The Experts below are selected from a list of 3657 Experts worldwide ranked by ideXlab platform
Giovanna Tosi - One of the best experts on this subject based on the ideXlab platform.
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The MHC-II transactivator CIITA inhibits Tat function and HIV-1 replication in human myeloid cells
Journal of translational medicine, 2016Co-Authors: Greta Forlani, Roberto S. Accolla, Filippo Turrini, Silvia Ghezzi, Alessandra Tedeschi, Guido Poli, Giovanna TosiAbstract:We previously demonstrated that the HLA class II transactivator CIITA inhibits HIV-1 replication in T cells by competing with the viral transactivator Tat for the binding to Cyclin T1 subunit of the P-TEFb complex. Here, we analyzed the anti-viral function of CIITA in myeloid cells, another relevant HIV-1 target cell type. We sinvestigated clones of the U937 promonocytic cell line, either permissive (Plus) or non-permissive (Minus) to HIV-1 replication. This different phenotype has been associated with the expression of TRIM22 in U937 Minus but not in Plus cells. U937 Plus cells stably expressing CIITA were generated and HLA-II positive clones were selected by cell sorting and cloning. HLA and CIITA proteins were analyzed by cytofluorometry and western blotting, respectively. HLA-II DR and CIITA mRNAs were quantified by qRT-PCR. Tat-dependent transactivation was assessed by performing the HIV-1 LTR luciferase gene reporter assay. Cells were infected with HIV-1 and viral replication was evaluated by measuring the RT activity in culture supernatants. CIITA was expressed only in HLA-II-positive U937 Minus cells, and this was strictly correlated with inhibition of Tat-dependent HIV-1 LTR transactivation in Minus but not in Plus cells. Overexpression of CIITA in Plus cells restored the suppression of Tat transactivation, confirming the inhibitory role of CIITA. Importantly, HIV-1 replication was significantly reduced in Plus-CIITA cells with respect to Plus parental cells. This effect was independent of TRIM22 as CIITA did not induce TRIM22 expression in Plus-CIITA cells. U937 Plus and Minus cells represent an interesting model to study the role of CIITA in HIV-1 restriction in the monocytic/macrophage cell lineage. The differential expression of CIITA in CIITA-negative Plus and CIITA-positive Minus cells correlated with their capacity to support or not HIV-1 replication, respectively. In Minus cells CIITA targeted the viral transactivator Tat to inhibit HIV-1 replication. The generation of Plus-CIITA cells was instrumental to demonstrate the specific contribution of CIITA in terms of inhibition of Tat activity and HIV-1 restriction, independently from other cellular factors, including TRIM22. Thus, CIITA acts as a general restriction factor against HIV-1 not only in T cells but also in myeloid cells.
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The MHC Class II transactivator CIITA inhibits the persistent activation of NF-kB by Tax-1
Retrovirology, 2015Co-Authors: Greta Forlani, Rawan Abdallah, Roberto S. Accolla, Luisa Guidali, Giovanna TosiAbstract:Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Many studies have shown that the constitutive activation of NF-kB pathway by the viral transactivator Tax-1 is crucial for T-cell transformation. We previously identified the cellular factor Class II transactivator (CIITA), the master regulator of Major Histo compatibility Complex Class II gene transcription, as a restriction factor inhibiting HTLV-1 replication by blocking Tax-1-mediated activation of the viral LTR promoter (1). Here we show that CIITA suppresses also the activation of the canonical NF-kB pathway by Tax-1 and mapped the region of CIITA mediating this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm and this correlates with an impaired migration of Rel Ain to the nucleus. By using nuclear and cytoplasmic deletion mutants of CIITA, we demonstrate that CIITA suppresses the activation of NF-kB by Tax-1 in both the subcellular compartments. Interestingly, CIITA binds to Tax-1 in vivo without preventing the binding of Tax-1 to both IKKg and RelA. Nevertheless, Tax-1-induced IKK kinase activity is affected in the presence of CIITA as demonstrated by impaired phosphorylation of IkB inhibitor, which is responsible for the impaired migration of RelA into the nucleus. Thus, the inactive p50/RelA heterodimer is trapped in the cytoplasm and this results in the suppression of the activation of NF-kB responsive genes by Tax-1. Overall, these findings indicate that CIITA has evolved as a versatile molecule that, besides inhibiting viral gene expression promoted by Tax-1, it might counteract also Tax-1 transforming activity. Thus, unveiling the molecular basis of CIITA-mediated Tax-1 inhibition may be important in defining new strategies to control HTLV-1 spreading and on cogenic potential
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The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators
Frontiers in Microbiology, 2013Co-Authors: Greta Forlani, Rawan Abdallah, Roberto S. Accolla, Giovanna TosiAbstract:The activation of CD4+ T helper cells is strictly dependent on the presentation of antigenic peptides by MHC Class II molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (Class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Beside this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution.
