Also, the loss of HPK1 from dendritic cells (DCs) endows them with superior antigen presentation ability, enabling HPK1 −/− DCs to elicit a more potent anti-tumor immune response when used as cancer vaccine. It is probable that blocking the HPK1 kinase activity with a small molecule inhibitor may activate the superior anti-tumor activity of both cell types, resulting in a synergistic amplification of anti-tumor potential. Given that HPK1 is not expressed in any major organs, it is less likely that an inhibitor of HPK1 kinase activity would cause any serious side effects.
    Full-text · Article · Apr 2012 · Immunologic Research
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    ABSTRACT: T cell (TC) activation requires the coordinated signaling of the T cell receptor (TCR) and coreceptor molecules, allowing TCs to respond to lower degrees of TCR occupancy. Coreceptor molecules set the threshold for TC activation by controlling different regulatory signaling loops. The Cbl family members prevent undesired activation of T cells by regulating TCR signals. In this report, we show that TC prestimulation by the CD43 coreceptor molecule before TCR engagement inhibits TCR-dependent c-Cbl tyrosine phosphorylation, c-Cbl interaction with the adapter molecule Crk-L and promotes Cbl-b degradation in a PKCθ-dependent manner. Consequently, the prolonged tyrosine phosphorylation and delayed degradation of ZAP-70 and of the ζ chain lead to enhanced mitogen-activated protein kinase activation and robust TC response. These data indicates that CD43-mediated signals lower the threshold for TC activation by restricting the c-Cbl and Cbl-b inhibitory effects on TCR signaling. In addition to the strength and duration of intracellular signals, our data underscore temporality with which certain molecules are engaged as yet another mechanism to fine tune TC signal quality, and ultimately immune function.
    Full-text · Article · Oct 2011 · International Union of Biochemistry and Molecular Biology Life
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    ABSTRACT: HIV-1 and SIV Nef proteins downregulate cell surface CD4 and MHC class I (MHC-I) molecules of infected cells, which are necessary for efficient viral replication and pathogenicity. We previously reported that K144 in HIV-1 Nef is di-ubiquitinated, and K144R substitution impairs Nef-mediated CD4 downregulation. In this report, we extend the role of ubiquitination at this lysine residue from Nef-mediated CD4 downregulation to Nef-mediated MHC-I downregulation and from HIV Nef to SIV Nef. All HIV-1 Nef mutants that contain K144R substitution are inactive in MHC-I downregulation. Tested MHC-I alleles include HLA-ABC endogenously expressed and HLA-A2 exogenously expressed in Jurkat T cells. CD4 downregulation by SIV Nef involves K176 that aligns with K144 in HIV-1 Nef, as well as an N-terminal tyrosine motif Y28Y39 not present in HIV-1 Nef. Dual mutation at K176 and Y28Y39 completely impaired SIV Nef-mediated CD4 and MHC-I downregulation, whereas a single mutation at K176 or Y28Y39 did not. The involvement of tyrosine motif in SIV Nef-mediated CD4 and MHC-I downregulation prompted us to investigate a putative tyrosine motif (Y202Y/F203) in HIV-1 Nef that is conserved among HIV-1 species. Single mutation at the tyrosine motif Y202F203 in HIV-1 Nef (NA7) greatly impaired Nef-mediated CD4 downregulation, which is similar to what we observed previously with the single mutation at lysine K144. Thus, our study demonstrated that Nef-mediated receptor endocytosis involves the ubiquitination motif and tyrosine motif.
