Epigenetic silencing of HTLV-1 expression by the HBZ RNA through interference with the basal transcription machinery

Gazon, Hélène; Chauhan, Pradeep S.; Porquet, Florent; Hoffmann, Gabriela Brunsting; Accolla, Roberto S.; Willems, Luc

doi:10.1182/bloodadvances.2020001675

Cited by 19 publications

(13 citation statements)

References 22 publications

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“…It has been previously suggested that HBZ mRNA plays a role in supporting proliferation of ATL cells ( 16 ). The rather unexpected nuclear compartmentalization of HBZ mRNA ( 40 ), confirmed and extended in a recent investigation ( 41 ) gives further support to the notion that HBZ mRNA is acting as a transcriptional modulator not only of the viral genome, where it may participate to viral latency ( 42 ), but also of host gene expression ( 16 , 41 , 43 ). Within this frame, HBZ mRNA behaves therefore as a bifunctional molecule with coding capacity and regulatory properties ( 44 ).…”

Section: Future Directionssupporting

confidence: 68%

The Road to HTLV-1-Induced Leukemia by Following the Subcellular Localization of HTLV-1-Encoded HBZ Protein

Accolla

2022

Front. Immunol.

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Human T cell leukemia virus-1 (HTLV-1) is the causative agent of a severe cancer of the lymphoid lineage that develops in 3-5% of infected individuals after many years. HTLV-1 infection may also induce a serious inflammatory pathology of the nervous system designated HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Two virus-encoded proteins, the viral transactivator Tax-1 and the HTLV-1 basic leucine-zipper factor HBZ, are strongly involved in the oncogenic process. Tax-1 is involved in initial phases of the oncogenic process. Conversely, HBZ seems to be involved in maintenance of the neoplastic state as witnessed by the generation of leukemic/lymphomatous phenotype in HBZ transgenic mice and the persistent expression of HBZ in all phases of the oncogenic process. Nevertheless, the intimate molecular and cellular mechanism mediated by the two viral proteins, particularly HBZ, in oncogenesis still remain elusive. An important step toward the complete comprehension of HBZ-associated oncogenicity is the clarification of the anatomical correlates of HBZ during the various phases of HTLV-1 infection to development of HTLV-1-associated inflammatory pathology and ultimately to the establishment of leukemia. In this review, I will summarize recent studies that have established for the first time a temporal and unidirectional expression of HBZ, beginning with an exclusive cytoplasmic localization in infected asymptomatic individuals and in HAM/TSP patients and ending to a progressive cytoplasmic-to-nuclear transition in leukemic cells. These results are framed within the present knowledge of HTLV-1 infection and the future lines of research that may shed new light on the complex mechanism of HTLV-1- mediated oncogenesis.

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Section: Future Directionssupporting

confidence: 68%

The Road to HTLV-1-Induced Leukemia by Following the Subcellular Localization of HTLV-1-Encoded HBZ Protein

Accolla

2022

Front. Immunol.

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“…HBZ plays important roles in the proliferation and survival not only of ATL cells but also of infected nonleukemic cells. We and others have reported the distinct functions of HBZ protein and HBZ RNA (Gazon et al, 2020; Mitobe et al ., 2015; Satou et al ., 2006). RNAs imbued with both coding and non-coding functions are known to exist in bacteria, plants, and animals and are referred to as “bifunctional RNAs” or “coding and non-coding RNAs (cncRNAs)” (Sampath and Ephrussi, 2016).…”

Section: Discussionmentioning

confidence: 89%

Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia

Toyoda

Yasunaga

Arima

et al. 2022

Preprint

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Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is properly secreted from cancer cells, since its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminished development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreased the growth of ATL cells in vitro and in vivo. MCT1/4 expression was positively correlated with TAp73 in many cancers, and their upregulations were associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to oncogenesis.

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“…HBZ mRNA promotes the proliferation of T cells and enhances transcription of anti-apoptotic genes including survivin (46). Furthermore, HBZ mRNA interferes with the basal transcription machinery, leading to suppression of sensetranscription from the LTR (49). It is reported that HBZ protein also suppresses sense-transcription from the LTR (11).…”

Section: Function Of Hbzmentioning

confidence: 99%

“…It is reported that HBZ protein also suppresses sense-transcription from the LTR (11). Thus, both HBZ mRNA and protein are involved in the suppression of sense transcription of viral genes (11,49). Viral proteins that are encoded in the plus strand are well-recognized by CTLs.…”

Section: Function Of Hbzmentioning

confidence: 99%

HTLV-1's Foxy Strategy for Survival and Transmission

2022

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Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases including HTLV-1-associated myelopathy (HAM). A remarkable feature of HTLV-1 is that this virus transmits primarily through cell-to-cell contact. HTLV-1 increases the number of infected cells in vivo to ensure its survival and transmission. Therefore, survival of HTLV-1-infected cells in vivo is very critical for transmission under the host immune surveillance. HTLV-1 possesses multiple strategies to evade host immune responses. Among viral genes, Tax and HTLV-1 bZIP factor (HBZ) play crucial roles in the proliferation of infected cells and the subsequent development of ATL. Although Tax strongly activates the NF-kB pathway, the immunogenicity of Tax is very high; it is a major target of cytotoxic T lymphocytes. Therefore, the virus minimizes Tax production, expressing it only intermittently in vivo. On the other hand, the immunogenicity of HBZ is low, and its expression is maintained in all ATL cases. HBZ transforms the immunophenotype of infected cells into regulatory T cell-like (CD4+ CD25+ CCR4+ TIGIT+ Foxp3+), and promotes the production of immunosuppressive cytokines. Furthermore, HBZ mRNA not only encodes the protein but also functions itself like long non-coding RNA. As a result, Tax and HBZ enable long-term escape from host immunity, persistent infection, and proliferation of infected cells. Here, we review the viral strategies to counteract to host immune surveillance system.

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Epigenetic silencing of HTLV-1 expression by the HBZ RNA through interference with the basal transcription machinery

Abstract: Key Points By disrupting basal transcription machinery, HBZ RNA inhibits sense transcription of human T-cell leukemia virus type 1. Repression of genomic expression may allow entry into proviral latency and escape from immune response.

Cited by 19 publications

References 22 publications

The Road to HTLV-1-Induced Leukemia by Following the Subcellular Localization of HTLV-1-Encoded HBZ Protein

The Road to HTLV-1-Induced Leukemia by Following the Subcellular Localization of HTLV-1-Encoded HBZ Protein

Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia

HTLV-1's Foxy Strategy for Survival and Transmission

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