HTLV-1 is the etiologic agent of an aggressive form of T cell leukemia/lymphoma. The viral transactivator Tax-1 plays a major role in T cell transformation by deregulating several cellular pathways including the NF-kB pathway. Here we show that the MHC-II transcriptional activator CIITA, previously found to inhibit the transactivating function of Tax-1, inhibits also its capacity to activate NF-kB via the canonical pathway. CIITA affects the subcellular localization of Tax-1, by retaining it in the cytoplasm of the majority of the cells. In addition, Tax-1-mediated recruitment of RelA into nuclear bodies, a crucial event for NF-kB activation, is impaired in the presence of CIITA. Interestingly, CIITA interacts with Tax-1 and this interaction does not affect the binding of Tax-1 to both RelA and IKKγ. Nevertheless, IKK-dependent phosphorylation and, thus, degradation of IKB is impaired in the presence of CIITA. By using deletion mutants having different subcellular localization, we could demonstrate that different regions of CIITA exploit different mechanisms to inhibit Tax-1-dependent activation of NF-kB. N-terminal fragments of CIITA containing the minimal region inhibiting Tax-1-dependent activation of the LTR and able to shuttle into the nucleus, inhibit also NF-kB activation by Tax-1. Moreover, cytoplasmic CIITA mutants can still inhibit the activation of NF-kB and this effect is dependent on the presence of the C-terminus of CIITA. Overall, our results suggest that CIITA besides inhibiting HTLV-1 replication, might also counteract the oncogenic potential of Tax-1 implicating a more broad inhibitory effect of CIITA on HTLV-1 infection.

Tax-1-mediated NF-kB activation is inhibited by the MHC-II transactivator CIITA

ABDALLAH, RAWAN;FORLANI, GRETA;ACCOLLA, ROBERTO;TOSI, GIOVANNA
2014

Abstract

HTLV-1 is the etiologic agent of an aggressive form of T cell leukemia/lymphoma. The viral transactivator Tax-1 plays a major role in T cell transformation by deregulating several cellular pathways including the NF-kB pathway. Here we show that the MHC-II transcriptional activator CIITA, previously found to inhibit the transactivating function of Tax-1, inhibits also its capacity to activate NF-kB via the canonical pathway. CIITA affects the subcellular localization of Tax-1, by retaining it in the cytoplasm of the majority of the cells. In addition, Tax-1-mediated recruitment of RelA into nuclear bodies, a crucial event for NF-kB activation, is impaired in the presence of CIITA. Interestingly, CIITA interacts with Tax-1 and this interaction does not affect the binding of Tax-1 to both RelA and IKKγ. Nevertheless, IKK-dependent phosphorylation and, thus, degradation of IKB is impaired in the presence of CIITA. By using deletion mutants having different subcellular localization, we could demonstrate that different regions of CIITA exploit different mechanisms to inhibit Tax-1-dependent activation of NF-kB. N-terminal fragments of CIITA containing the minimal region inhibiting Tax-1-dependent activation of the LTR and able to shuttle into the nucleus, inhibit also NF-kB activation by Tax-1. Moreover, cytoplasmic CIITA mutants can still inhibit the activation of NF-kB and this effect is dependent on the presence of the C-terminus of CIITA. Overall, our results suggest that CIITA besides inhibiting HTLV-1 replication, might also counteract the oncogenic potential of Tax-1 implicating a more broad inhibitory effect of CIITA on HTLV-1 infection.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11383/2011321
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