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major histocompatibility complex class ii transactivator CIITA is a viral restriction factor that targets human t cell lymphotropic virus type 1 tax 1 function and inhibits viral replication
Journal of Virology, 2011Co-Authors: Giovanna Tosi, Greta Forlani, Guido Poli, Vibeke Andresen, Marco Turci, Umberto Bertazzoni, Genoveffa Franchini, Roberto S. AccollaAbstract:Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Since the viral transactivator Tax-1 is a major player in T-cell transformation, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and to counteract neoplastic transformation. We demonstrate that CIITA, the master regulator of major histocompatibility complex class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo via the first 108 amino acids of Tax-1 and two CIITA adjacent regions (amino acids 1 to 252 and 253 to 410). Interestingly, only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64 to 124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2. Instead, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular coactivators p300/CBP-associated factor (PCAF), cyclic AMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1), which are required for the optimal activation of HTLV-1 promoter. Accordingly, the overexpression of PCAF, CREB, and ATF1 restored Tax-1-dependent transactivation of the viral long-terminal-repeat promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.
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the mhc ii transactivator CIITA a viral restriction factor inhibiting the replication of human t cell lymphotropic virus type 1
Retrovirology, 2011Co-Authors: Giovanna Tosi, Greta Forlani, Vibeke Andresen, Marco Turci, Umberto Bertazzoni, Genoveffa Franchini, Roberto S. AccollaAbstract:Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. It is believed that the viral transactivator Tax-1 is a major player in T-cell transformation. Thus, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and ultimately to counteract neoplastic transformation. Here, we demonstrated that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1. Co-immunoprecipitation experiments have shown that CIITA and Tax-1 physically interact in vivo and that the first 108 amino acids of Tax-1 were necessary for this binding. Two adjacent regions (1-252 and 253-410) of CIITA bound independently to Tax-1, but only region 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64-124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 function correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2, a virus with still elusive pathogenic action. Furthermore, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular co-activator PCAF, which is required for the optimal activation of HTLV-1 promoter. Accordingly, the over-expression of PCAF restored Tax-1-dependent transactivation of the viral LTR promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.
Roberto S. Accolla - One of the best experts on this subject based on the ideXlab platform.
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The MHC-II transactivator CIITA inhibits Tat function and HIV-1 replication in human myeloid cells
Journal of translational medicine, 2016Co-Authors: Greta Forlani, Roberto S. Accolla, Filippo Turrini, Silvia Ghezzi, Alessandra Tedeschi, Guido Poli, Giovanna TosiAbstract:We previously demonstrated that the HLA class II transactivator CIITA inhibits HIV-1 replication in T cells by competing with the viral transactivator Tat for the binding to Cyclin T1 subunit of the P-TEFb complex. Here, we analyzed the anti-viral function of CIITA in myeloid cells, another relevant HIV-1 target cell type. We sinvestigated clones of the U937 promonocytic cell line, either permissive (Plus) or non-permissive (Minus) to HIV-1 replication. This different phenotype has been associated with the expression of TRIM22 in U937 Minus but not in Plus cells. U937 Plus cells stably expressing CIITA were generated and HLA-II positive clones were selected by cell sorting and cloning. HLA and CIITA proteins were analyzed by cytofluorometry and western blotting, respectively. HLA-II DR and CIITA mRNAs were quantified by qRT-PCR. Tat-dependent transactivation was assessed by performing the HIV-1 LTR luciferase gene reporter assay. Cells were infected with HIV-1 and viral replication was evaluated by measuring the RT activity in culture supernatants. CIITA was expressed only in HLA-II-positive U937 Minus cells, and this was strictly correlated with inhibition of Tat-dependent HIV-1 LTR transactivation in Minus but not in Plus cells. Overexpression of CIITA in Plus cells restored the suppression of Tat transactivation, confirming the inhibitory role of CIITA. Importantly, HIV-1 replication was significantly reduced in Plus-CIITA cells with respect to Plus parental cells. This effect was independent of TRIM22 as CIITA did not induce TRIM22 expression in Plus-CIITA cells. U937 Plus and Minus cells represent an interesting model to study the role of CIITA in HIV-1 restriction in the monocytic/macrophage cell lineage. The differential expression of CIITA in CIITA-negative Plus and CIITA-positive Minus cells correlated with their capacity to support or not HIV-1 replication, respectively. In Minus cells CIITA targeted the viral transactivator Tat to inhibit HIV-1 replication. The generation of Plus-CIITA cells was instrumental to demonstrate the specific contribution of CIITA in terms of inhibition of Tat activity and HIV-1 restriction, independently from other cellular factors, including TRIM22. Thus, CIITA acts as a general restriction factor against HIV-1 not only in T cells but also in myeloid cells.