    Full-text · Article · May 2011 · The Journal of Immunology
  • Qin Wang · Wei Luan · Vadim Goz · Steven J Burakoff · Spiros P Hiotis
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    ABSTRACT: Maintenance of complex transgenic colonies and labour-intensive techniques pose significant challenges in work involving mouse models for hepatocellular carcinoma (HCC). Other animal models of unusual species are generally impractical for research purposes. To develop a highly reproducible orthotopic mouse model for HCC based on the murine α-foetoprotein (AFP), producing cell line Hepa1-6 and to monitor liver tumour progression via in vivo imaging, and measurement of plasma AFP. Intrahepatic tumour was induced following subcapsular implantation of 10(+6) Hepa1-6 cells into C57L/J mice. AFP production was examined in vitro and in vivo using immunoblotting. Three confirmatory non-invasive imaging modalities were applied to follow tumour progression over time including ultrasound biomicroscopy (UBM), micromagnetic resonance imaging (microMRI), and bioluminescence. Results: α-foetoprotein expression was confirmed both in vitro and in vivo, with increasing levels in the plasma as tumours progressed. UBM, microMRI and bioluminescence detected intrahepatic tumours to a 2 mm resolution by day 14. Sequential imaging studies demonstrated an intrahepatic pattern of disease progression with an observed median survival of 29 days. Immunosuppression of tumour-bearing mice led to a greater tumour size and decreased survival. Intrahepatic implantation of Hepa1-6 as a mouse model for HCC is a highly reproducible in vivo system with tumour biology analogous to human disease and is regulated by the presence of an intact host immune system. Tumour progression may be monitored in vivo by UBM, microMRI and bioluminescence. Plasma AFP increases over time, allowing redundancy in non-invasive means of following tumour progression.
    No preview · Article · Apr 2011 · Liver international: official journal of the International Association for the Study of the Liver
  • William K Oh · Steven J Burakoff

    No preview · Article · Nov 2010 · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine
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    Yong-Jiu Jin · Xiaoping Zhang · Catherine Yi Cai · Steven J Burakoff
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    ABSTRACT: Nef is a 27 KDa HIV-1 accessory protein. It downregulates CD4 from infected cell surface, a mechanism critical for efficient viral replication and pathogenicity. Agents that antagonize the Nef-mediated CD4 downregulation may offer a new class of drug to combat HIV infection and disease. TPCK (N-alpha-p-tosyl-L-phenylalanine chloromethyl ketone) and TLCK (N-alpha-p-tosyl-L-lysine chloromethyl ketone) are alkylation reagents that chemically modify the side chain of His or Cys residues in a protein. In search of chemicals that inhibit Nef function, we discovered that TPCK and TLCK alkylated HIV Nef. Nef modification by TPCK was demonstrated on reducing SDS-PAGE. The specific cysteine residues modified were determined by site-directed mutagenesis and mass spectrometry (MS). The effect of TPCK modification on Nef-CD4 interaction was studied using fluorescence titration of a synthetic CD4 tail peptide with recombinant Nef-His protein. The conformational change of Nef-His protein upon TPCK-modification was monitored using CD spectrometry Incubation of Nef-transfected T cells, or recombinant Nef-His protein, with TPCK resulted in mobility shift of Nef on SDS-PAGE. Mutagenesis analysis indicated that the modification occurred at Cys55 and Cys206 in Nef. Mass spectrometry demonstrated that the modification was a covalent attachment (alkylation) of TPCK at Cys55 and Cys206. Cys55 is next to the CD4 binding motif (A56W57L58) in Nef required for Nef-mediated CD4 downregulation and for AIDS development. This implies that the addition of a bulky TPCK molecule to Nef at Cys55 would impair Nef function and reduce HIV pathogenicity. As expected, Cys55 modification reduced the strength of the interaction between Nef-His and CD4 tail peptide by 50%. Our data suggest that this Cys55-specific alkylation mechanism may be exploited to develop a new class of anti HIV drugs.
    Preview · Article · Jul 2010 · AIDS Research and Therapy
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    ABSTRACT: Lung cancer is the leading cause of cancer-related mortality in the world, resulting in over a million deaths each year. Non-small cell lung cancers (NSCLCs) are characterized by a poor immunogenic response, which may be the result of immunosuppressive factors such as prostaglandin E2 (PGE2) present in the tumor environment. The effect of PGE2 in the suppression of anti-tumor immunity and its promotion of tumor survival has been established for over three decades, but with limited mechanistic understanding. We have previously reported that PGE2 activates hematopoietic progenitor kinase 1 (HPK1), a hematopoietic-specific kinase known to negatively regulate T-cell receptor signaling. Here, we report that mice genetically lacking HPK1 resist the growth of PGE2-producing Lewis lung carcinoma (LLC). The presence of tumor-infiltrating lymphocytes (TILs) and T-cell transfer into T cell-deficient mice revealed that tumor rejection is T cell mediated. Further analysis demonstrated that this may be significantly due to the ability of HPK1−/− T cells to withstand PGE2-mediated suppression of T-cell proliferation, IL-2 production, and apoptosis. We conclude that PGE2 utilizes HPK1 to suppress T cell-mediated anti-tumor responses. Electronic supplementary material The online version of this article (doi:10.1007/s00262-009-0761-0) contains supplementary material, which is available to authorized users.
