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Novel interactions between the HTLV-1 antisense protein HBZ and the SWI/SNF chromatin remodeling family: Implications for viral life cycle.

Alasiri A, Abboud Guerr J, Hall WW, Sheehy N

The human T-cell leukemia virus type 1 (HTLV-1) regulatory proteins Tax and HBZ play indispensable roles in regulating viral and cellular gene expression. BRG1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, has been demonstrated to be essential not only for Tax transactivation but also for viral replication. We sought to investigate the physical interaction between HBZ and BRG1 and to determine the effect of those interactions on Tax-mediated LTR activation. We reveal that HTLV-1 cell lines and ATL cells harbour high levels of BRG1. Using GST pulldown and co-immunoprecipitation assays we have demonstrated physical interactions between BRG1 and HBZ and characterised the protein domains involved. Moreover, we have identified PBAF-signature subunits BAF200 and BAF180 as novel interaction partners of HBZ suggesting that PBAF complex may be required for HTLV-1 transcriptional repression by HBZ. Additionally, we found that BRG1 expression translocates HBZ into distinct nuclear foci. We show that HBZ substantially represses HTLV-1 LTR activation by Tax/BRG1. Interestingly, we found that Tax stabilizes the expression of exogenous and endogenous BRG1 and HBZ reverses this effect. Finally, using Chromatin Immunoprecipitation-qPCR (ChIP-qPCR) assay we illustrate that HBZ facilitates the down-regulation of HTLV-1 transcription by deregulating the recruitment of SWI/SNF complexes to the promoter. Overall, we conclude that SWI/SNF complexes, in addition to other cellular transcription factors are involved in HBZ-mediated suppression of HTLV-1 viral gene expression.The pathogenic potential of HTLV-1 is linked to the indispensable multifaceted functions of the viral regulatory proteins Tax and HBZ, encoded by the sense and antisense viral transcripts, respectively. The interaction between Tax and SWI/SNF family of chromatin-remodeling complexes has been associated with HTLV-1 transcriptional activation. To date, the relationship between SWI/SNF chromatin remodeling family and HBZ, the only viral protein that is consistently expressed in infected cells and ATL cells, has not been elucidated. Here, we have characterized the biological significance of SWI/SNF family in regard to viral transcriptional repression by HBZ. This is important because it provides a better understanding of the function and role of HBZ in down-regulating viral transcription and hence its contribution to viral latency and persistence , a process that may ultimately lead to development of ATL.

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May, 2019


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