Human T-cell leukemia viruses type 1 and 2 (HTLV-1 and 2) are genetically related retroviruses that differ in terms of clinical impact. HTLV-1 is the causative agent of adult T-cell leukemia (ATL), whereas HTLV-2 is sporadically associated with neurological disorders. HTLV genome encodes a regulatory protein Tax, which transactivates viral and host genes and induces cell transformation. An additional key factor involved in viral pathogenesis is the unique regulatory protein expressed by the minus strand of HTLV-1 and 2, namely HBZ (HTLV-1 b-Zip factor) and APH-2 (HTLV-2 antisense protein). APH-2 and HBZ share the ability to suppress Tax-dependent viral transcription, although not to a similar extent. We have previously demonstrated that Tax proteins form complexes with several host factors deregulating the NF-κB pathway. In the present study, we aimed to investigate HBZ and APH-2 interactions with cellular and viral factors and their involvement in the NF-kB activation. We observed that both APH-2 and HBZ proteins, form complexes with p65. In transactivation assays they inhibit the p65-induced NF-kB activation, even in the presence of Tax that is known to induce a persistent activation of NF-kB. Immunoprecipitation analyses showed that, compared to HBZ, only APH-2 is able to interact with Tax. Confocal microscopy observations confirm a different cellular distribution of the viral proteins: HBZ has a prevalently punctuate nuclear distribution, whereas APH-2 is distributed both in the nucleus and cytoplasm. By immunoprecipitation analyses, we found that the cellular factor TNF receptor associated factor 3 (TRAF3), involved in the alternative NF-κB cell signaling pathway, forms complexes with APH-2. Further studies will be performed to investigate the molecular mechanism by which HBZ and APH-2 antisense viral proteins cellular interactions modulate the alternative NF-κB cell signaling pathway.
Human T-cell leukemia virus HBZ and APH-2 antisense proteins interaction with host factors and their involvement in NF-Kb activation
Fochi, Stefania;Bergamo, Elisa;Serena, Michela;ZIPETO, Donato;ROMANELLI, Maria
2016-01-01
Abstract
Human T-cell leukemia viruses type 1 and 2 (HTLV-1 and 2) are genetically related retroviruses that differ in terms of clinical impact. HTLV-1 is the causative agent of adult T-cell leukemia (ATL), whereas HTLV-2 is sporadically associated with neurological disorders. HTLV genome encodes a regulatory protein Tax, which transactivates viral and host genes and induces cell transformation. An additional key factor involved in viral pathogenesis is the unique regulatory protein expressed by the minus strand of HTLV-1 and 2, namely HBZ (HTLV-1 b-Zip factor) and APH-2 (HTLV-2 antisense protein). APH-2 and HBZ share the ability to suppress Tax-dependent viral transcription, although not to a similar extent. We have previously demonstrated that Tax proteins form complexes with several host factors deregulating the NF-κB pathway. In the present study, we aimed to investigate HBZ and APH-2 interactions with cellular and viral factors and their involvement in the NF-kB activation. We observed that both APH-2 and HBZ proteins, form complexes with p65. In transactivation assays they inhibit the p65-induced NF-kB activation, even in the presence of Tax that is known to induce a persistent activation of NF-kB. Immunoprecipitation analyses showed that, compared to HBZ, only APH-2 is able to interact with Tax. Confocal microscopy observations confirm a different cellular distribution of the viral proteins: HBZ has a prevalently punctuate nuclear distribution, whereas APH-2 is distributed both in the nucleus and cytoplasm. By immunoprecipitation analyses, we found that the cellular factor TNF receptor associated factor 3 (TRAF3), involved in the alternative NF-κB cell signaling pathway, forms complexes with APH-2. Further studies will be performed to investigate the molecular mechanism by which HBZ and APH-2 antisense viral proteins cellular interactions modulate the alternative NF-κB cell signaling pathway.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