    Full-text · Article · Sep 2009 · Cancer Immunology and Immunotherapy
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    ABSTRACT: Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 kinases that acts as a negative regulator of T cell functions through the AP-1, NFAT, and NFkappaB pathways. Using HPK1-deficient (HPK1(-/-)) mice, we report in this study a novel role for HPK1 in dendritic cells (DCs). Specifically, we observed that matured HPK1(-/-) bone marrow-derived DCs (BMDCs) are superior to their wild-type (WT) counterpart in stimulating T cell proliferation in vivo and in vitro. Several characteristics of HPK1(-/-) BMDCs may account for this enhanced activity: Matured HPK1(-/-) BMDCs express higher levels of costimulatory molecules CD80, CD86, and I-A(b) as well as produce more proinflammatory cytokines IL-12, IL-1beta, TNF-alpha, and IL-6 than their WT littermates. The role of HPK1 as a proapoptotic molecule was assessed post activation with LPS, and results indicated that HPK1(-/-) BMDCs are significantly resistant to LPS-induced apoptosis. Our results led us to investigate the role of HPK1(-/-) BMDCs in tumor immunotherapy. Using a s.c. murine model of Lewis Lung Carcinoma, we found that HPK1(-/-) BMDCs eliminate established s.c. Lewis Lung Carcinoma more efficiently than their WT counterpart. Our data reveal a novel role for HPK1 as a negative regulator of DC functions, identifying its potential as a molecular target for DC-based immunotherapy against cancers.
    Full-text · Article · Jun 2009 · The Journal of Immunology
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    ABSTRACT: Interleukin-3 (IL-3) regulates cell growth by affecting various processes such as cell death, survival, and proliferation. Cues from the external environment are sensed by surface receptors, and complex signaling mechanisms arise within the cells, leading to specific functional outcomes. In this study, we demonstrate that the cytokine IL-3 induces the activation of the Ca2+-dependent phosphatase, calcineurin (Cn). Furthermore Cn dephosphorylates Gab2, resulting in c-fos activation and cell proliferation. We also report that there is a direct interaction between Cn and Gab2 upon IL-3 stimulation, and Akt can regulate this interaction.
    Preview · Article · Jul 2008 · Journal of Biological Chemistry
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    Yong-Jiu Jin · Catherine Yi Cai · Xiaoping Zhang · Steven J Burakoff
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    ABSTRACT: Nef is a HIV-1 accessory protein critical for the replication of the virus and the development of AIDS. The major pathological activity of Nef is the down-regulation of CD4, the primary receptor of HIV-1 infection. The mechanism underlying Nef-mediated CD4 endocytosis and degradation remains incompletely understood. Since protein ubiquitination is the predominant sorting signal in receptor endocytosis, we investigated whether Nef is ubiquitinated. The in vivo ubiquitination assay showed that both HIV-1 and SIV Nef proteins expressed in Jurkat T cells and 293T cells were multiple ubiquitinated by ubiquitin-His. The lysine-free HIV-1 Nef mutant (Delta10K) generated by replacing all 10 lysines with arginines was not ubiquitinated and the major ubiquitin-His attachment sites in HIV-1 Nef were determined to be lysine 144 (di-ubiquitinated) and lysine 204 (mono-ubiquitinated). Lysine-free HIV-1 Nef was completely inactive in Nef-mediated CD4 down-regulation, so was the Nef mutant with a single arginine substitution at K144 but not at K204. A mutant HIV-1 provirion NL4-3 with a single arginine substitution in Nef at K144 was also inactive in Nef-mediated CD4 down-regulation. Lysine-free Nef mutant reintroduced with lysine 144 (DeltaK10 + K144) was shown active in CD4 down-regulation. These data suggest that ubiquitination of Nef, particularly diubiquitination of the lysine 144, is necessary for Nef-mediated CD4 down-regulation.