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The MHC Class II transactivator CIITA inhibits the persistent activation of NF-kB by Tax-1
Retrovirology, 2015Co-Authors: Greta Forlani, Rawan Abdallah, Roberto S. Accolla, Luisa Guidali, Giovanna TosiAbstract:Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Many studies have shown that the constitutive activation of NF-kB pathway by the viral transactivator Tax-1 is crucial for T-cell transformation. We previously identified the cellular factor Class II transactivator (CIITA), the master regulator of Major Histo compatibility Complex Class II gene transcription, as a restriction factor inhibiting HTLV-1 replication by blocking Tax-1-mediated activation of the viral LTR promoter (1). Here we show that CIITA suppresses also the activation of the canonical NF-kB pathway by Tax-1 and mapped the region of CIITA mediating this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm and this correlates with an impaired migration of Rel Ain to the nucleus. By using nuclear and cytoplasmic deletion mutants of CIITA, we demonstrate that CIITA suppresses the activation of NF-kB by Tax-1 in both the subcellular compartments. Interestingly, CIITA binds to Tax-1 in vivo without preventing the binding of Tax-1 to both IKKg and RelA. Nevertheless, Tax-1-induced IKK kinase activity is affected in the presence of CIITA as demonstrated by impaired phosphorylation of IkB inhibitor, which is responsible for the impaired migration of RelA into the nucleus. Thus, the inactive p50/RelA heterodimer is trapped in the cytoplasm and this results in the suppression of the activation of NF-kB responsive genes by Tax-1. Overall, these findings indicate that CIITA has evolved as a versatile molecule that, besides inhibiting viral gene expression promoted by Tax-1, it might counteract also Tax-1 transforming activity. Thus, unveiling the molecular basis of CIITA-mediated Tax-1 inhibition may be important in defining new strategies to control HTLV-1 spreading and on cogenic potential
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The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators
Frontiers in Microbiology, 2013Co-Authors: Greta Forlani, Rawan Abdallah, Roberto S. Accolla, Giovanna TosiAbstract:The activation of CD4+ T helper cells is strictly dependent on the presentation of antigenic peptides by MHC Class II molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (Class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Beside this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution.
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major histocompatibility complex class ii transactivator CIITA is a viral restriction factor that targets human t cell lymphotropic virus type 1 tax 1 function and inhibits viral replication
Journal of Virology, 2011Co-Authors: Giovanna Tosi, Greta Forlani, Guido Poli, Vibeke Andresen, Marco Turci, Umberto Bertazzoni, Genoveffa Franchini, Roberto S. AccollaAbstract:Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Since the viral transactivator Tax-1 is a major player in T-cell transformation, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and to counteract neoplastic transformation. We demonstrate that CIITA, the master regulator of major histocompatibility complex class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo via the first 108 amino acids of Tax-1 and two CIITA adjacent regions (amino acids 1 to 252 and 253 to 410). Interestingly, only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64 to 124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2. Instead, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular coactivators p300/CBP-associated factor (PCAF), cyclic AMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1), which are required for the optimal activation of HTLV-1 promoter. Accordingly, the overexpression of PCAF, CREB, and ATF1 restored Tax-1-dependent transactivation of the viral long-terminal-repeat promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.
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the mhc ii transactivator CIITA a viral restriction factor inhibiting the replication of human t cell lymphotropic virus type 1
Retrovirology, 2011Co-Authors: Giovanna Tosi, Greta Forlani, Vibeke Andresen, Marco Turci, Umberto Bertazzoni, Genoveffa Franchini, Roberto S. AccollaAbstract:Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. It is believed that the viral transactivator Tax-1 is a major player in T-cell transformation. Thus, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and ultimately to counteract neoplastic transformation. Here, we demonstrated that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1. Co-immunoprecipitation experiments have shown that CIITA and Tax-1 physically interact in vivo and that the first 108 amino acids of Tax-1 were necessary for this binding. Two adjacent regions (1-252 and 253-410) of CIITA bound independently to Tax-1, but only region 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64-124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 function correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2, a virus with still elusive pathogenic action. Furthermore, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular co-activator PCAF, which is required for the optimal activation of HTLV-1 promoter. Accordingly, the over-expression of PCAF restored Tax-1-dependent transactivation of the viral LTR promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.
Greta Forlani - One of the best experts on this subject based on the ideXlab platform.
