The constitutive activation of NF-kB by HTLV-1 Tax-1 oncoprotein is inhibited by the MHC class II transactivator CIITA Greta Forlani, PhD, University of Insubria; Rawan Abdallah, PhD, University of Insubria; Roberto Accolla, MD, PhD, University of Insubria; Giovanna Tosi, PhD, University of Insubria Human T cell lymphotropic virus type 1 (HTLV-1) Tax-1, induces T cell transformation deregulating diverse cell signaling pathways. Tax-1 activates the NF-kB pathway through binding to NF-kB proteins and activation of the IkB kinase (IKK). Upon IKK-mediated phosphorylation of IkB and consequent IkB degradation, NF-kB migrates into the nucleus mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-kB pathway by Tax-1 and we mapped the CIITA region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with the impaired migration of the NF-kB RelA subunit into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-kB activation in both sub-cellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKg and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing the retention of the inactive p50/RelA/IkB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NFkB-responsive genes. Thus, CIITA inhibits both cytoplasmic and nuclear steps of Tax-1-mediated NF-kB activation. These results, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-1

The constitutive activation of NF-kB by HTLV-1 Tax-1 oncoprotein is inhibited by the MHC class II transactivator CIITA

FORLANI, GRETA
Primo
;
ACCOLLA, ROBERTO
;
TOSI, GIOVANNA
Ultimo
;
2017

Abstract

The constitutive activation of NF-kB by HTLV-1 Tax-1 oncoprotein is inhibited by the MHC class II transactivator CIITA Greta Forlani, PhD, University of Insubria; Rawan Abdallah, PhD, University of Insubria; Roberto Accolla, MD, PhD, University of Insubria; Giovanna Tosi, PhD, University of Insubria Human T cell lymphotropic virus type 1 (HTLV-1) Tax-1, induces T cell transformation deregulating diverse cell signaling pathways. Tax-1 activates the NF-kB pathway through binding to NF-kB proteins and activation of the IkB kinase (IKK). Upon IKK-mediated phosphorylation of IkB and consequent IkB degradation, NF-kB migrates into the nucleus mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-kB pathway by Tax-1 and we mapped the CIITA region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with the impaired migration of the NF-kB RelA subunit into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-kB activation in both sub-cellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKg and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing the retention of the inactive p50/RelA/IkB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NFkB-responsive genes. Thus, CIITA inhibits both cytoplasmic and nuclear steps of Tax-1-mediated NF-kB activation. These results, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-1
Forlani, Greta; Accolla, Roberto; Tosi, Giovanna; Abdallah, Rawan
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11383/2063568
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