    Preview · Article · Jun 2008 · The Journal of Immunology
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    ABSTRACT: Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. We recently reported that the immunosuppressive eicosanoid, prostaglandin E(2) (PGE(2)), is capable of activating HPK1 in T cells. In this report, we demonstrate that unlike the TCR-induced activation of HPK1 kinase activity, the induction of HPK1 catalytic activity by PGE(2) does not require the presence of phosphotyrosine-based signaling molecules such as Lck, ZAP-70, SLP-76, and Lat. Nor does the PGE(2)-induced HPK1 activation require the intermolecular interaction between its proline-rich regions and the SH3 domain-containing adaptor proteins, as required by the signaling from the TCR to HPK1. Instead, our study reveals that PGE(2) signal to HPK1 via a 3' -5 '-cyclic adenosine monophosphate-regulated, PKA-dependent pathway. Consistent with this observation, changing the serine 171 residue that forms the optimal PKA phosphorylation site within the "activation loop" of HPK1 to alanine completely prevents this mutant from responding to PGE(2)-generated stimulation signals. Moreover, the inability of HPK1 to respond to PGE(2) stimulation in PKA-deficient S49 cells further supports the importance of PKA in this signaling pathway. We speculate that this unique signaling pathway enables PGE(2) signals to engage a proven negative regulator of TCR signal transduction pathway and uses it to inhibit T cell activation.
    Full-text · Article · Dec 2007 · Journal of Biological Chemistry
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    ABSTRACT: A long—term CD4— CD8—TCR αβ human T—cell line, as well as similar CD4— CD8— TCR γδ T—cell lines for comparison, were generated from various tissues by negative selection using anti—CD4 and anti—CD8 monoclonal antibodies (MAbs) followed by positive selection with specific anti—TCR MAb and then repeated in vitro stimulation with interleukin—enriched media and lectin. These cell lines all demonstrated non—MHC—restricted cytolysis on a variety of human tumor cell lines. However, removal of lymphokines from the culture media for 24 hr abrogated most of the non—MHC—restricted target—cell lysis without affecting TCR αβ or TCR γδ cell viability or TCR function as determined by antibody—triggered redirected target—cell lysis. Subsequent re—exposure to lymphokines reconstituted non—MHC—restricted cytolysis by these cell lines. Thus, much of the non—specific, non—MHC—restricted cytolytic activity generated by CD4—CD8—TCRαβ or TCRγδ cells is secondary to lymphokine—activated killing (LAK) activity. These cells have potent LAK activity and may be prominent in LAK—cell populations. In addition, after lymphokine deprivation, both CD4—CD8—TCRαβ and TCRγδ cells showed residual activity against some tumor—cell targets, the nature of which remains to be defined.
    No preview · Article · Apr 2007 · International Journal of Cancer
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    ABSTRACT: ajor advances in genome science and molecular technologies provide new opportunities at the interface between basic biological research and medical practice. The unprecedented completeness, accuracy, and volume of genomic and molecular data necessitate a new kind of computational biology for translational research. Key challenges are standardization of data capture and communication, organization of easily accessible repositories, and algorithms for integrated analysis based on heterogeneous sources of information. Also required are new ways of using complementary clinical and biological data, such as computational methods for predicting disease phenotype from molecular and genetic profiling. New combined experimental and computational methods hold the promise of more accurate diagnosis and prognosis as well as more effective prevention and therapy.
    Full-text · Article · Mar 2007 · PLoS Computational Biology
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    Ruben C Fragoso · Saiju Pyarajan · Hanna Yoko Irie · Steven J Burakoff
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    ABSTRACT: Efficient development of thymocytes requires participation of a CD8 or CD4 coreceptor in the TCR:MHC interaction. Both CD8 and CD4 coreceptor cytoplasmic domains associate with Lck. In this study, we attempted to delineate the role of CD8alpha-associated Lck in driving CD8 single positive (SP) thymocyte development. We used a chimeric molecule encoding the extracellular and transmembrane domains of CD8alpha fused to full-length Lck. In mice deficient for CD8alpha and transgenic for 2C, a MHC class I-restricted TCR, robust reconstitution of CD8 SP thymocytes occurred both centrally and peripherally. The reconstituted CD8 SP population was phenotypically and functionally comparable to 2C wild-type counterparts expressing endogenous CD8alpha. A CD8alpha/Lck kinase-dead chimera also resulted in reconstitution of CD8 SP thymocytes. Our results suggest that CD8alpha-associated Lck is sufficient to drive CD8 SP thymocyte development. Furthermore, this CD8 SP development may not necessarily depend on Lck kinase activity.
