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

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