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The MHC-II transactivator CIITA inhibits Tat function and HIV-1 replication in human myeloid cells
Journal of translational medicine, 2016Co-Authors: Greta Forlani, Roberto S. Accolla, Filippo Turrini, Silvia Ghezzi, Alessandra Tedeschi, Guido Poli, Giovanna TosiAbstract:We previously demonstrated that the HLA class II transactivator CIITA inhibits HIV-1 replication in T cells by competing with the viral transactivator Tat for the binding to Cyclin T1 subunit of the P-TEFb complex. Here, we analyzed the anti-viral function of CIITA in myeloid cells, another relevant HIV-1 target cell type. We sinvestigated clones of the U937 promonocytic cell line, either permissive (Plus) or non-permissive (Minus) to HIV-1 replication. This different phenotype has been associated with the expression of TRIM22 in U937 Minus but not in Plus cells. U937 Plus cells stably expressing CIITA were generated and HLA-II positive clones were selected by cell sorting and cloning. HLA and CIITA proteins were analyzed by cytofluorometry and western blotting, respectively. HLA-II DR and CIITA mRNAs were quantified by qRT-PCR. Tat-dependent transactivation was assessed by performing the HIV-1 LTR luciferase gene reporter assay. Cells were infected with HIV-1 and viral replication was evaluated by measuring the RT activity in culture supernatants. CIITA was expressed only in HLA-II-positive U937 Minus cells, and this was strictly correlated with inhibition of Tat-dependent HIV-1 LTR transactivation in Minus but not in Plus cells. Overexpression of CIITA in Plus cells restored the suppression of Tat transactivation, confirming the inhibitory role of CIITA. Importantly, HIV-1 replication was significantly reduced in Plus-CIITA cells with respect to Plus parental cells. This effect was independent of TRIM22 as CIITA did not induce TRIM22 expression in Plus-CIITA cells. U937 Plus and Minus cells represent an interesting model to study the role of CIITA in HIV-1 restriction in the monocytic/macrophage cell lineage. The differential expression of CIITA in CIITA-negative Plus and CIITA-positive Minus cells correlated with their capacity to support or not HIV-1 replication, respectively. In Minus cells CIITA targeted the viral transactivator Tat to inhibit HIV-1 replication. The generation of Plus-CIITA cells was instrumental to demonstrate the specific contribution of CIITA in terms of inhibition of Tat activity and HIV-1 restriction, independently from other cellular factors, including TRIM22. Thus, CIITA acts as a general restriction factor against HIV-1 not only in T cells but also in myeloid cells.
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The MHC Class II transactivator CIITA inhibits the persistent activation of NF-kB by Tax-1
Retrovirology, 2015Co-Authors: Greta Forlani, Rawan Abdallah, Roberto S. Accolla, Luisa Guidali, Giovanna TosiAbstract:Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Many studies have shown that the constitutive activation of NF-kB pathway by the viral transactivator Tax-1 is crucial for T-cell transformation. We previously identified the cellular factor Class II transactivator (CIITA), the master regulator of Major Histo compatibility Complex Class II gene transcription, as a restriction factor inhibiting HTLV-1 replication by blocking Tax-1-mediated activation of the viral LTR promoter (1). Here we show that CIITA suppresses also the activation of the canonical NF-kB pathway by Tax-1 and mapped the region of CIITA mediating this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm and this correlates with an impaired migration of Rel Ain to the nucleus. By using nuclear and cytoplasmic deletion mutants of CIITA, we demonstrate that CIITA suppresses the activation of NF-kB by Tax-1 in both the subcellular compartments. Interestingly, CIITA binds to Tax-1 in vivo without preventing the binding of Tax-1 to both IKKg and RelA. Nevertheless, Tax-1-induced IKK kinase activity is affected in the presence of CIITA as demonstrated by impaired phosphorylation of IkB inhibitor, which is responsible for the impaired migration of RelA into the nucleus. Thus, the inactive p50/RelA heterodimer is trapped in the cytoplasm and this results in the suppression of the activation of NF-kB responsive genes by Tax-1. Overall, these findings indicate that CIITA has evolved as a versatile molecule that, besides inhibiting viral gene expression promoted by Tax-1, it might counteract also Tax-1 transforming activity. Thus, unveiling the molecular basis of CIITA-mediated Tax-1 inhibition may be important in defining new strategies to control HTLV-1 spreading and on cogenic potential
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The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators
Frontiers in Microbiology, 2013Co-Authors: Greta Forlani, Rawan Abdallah, Roberto S. Accolla, Giovanna TosiAbstract:The activation of CD4+ T helper cells is strictly dependent on the presentation of antigenic peptides by MHC Class II molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (Class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Beside this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution.