    Preview · Article · Dec 2006 · The Journal of Immunology
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    ABSTRACT: Interleukin 2 (IL-2) and interleukin 15 (IL-15) bind to common T-cell surface receptors comprised of unique alpha (IL-2R alpha or IL-15R alpha) and shared beta/gamma chain subunits. Ligation of this receptor by IL-2 can lead to apoptosis whereas IL-15 ligation favors cell survival. Our study examined intra-cellular signaling events associated with IL-2- and IL-15-induced apoptosis and survival in human T cells. We found IL-2 and IL-15 could both induce apoptosis and survival; the outcome depended on cytokine concentration. No qualitative differences in Jak/Stat, Ras/MAPK or PI3K/AKT signaling were seen over a wide range of IL-2 and IL-15 concentrations. These findings suggest that, like T-cell receptor signaling, IL-2R beta/gamma chain signaling is regulated, or "tuned," by the concentration of cytokine.
    Full-text · Article · Dec 2005 · American Journal of Transplantation
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    ABSTRACT: Nef is a crucial viral protein for HIV to replicate at high titers and in the development of AIDS. One Nef function is down-regulating CD4 from the cell surface, which correlates with Nef-enhanced viral pathogenicity. Nef down-regulates CD4 by linking CD4 to clathrin-coated pits. However, the mechanistic connection between the C-terminal dileucine motif of Nef and the component(s) of the clathrin-coated pits has not been pinpointed. In this report we used two AP-2 complex-specific inhibitors: a dominant negative mutant of Eps15 (Eps15DIII) that binds to the alpha subunit of AP-2 complex and a small interference RNA that is specific for the mu2 subunit of AP-2 complex. We show that both HIV Nef- and SIV Nef-mediated CD4 down-regulations were profoundly blocked by the synergistic effect of Eps15DIII and RNA interference of AP-2 expression. The results demonstrate that HIV/SIV Nef-mediated CD4 down-regulation is AP-2 dependent. We also show that the PMA-induced CD4 down-regulation was blocked by these two inhibitors. Therefore, PMA-induced CD4 down-regulation is also AP-2 dependent. The results demonstrate that, like the tyrosine sorting motif-dependent endocytosis (for which the transferrin receptor and the epidermal growth factor receptor are the two prototypes), dileucine sorting motif-dependent endocytosis of Nef and CD4 are also AP-2 dependent.
    Preview · Article · Oct 2005 · The Journal of Immunology

Publication Stats

19k Citations
2,787.89 Total Impact Points


  • 2010-2014
    • Icahn School of Medicine at Mount Sinai
      • Department of Oncological Sciences
      Borough of Manhattan, New York, United States
  • 2008-2012
    • Moncrief Cancer Institute
      Fort Worth, Texas, United States
  • 2011
    • Mount Sinai Medical Center
      New York City, New York, United States
  • 2009
    • NYU Langone Medical Center
      New York, New York, United States
  • 2004-2009
    • CUNY Graduate Center
      New York, New York, United States
    • University of Oxford
      Oxford, England, United Kingdom
  • 1976-2007
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Pediatrics
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 1982-2006
    • Dana-Farber Cancer Institute
      • • Department of Pediatric Oncology
      • • Department of Cancer Biology
      Boston, MA, United States
  • 2002
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, Michigan, United States
  • 2001-2002
    • Memorial Sloan-Kettering Cancer Center
      • Department of Medicine
      New York City, NY, United States
  • 1983-2000
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Department of Surgery
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 1975-1999
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 1995
    • Brandeis University
      • Department of Biology
      Waltham, Massachusetts, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1993
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
  • 1991
    • Institut de recherches cliniques de Montréal
      Montréal, Quebec, Canada
  • 1984-1991
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 1988
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States