Human T cell Lymphotropic Virus type-1 (HTLV-1) Tax-1 protein, a key mediator of HTLV-1-induced T-cell transformation, deregulates diverse cell-signalling pathways. Among them, the NF-kB pathway is constitutively activated by Tax-1, which binds to NF-kB family members and activates the IkB-kinase (IKK). Upon phosphorylation-dependent degradation of IkB, NF-kB migrates into the nucleus and mediates Tax-1-stimulated gene expression. We show that CIITA, the transcriptional regulator of Major Histocompatibility Complex Class II genes, inhibits the activation of the canonical NF-kB pathway by Tax-1 and map the region 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 RelA into the nucleus. Cytoplasmic and nuclear CIITA mutants reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-kB activation in both subcellular 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 the activation of NF-kB-responsive genes by Tax-1. Thus, CIITA inhibits critical cytoplasmic and nuclear steps of Tax-1-mediated NF-kB activation. These results, together with our previous finding that CIITA acts as a restriction factor inhibiting Tax-1-promoted HTLV-1 gene expression and replication, 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 spreading and oncogenic potential.
|Titolo:||The MHC class II transactivator CIITA inhibits the persistent activation of NF-kB by Human T cell Lymphotropic Virus type-1 Tax-1 oncoprotein|
|Data di pubblicazione:||2016|
|Appare nelle tipologie:||Abstract (in Rivista)|