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major histocompatibility complex class ii transactivator CIITA is a viral restriction factor that targets human t cell lymphotropic virus type 1 tax 1 function and inhibits viral replication
Journal of Virology, 2011Co-Authors: Giovanna Tosi, Greta Forlani, Guido Poli, Vibeke Andresen, Marco Turci, Umberto Bertazzoni, Genoveffa Franchini, Roberto S. AccollaAbstract:Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Since the viral transactivator Tax-1 is a major player in T-cell transformation, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and to counteract neoplastic transformation. We demonstrate that CIITA, the master regulator of major histocompatibility complex class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo via the first 108 amino acids of Tax-1 and two CIITA adjacent regions (amino acids 1 to 252 and 253 to 410). Interestingly, only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64 to 124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2. Instead, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular coactivators p300/CBP-associated factor (PCAF), cyclic AMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1), which are required for the optimal activation of HTLV-1 promoter. Accordingly, the overexpression of PCAF, CREB, and ATF1 restored Tax-1-dependent transactivation of the viral long-terminal-repeat promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.
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the mhc ii transactivator CIITA a viral restriction factor inhibiting the replication of human t cell lymphotropic virus type 1
Retrovirology, 2011Co-Authors: Giovanna Tosi, Greta Forlani, Vibeke Andresen, Marco Turci, Umberto Bertazzoni, Genoveffa Franchini, Roberto S. AccollaAbstract:Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. It is believed that the viral transactivator Tax-1 is a major player in T-cell transformation. Thus, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and ultimately to counteract neoplastic transformation. Here, we demonstrated that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1. Co-immunoprecipitation experiments have shown that CIITA and Tax-1 physically interact in vivo and that the first 108 amino acids of Tax-1 were necessary for this binding. Two adjacent regions (1-252 and 253-410) of CIITA bound independently to Tax-1, but only region 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64-124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 function correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2, a virus with still elusive pathogenic action. Furthermore, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular co-activator PCAF, which is required for the optimal activation of HTLV-1 promoter. Accordingly, the over-expression of PCAF restored Tax-1-dependent transactivation of the viral LTR promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.
Cheong Hee Chang - One of the best experts on this subject based on the ideXlab platform.
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Role of PKCδ in IFN-γ-inducible CIITA gene expression
Molecular immunology, 2007Co-Authors: Myung Ja Kwon, Yongxue Yao, Michael J. Walter, Michael J. Holtzman, Cheong Hee ChangAbstract:Abstract The class II transactivator (CIITA) is a key regulatory factor for MHC class II expression. Here, we demonstrate that PKCδ plays an important role in regulating IFN-γ-inducible CIITA gene expression in macrophages. Inhibition of PKCδ by either a PKCδ inhibitor or a dominant negative (DN) mutant form of PKCδ led to down-regulation of CIITA expression. The decrease in CIITA expression by PKCδ inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter. As a result, IFN-γ induced histone acetylation at the CIITA promoter is also compromised. However, inhibition of PKCδ did not affect IRF-1 expression or IRF-1 binding to the CIITA promoter. Therefore, we report, for the first time, that PKCδ is an essential signaling molecule to achieve the maximal expression of CIITA in response to IFN-γ in macrophages. In addition, although IRF-1 is a key transcription factor to activate the IFN-γ inducible CIITA promoter, the effect of PKCδ on CIITA expression is mediated primarily by serine phosphorylation of Stat 1.
