Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis

Ma, Guangyong; Yasunaga, Jun-ichirou; Matsuoka, Masao

doi:10.1186/s12977-016-0249-x

Cited by 110 publications

(134 citation statements)

References 96 publications

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“…The HTLV-1 antisense genomic strand encodes a basic leucine zipper (bZIP)-containing protein, designated HBZ. Although HTLV-1 is capable of infecting different cell types in vitro , HBZ protein is mainly detected in CD4 + T cells in vivo [3, 24, 25]. This cell-type specific expression of HBZ has been shown to play a variety of roles in the pathogenesis of HTLV-mediated T-cell leukemia (reviewed in [3, 26]).…”

Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

“…Although HTLV-1 is capable of infecting different cell types in vitro , HBZ protein is mainly detected in CD4 + T cells in vivo [3, 24, 25]. This cell-type specific expression of HBZ has been shown to play a variety of roles in the pathogenesis of HTLV-mediated T-cell leukemia (reviewed in [3, 26]). For instance, HBZ transforms T-cells into a cancerous phenotype, in part by enhancing the expression of chemokine receptor CCR4 in this cell type, which promotes T-cell proliferation and migration [27].…”

Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

“…For instance, HBZ transforms T-cells into a cancerous phenotype, in part by enhancing the expression of chemokine receptor CCR4 in this cell type, which promotes T-cell proliferation and migration [27]. HBZ also inhibits HTLV-1 sense transcription by recruiting essential transcription factors, such as CREB, away from the proviral sense promoter – this process facilitates HTLV-1 latency in infected T cells [3]. HBZ also affects many other cellular processes, including host gene expression, innate immune signaling, apoptosis, autophagy, and DNA repair – all of which further influence the pathology of the HTLV-1 infection (reviewed in [3]).…”

Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

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The sense behind retroviral anti-sense transcription

Manghera

Magnusson

Douville

2017

Virol J

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Retroviruses are known to rely extensively on the expression of viral proteins from the sense proviral genomic strand. Yet, the production of regulatory retroviral proteins from antisense-encoded viral genes is gaining research attention, due to their clinical significance. This report will discuss what is known about antisense transcription in Retroviridae, and provide new information about antisense transcriptional regulation through a comparison of Human Immunodeficiency Virus (HIV), Human T-cell Lymphotrophic Virus (HTLV-1) and endogenous retrovirus-K (ERVK) long terminal repeats (LTRs). We will attempt to demonstrate that the potential for antisense transcription is more widespread within retroviruses than has been previously appreciated, with this feature being the rule, rather than the exception.

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Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

Section: Antisense Transcription Among Exogenous Retrovirusesmentioning

confidence: 99%

See 1 more Smart Citation

The sense behind retroviral anti-sense transcription

Manghera

Magnusson

Douville

2017

Virol J

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“…HBZ is considered to play an important role in the oncogenic process because of its ability to drive infected cell proliferation, to increase hTERT transcription, to inhibit apoptosis, and to disrupt host genomic integrity depending on several HBZ-induced microRNAs (miRNAs). 17,[26][27][28] …”

Section: Introductionmentioning

confidence: 99%

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Watanabe

2017

Blood

144

117

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Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

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“…Also, HBZ contains a functional nuclear export signal motif within its N-terminal region and can shuttle between the cytoplasm and nucleus (22). Previous reports showed that HBZ interacts with various cellular factors and modulates their functional activities in both the cytoplasmic and nuclear compartments (22,23). In contrast to Tax, HBZ is constitutively expressed in all ATL patient samples because its 3= LTR is conserved and unmethylated in ATL patient cells (24,25).…”

mentioning

confidence: 99%

Enhanced Stabilization of MCL1 by the Human T-Cell Leukemia Virus Type 1 bZIP Factor Is Modulated by Blocking the Recruitment of Cullin 1 to the SCF Complex

Mukai

Ohshima

2016

Molecular and Cellular Biology

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Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the etiological agent of adult T-cell leukemia (ATL). The HTLV-1 basic leucine zipper factor (HBZ), which is encoded by the minus strand of the provirus, is constitutively expressed in all ATL patient cells and likely contributes to the development and maintenance of ATL. Furthermore, the overexpression of the myeloid cell leukemia 1 (MCL1) protein is frequently observed in hematological cancers as well as several other types of cancers. Here, we found that the expression of HBZ in cells stabilized MCL1 protein expression and suppressed the MCL1-mediated release of cytochrome c from the mitochondria. This effect was mediated by inhibition of the ubiquitin-dependent degradation of MCL1. In a serial binding assay, HBZ interacted with cullin 1 (CUL1) through a head-to-tail interaction. The association between CUL1 and Skp1, which serves as the molecular scaffold for the components of SCF ubiquitin ligase complexes, was markedly repressed in the presence of HBZ. Mechanistic analysis indicated that HBZ abrogated the CUL1 association with Skp1, which in turn promoted the cellular expression of MCL1. This novel function of HBZ likely plays a role in the viral pathogenesis of HTLV-1 and provides important insights into our understanding of the development of ATL.H uman T-cell leukemia virus type 1 (HTLV-1) infects at least 5 million to 10 million people worldwide and is the causative agent of adult T-cell leukemia (ATL) (1-4). In most cases, HTLV-1 infection is transmitted through breast milk, blood cells, and dendritic cells in vivo (5). The majority of HTLV-1 carriers do not develop any significant clinical symptoms throughout their lives; however, approximately 5% of HTLV-1-infected subjects progress to ATL (6). Although ATL was discovered 40 years ago, there is still no effective treatment for this disease, in part because the underlying mechanisms of HTLV-1-mediated oncogenesis have not been fully elucidated.The HTLV-1 genome encodes three common retroviral structural and enzymatic proteins (gag, pol, and env proteins) and is flanked by long terminal repeats (LTR) at each end. There is a pX region located between the env gene and the 3= LTR (7). The plus strand of the pX region encodes regulatory and accessory proteins, including p12 I , p21 I , p13 II , p30 II , Rex, and Tax (7). It is well established that the Tax protein is a potent oncoprotein that either strongly activates or inactivates the transcription of target genes as well as interacts with numerous cellular factors that promote the survival and immortalization of HTLV-1-infected T cells (8-13). Interestingly, the Tax protein was detected in only 40% of ATL cases (14, 15) due to nonsense mutations, insertions, deletions, and epigenetic alterations, such as DNA methylation and histone modifications of the 5= LTR of the HTLV-1 provirus (16)(17)(18)(19). These studies suggested that Tax is required for the virus to enhance viral spreading during the earliest stage of HTLV-1 infec...

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Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis

Cited by 110 publications

References 96 publications

The sense behind retroviral anti-sense transcription

The sense behind retroviral anti-sense transcription

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Enhanced Stabilization of MCL1 by the Human T-Cell Leukemia Virus Type 1 bZIP Factor Is Modulated by Blocking the Recruitment of Cullin 1 to the SCF Complex

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