title: The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein.
abstract: Human T cell lymphotropic virus type 1 (HTLV-1) Tax-1, a key protein in HTLV-1-induced T cell transformation, deregulates diverse cell signaling pathways. Among them, the NF-κB pathway is constitutively activated by Tax-1, which binds to NF-κB proteins and activates the IκB kinase (IKK). Upon phosphorylation-dependent IκB degradation, NF-κB migrates into the nucleus, mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA (class II transactivator), endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-κB pathway by Tax-1 and map the region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with impaired migration of RelA into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-κB activation in both subcellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKγ and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing retention of the inactive p50/RelA/IκB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NF-κB-responsive genes. Thus, CIITA inhibits cytoplasmic and nuclear steps of Tax-1-mediated NF-κB 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.
  
  
  OBJECTIVE
  HTLV-1 is the causative agent of human adult T cell leukemia-lymphoma (ATLL). The viral transactivator Tax-1 plays a central role in the onset of ATLL, mostly by deregulating the NF-κB pathway. We demonstrate that CIITA, a key regulator of adaptive immunity, suppresses Tax-1-dependent activation of NF-κB by acting at several levels: it retains most of Tax-1 and RelA in the cytoplasm and inhibits their residual functional activity in the nucleus. Importantly, this inhibition occurs in cells that are targets of HTLV-1 infection. These findings are of interest in the field of virology because they expand the current knowledge of the functional relationship between viral products and cellular interactors and provide the basis for a better understanding of the molecular countermeasures adopted by the host cell to antagonize HTLV-1 spreading and transforming properties. Within this framework, our results may contribute to the establishment of novel strategies against HTLV-1 infection and virus-dependent oncogenic transformation.
authors.affiliation: General Pathology and Immunology Laboratory, Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Forlani
authors.affiliation: General Pathology and Immunology Laboratory, Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Rawan
authors.initials: R
authors.lastname: Abdallah
authors.affiliation: General Pathology and Immunology Laboratory, Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy giovanna.tosi@uninsubria.it accolla.roberto@gmail.com.
authors.forename: Roberto S
authors.initials: RS
authors.lastname: Accolla
authors.affiliation: General Pathology and Immunology Laboratory, Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy giovanna.tosi@uninsubria.it accolla.roberto@gmail.com.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosi
mesh_terms: D016356:Gene Products, tax / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D016356:Gene Products, tax; C083728:MHC class II transactivator protein; D016328:NF-kappa B; D009687:Nuclear Proteins; D015534:Trans-Activators; C514970:tax protein, Human T-lymphotrophic virus 1