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Class II transactivator-mediated regulation of major histocompatibility complex class II antigen expression is important for hematopoietic progenitor cell suppression by chemokines and iron-binding proteins
Experimental Hematology, 2006Co-Authors: Hal E. Broxmeyer, Giao Hangoc, Cheong Hee ChangAbstract:Objective Iron-binding proteins H-ferritin (HF) and lactoferrin (LF), as well as chemokines, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ suppress hematopoietic progenitor cell (HPC) proliferation. Major histocompatibility complex (MHC) class II antigens have been associated with suppressive effects of HF and LF. Because the transcription factor class II transactivator (CIITA) regulates expression of MHC class II antigens, we evaluated influences of CIITA and MHC class II antigens on suppression of colony formation by murine bone marrow HPC in response to HF, LF, CC, and CXC chemokines, TNF-α, and IFN-γ. We also evaluated hematopoiesis in mice deficient in both CIITA and MHC class II antigens (CIITA −/−), in mice deficient in MHC class II antigens but not in CIITA (MHC class II −/−), and in mice deficient in CIITA but not in MHC class II antigens (CIITA-IE). Materials and Methods HF, LF, CCL3/MIP-1α, CXCL5/ENA-78, CXCL8/IL-8, CCL5/RANTES, TNF-α, and IFN-γ were assessed for effects on colony formation by bone marrow HPC (colony-forming unit granulocyte-macrophage, burst-forming unit erythroid, and colony-forming unit multipotential) stimulated in vitro by combinations of growth factors including erythropoietin, stem cell factor, pokeweed mitogen mouse spleen cell conditioned medium, and hemin. Bone marrow cells were from CIITA −/−, MHC class II antigen −/−, CIITA-IE, and littermate control mice. We also evaluated cycling status (percent cells in S-phase) and absolute numbers of marrow and spleen HPC in these mice. Results Multiple growth factor–stimulated colony formation by control bone marrow HPC was significantly suppressed by HF, LF, CCL3, CXCL5, CXCL8, TNF-α, and IFN-γ, but not by CCL5. However, HPC from CIITA −/− and MHC class II antigen −/− mouse marrow was insensitive to inhibition by HF, LF, CCL3, CXCL5, CXCL8, and CCL5; these HPC were inhibited by TNF-α and IFN-γ. Restoration of MHC class II expression in CIITA −/− (CIITA-IE) mice restored responsiveness of HPC to inhibition by HF, LF, CCL3, CXCL5, and CXCL8. Increased cycling of splenic HPC in CIITA −/− and MHC class II antigen −/−, compared to control and CIITA-IE, mice was noted. Conclusions Myelosuppressive effects of iron-binding proteins HF and LF and chemokines CCL3, CXCL5, and CXCL8 on mouse bone marrow HPC require expression of MHC class II antigens, and CIITA is involved in this responsiveness through its regulation of expression of MHC class II antigens.
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Protein Kinase Cδ Is Essential to Maintain CIITA Gene Expression in B Cells
Journal of immunology (Baltimore Md. : 1950), 2006Co-Authors: Myung Ja Kwon, Jae-won Soh, Cheong Hee ChangAbstract:Expression of MHC class II genes requires CIITA. Although the transactivation function of CIITA is well characterized, the signaling events that regulate CIITA expression are less understood. In this study, we report that CIITA expression in B cells depends on protein kinase Cδ (PKCδ). PKCδ controls CIITA gene transcription mainly via modulating CREB recruitment to the CIITA promoter without affecting CIITA mRNA stability. Inhibition of PKCδ by a pharmacological inhibitor or knocking down of endogenous PKCδ expression by small interfering RNA reduced CREB binding to the CIITA promoter. The decrease of CIITA gene expression in the presence of the PKCδ inhibitor was prevented by ectopically expressing a constitutively active form of CREB. In addition, histone acetylation of the CIITA promoter is regulated by PKCδ since the PKCδ inhibitor treatment or PKCδ small interfering RNA resulted in decreased histone acetylation. Taken together, our study reveals that PKCδ is an important signaling molecule necessary to maintain CIITA and MHC class II expression in B cells.
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ERK and p38 MAPK signaling pathways negatively regulate CIITA gene expression in dendritic cells and macrophages.
Journal of immunology (Baltimore Md. : 1950), 2006Co-Authors: Yongxue Yao, Myung Ja Kwon, Ranyia Matta, Yusen Liu, Soon Choel Hong, Cheong Hee ChangAbstract:The CIITA is a master regulator for MHC class II expression, but the signaling events that control CIITA expression remain poorly understood. In this study, we report that both constitutive and IFN-gamma-inducible expression of CIITA in mouse bone marrow-derived dendritic cells (DC) and macrophages, respectively, are regulated by MAPK signals. In DC, the inhibitory effect of LPS on CIITA expression was prevented by MyD88 deficiency or pharmacological MAPK inhibitors specific for MEK (U0126) and p38 (SB203580), but not JNK (SP600125). In macrophages, LPS inhibited IFN-gamma-inducible CIITA and MHC class II expression without affecting expression of IFN regulatory factor-1 and MHC class I. Blocking ERK and p38 by MAPK inhibitors not only rescued LPS-mediated inhibition, but also augmented IFN-gamma induction of CIITA. Moreover, the induction of CIITA by IFN-gamma was enhanced by overexpressing MAPK phosphatase-1 that inactivates MAPK. Conversely, CIITA expression was attenuated in the absence of MAPK phosphatase-1. The down-regulation of CIITA gene expression by ERK and p38 was at least partly due to decreased histone acetylation of the CIITA promoter. Our study indicates that both MAPK and phosphatase play an important role for CIITA regulation in DC and macrophages.
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Enhanced Production of IL-10 by Dendritic Cells Deficient in CIITA
Journal of immunology (Baltimore Md. : 1950), 2005Co-Authors: Christina S.k. Yee, Yongxue Yao, Brian P. Mccarthy, Deqin Sun-lin, Masahide Tone, Herman Waldmann, Cheong Hee ChangAbstract:Dendritic cells (DC) are professional APCs that play a critical role in regulating immunity. In DC, maturation-induced changes in MHC class II expression and Ag presentation require transcriptional regulation by CIITA. To study the role of CIITA in DC, we evaluated key cell functions in DC from CIITA-deficient (CIITA −/− ) mice. The ability to take up Ag, measured by fluid phase endocytosis, was comparable between CIITA −/− and control DC. Although CIITA −/− DC lack MHC class II, they maintained normal expression of costimulatory molecules CD80, CD86, and CD40. In contrast, CIITA −/− DC activated with LPS or CpG expressed increased IL-10 levels, but normal levels of TNF-α and IL-12 relative to control. Enhanced IL-10 was due to greater IL-10 mRNA in CIITA −/− DC. Aβ −/− DC, which lack MHC class II but express CIITA normally, had exhibited no difference in IL-10 compared with control. When CIITA was cotransfected with an IL-10 promoter-reporter into a mouse monocyte cell line, RAW 264.7, IL-10 promoter activity was decreased. In addition, reintroducing CIITA into CIITA −/− DC reduced production of IL-10. In all, these data suggest that CIITA negatively regulates expression of IL-10, and that CIITA may direct DC function in ways that extend beyond control of MHC class II.
Mingming Fang - One of the best experts on this subject based on the ideXlab platform.
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Class II transactivator （CIITA） mediates transcriptional repression of pdk4 gene by interacting with hypermethylated in cancer 1 （HIC1）
Journal of biomedical research, 2015Co-Authors: Mingming FangAbstract:Increased accumulation and/or impaired utilization of fatty acid in extra-adipose tissues are implicated in the pathogenesis of insulin resistance and type 2 diabetes. Pyruvate dehydrogenase kinase 4 (Pdk4) is a key enzyme involved in fatty oxidation and energy expenditure, and its expression can be repressed by pro-inflammatory stimuli. Previously, we have shown that class II transactivator (CIITA) mediates the adverse effect of interferon gamma (IFN-γ) in skeletal muscle cells by cooperating with hypermethylated in cancer 1 (HIC1) to repress silent information regulator 1 (SIRT1) transcription. Building upon this finding, we report here that CIITA interacted with HIC1 via the GTP-binding domain (GBD) while HIC1 interacted with CIITA via the BTB/POZ domain. The GBD domain was required for CIITA to repress SIRT1 transcription probably acting as a bridge for CIITA to bind to HIC1 and consequently to bind to the SIRT1 promoter. IFN-γ stimulation, CIITA over-expression, or HIC1 over-expression repressed Pdk4 promoter activity while silencing either CIITA or HIC1 normalized Pdk4 expression in the presence of IFN-γ. An increase in SIRT1 expression or activity partially rescued Pdk4 expression in the presence of CIITA, but SIRT1 inhibition abrogated Pdk4 normalization even in the absence of CIITA. Taken together, our data have identified a HIC1-CIITA-SIRT1 axis that regulates Pdk4 transcription in response to IFN-γ stimulation.
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a2b adenosine signaling represses CIITA transcription via an epigenetic mechanism in vascular smooth muscle cells
Biochimica et Biophysica Acta, 2015Co-Authors: Jun Xia, Yuyu Yang, Mingming Fang, Hui Kong, Hong Wang, Qi Tan, Weiping XieAbstract:Chronic inflammation plays a major role in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMC), by expressing and presenting major histocompatibility complex II (MHC II) molecules, help recruit T lymphocyte and initiate the inflammatory response within the vasculature. We have previously shown that VSMCs isolated from mice with deficient adenosine A2b receptor (A2b-null) exhibit higher expression of class II transactivator (CIITA), the master regulator of MHC II transcription, compared to wild type littermates. Here we report that activation of A2b adenosine signaling suppresses CIITA expression in human aortic smooth muscle cells. Down-regulation of CIITA expression was largely attributable to transcriptional repression of type III and IV promoters. Chromatin immunoprecipitation (ChIP) analyses revealed that A2b signaling repressed CIITA transcription by attenuating specific histone modifications on the CIITA promoters in a STAT1-dependent manner. STAT1 interacted with PCAF/GCN5, histone H3K9 acetyltransferases, and WDR5, a key component of the mammalian H3K4 methyltransferase complex, to activate CIITA transcription. A2b signaling prevented recruitment of PCAF/GCN5 and WDR5 to the CIITA promoters in a STAT1-dependent manner. In conclusion, our data suggest that adenosine A2b signaling represses CIITA transcription in VSMCs by manipulating the interaction between STAT1 and the epigenetic machinery.
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Adenosine signaling inhibits CIITA-mediated MHC class II transactivation in lung fibroblast cells.
European journal of immunology, 2013Co-Authors: Mingming Fang, Jun Xia, Hui Kong, Hong Wang, Weiping XieAbstract:Efficient antigen presentation by major histocompatibility complex (MHC) molecules represents a critical process in adaptive immunity. Class II transactivator (CIITA) is considered the master regulator of MHC class II (MHC II) transcription. Previously, we have shown that CIITA expression is upregulated in smooth muscle cells deficient in A2b adenosine receptor. Here, we report that treatment with the adenosine receptor agonist adenosine-5′N-ethylcarboxamide (NECA) attenuated MHC II transcription in lung fibro-blast cells as a result of CIITA repression. Further analysis revealed that NECA preferentially abrogated CIITA transcription through promoters III and IV. Blockade with a selective A2b receptor antagonist MRS-1754 restored CIITA-dependent MHC II transactivation. Forskolin, an adenylyl cyclase activator, achieved the same effect as NECA. A2b signaling repressed CIITA transcription by altering histone modifications and recruitment of key factors on the CIITA promoters in a STAT1-dependent manner. MRS-1754 blocked the antagonism of transforming growth factor beta (TGF-β) in CIITA induction by interferon gamma (IFN-γ), alluding to a potential dialogue between TGF-β and adenosine signaling pathways. Finally, A2b signaling attenuated STAT1 phosphorylation and stimulated TGF-β synthesis. In conclusion, we have identified an adenosine-A2b receptor-adenylyl cyclase axis that influences CIITA-mediated MHC II transactivation in lung fibroblast cells and as such have provided invaluable insights into the development of novel immune-modulatory strategies.
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SIRT1 links CIITA deacetylation to MHC II activation
Nucleic acids research, 2011Co-Authors: Xiaocen Kong, Yuhao Zhao, Dewei Chen, Minjie Xia, Mingming Fang, Fei Fang, Lina SunAbstract:Antigen-dependent stimulation of T cells plays a critical role in adaptive immunity and host defense. Activation of major histocompatibility complex II (MHC II) molecules, dictated by Class II transactivator (CIITA), is considered a pivotal step in this process. The mechanism underlying differential regulation of CIITA activity by the post-translational modification machinery (PTM) and its implications are not clearly appreciated. Here, we report that SIRT1, a type III deacetylase, interacts with and deacetylates CIITA. SIRT1 activation augments MHC II transcription by shielding CIITA from proteasomal degradation and promoting nuclear accumulation and target binding of CIITA. In contrast, depletion of SIRT1 upregulates CIITA acetylation and attenuates its activity. Nicotinamide phosphoribosyltransferase (NAMPT) that synthesizes NAD(+) required for SIRT1 activation exerts similar effects on CIITA activity. Two different types of stress stimuli, hypobaric hypoxia and oxidized low-density lipoprotein (oxLDL), induce the acetylation of CIITA and suppress its activity by inhibiting the SIRT1 expression and activity. Thus, our data link SIRT1-mediated deacetylation of CIITA to MHC II transactivation in macrophages and highlight a novel strategy stress cues may employ to manipulate host adaptive immune system.
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PPARγ enhances IFNγ-mediated transcription and rescues the TGFβ antagonism by stimulating CIITA in vascular smooth muscle cells
Journal of molecular and cellular cardiology, 2009Co-Authors: Xiaocen Kong, Mingming Fang, Fei FangAbstract:Abstract Chronic inflammatory response and active vascular remodeling are two featured pathophysiological events during atherogenesis. Gamma interferon (IFN-γ) modulates these two processes through transcriptional control of major histocompatibility complex II (MHC II) and collagen type I ( COL1A2 ) genes, mediated by class II transactivator (CIITA). Transforming growth factor (TGF-β) antagonizes the effect of IFN-γ in part by dampening the expression of CIITA. Here we report that peroxisome proliferator activated receptor γ (PPARγ) enhanced MHC II activation and COL1A2 repression by IFN-γ while rescuing the antagonism by TGF-β in a CIITA-dependent manner in human aortic smooth muscle cells judged by quantitative PCR and luciferase reporter assays. PPARγ exerted its effect by augmenting the levels of CIITA and stimulating CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays. The up-regulation of CIITA levels was the result of PPARγ-mediated transcriptional activation of CIITA through promoter IV, and increased CIITA protein stability. Thus, our data suggest that PPARγ could be a key factor in fine-tuning inflammation as well as restructuring of vessel walls during atherogenesis by acting as a “balance tipper” of the differential effects exerted by cytokines.