Correction: HTLV-1 bZIP Factor Enhances T-cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors

Kinosada, Haruka; Yasunaga, Jun Ichirou; Shimura, Kazuya; Miyazato, Paola; Onishi, Chiho; Iyoda, Tomonori; Inaba, Kayo; Matsuoka, Masao

doi:10.1371/journal.ppat.1006228

Cited by 33 publications

(9 citation statements)

References 2 publications

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“…Previously, higher nuclear retention of HBZ mRNA and localization of HBZ in the nucleus have been demonstrated ( Hivin et al, 2005 ; Rende et al, 2011 ), suggesting that HTLV-1 might favor viral persistence by reducing HBZ translation to escape the infected cells from HBZ-specific immune responses. However, HBZ protein has been recently reported to be localized in the cytoplasm of T cells depending on the expression of THEMIS (thymocyte-expressed molecule involved in selection), a recently identified T lineage-restricted protein ( Kinosada et al, 2017 ). HBZ interfered complex formation of THEMIS with Grb2 and SHP-2, which resulted in inhibition of suppressive function of co-inhibitory receptors, such as T cell immunoglobulin and ITIM domain (TIGIT) and program death-1 (PD-1), and enhanced activation of T cells ( Kinosada et al, 2017 ).…”

Section: Molecular Pathogenesis Of Hbz In Ham/tspmentioning

confidence: 99%

“…However, HBZ protein has been recently reported to be localized in the cytoplasm of T cells depending on the expression of THEMIS (thymocyte-expressed molecule involved in selection), a recently identified T lineage-restricted protein ( Kinosada et al, 2017 ). HBZ interfered complex formation of THEMIS with Grb2 and SHP-2, which resulted in inhibition of suppressive function of co-inhibitory receptors, such as T cell immunoglobulin and ITIM domain (TIGIT) and program death-1 (PD-1), and enhanced activation of T cells ( Kinosada et al, 2017 ). Localization of HBZ protein was also reported in the cytoplasm of PBMCs of HAM/TSP patients ( Baratella et al, 2017 ).…”

Section: Molecular Pathogenesis Of Hbz In Ham/tspmentioning

confidence: 99%

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Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP

2017

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Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. Understanding the interaction between host and HTLV-1 and the molecular mechanisms associated with disease pathogenesis is critical for development efficient therapies. Two HTLV-1 genes, tax and HTLV-1 basic leucine zipper factor (HBZ), have been demonstrated to play important roles in HTLV-1 infectivity and the growth and survival of leukemic cells. Increased HTLV-1 Tax expression induces the expression of various cellular genes such as IL-2 and IL-15, which directly contributes to lymphocyte activation and immunopathogenesis in HAM/TSP patients. However, little is known about the molecular and cellular mechanism of HBZ in development of HAM/TSP. It has been reported that HBZ mRNA expression was detected in HAM/TSP patients higher than in asymptomatic carriers and correlated with proviral load and disease severity. Unlike HTLV-1 tax, HBZ escapes efficient anti-viral immune responses and therefore these reactivities are difficult to detect. Thus, it is important to focus on understanding the function and the role of HTLV-1 tax and HBZ in disease development of HAM/TSP and discuss the potential use of these HTLV-1 viral gene products as biomarkers and therapeutic targets for HAM/TSP.

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Section: Molecular Pathogenesis Of Hbz In Ham/tspmentioning

confidence: 99%

Section: Molecular Pathogenesis Of Hbz In Ham/tspmentioning

confidence: 99%

Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP

2017

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“…Taken together, these observations let us to propose the cytoplasmic localization of HBZ protein in PBMC of HAM/TSP patients as the first molecular marker of disease, since until now the only associative parameters with the neurological disease were either clinical correlates or the rather non-specific high proviral load ( Nagai et al, 1998 ). Recently, it has been reported that HBZ-transfected cell lines, including the T cell line Jurkat, may partially segregate HBZ in the cytoplasm as result of interaction with THEMIS ( Kinosada et al, 2017 ). With the limitations expressed above on the physiological correlates of HBZ in overexpressing systems, THEMIS may represent a potential HBZ interactor contributing to the cytoplasmic segregation of HBZ also in HAM/TSP patients’ cells.…”

Section: Hbz: Biochemical Aspects and Distinct Subcellular Distributimentioning

confidence: 99%

HTLV-1 HBZ Viral Protein: A Key Player in HTLV-1 Mediated Diseases

2017

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Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic human retrovirus that has infected 10–15 million people worldwide. After a long latency, 3–5% of infected individuals will develop either a severe malignancy of CD4+ T cells, known as Adult T-cell Leukemia (ATL) or a chronic and progressive inflammatory disease of the nervous system designated Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (HAM/TSP). The precise mechanism behind HTLV-1 pathogenesis still remains elusive. Two viral regulatory proteins, Tax-1 and HTLV-1 bZIP factor (HBZ) are thought to play a critical role in HTLV-1-associated diseases. Tax-1 is mainly involved in the onset of neoplastic transformation and in elicitation of the host’s inflammatory responses; its expression may be lost during cell clonal proliferation and oncogenesis. Conversely, HBZ remains constantly expressed in all patients with ATL, playing a role in the proliferation and maintenance of leukemic cells. Recent studies have shown that the subcellular distribution of HBZ protein differs in the two pathologies: it is nuclear with a speckled-like pattern in leukemic cells and is cytoplasmic in cells from HAM/TSP patients. Thus, HBZ expression and distribution could be critical in the progression of HTLV-1 infection versus the leukemic state or the inflammatory disease. Here, we reviewed recent findings on the role of HBZ in HTLV-1 related diseases, highlighting the new perspectives open by the possibility of studying the physiologic expression of endogenous protein in primary infected cells.

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“…In addition, cytoplasmic HBZ interacts with GADD34 to suppress GADD34 function and positively regulate the mechanistic target of rapamycin (mTOR) signaling pathway ( Mukai and Ohshima, 2014 ) ( Figure 1 ). Finally, the cytoplasmic localization of HBZ protein in T cells depends on the host factor THEMIS ( Kinosada et al, 2017 ). Since THEMIS is expressed only in T cells, this function might explain why HTLV-1 promotes the proliferation of T cells.…”

Section: The Localization Of Hbz and Its Function In The Nucleus And mentioning

confidence: 99%

“…Although TIGIT is a co-inhibitory receptor that suppresses T-cell activation, it does not inhibit the proliferation of ATL cells or HTLV-1 infected cells ( Kinosada et al, 2017 ). TIGIT exerts inhibitory signal through the intracytoplasmic immunoreceptor tyrosine inhibitory motif (ITIM) that interacts with a complex of SHP-2, Grb2, and THEMIS.…”

Section: Tigit and Themismentioning

confidence: 99%

HTLV-1 Alters T Cells for Viral Persistence and Transmission

Tanaka

Matsuoka

2018

Front. Microbiol.

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Human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus to be discovered as a causative agent of adult T-cell leukemia-lymphoma (ATL) and chronic inflammatory diseases. Two viral factors, Tax and HTLV-1 bZIP factor (HBZ), are thought to be involved in the leukemogenesis of ATL. Tax expression is frequently lost due to DNA methylation in the promoter region, genetic changes to the tax gene, and deletion of the 5′ long terminal repeat (LTR) in approximately half of all ATL cases. On the other hand, HBZ is expressed in all ATL cases. HBZ is known to function in both protein form and mRNA form, and both forms play an important role in the oncogenic process of HTLV-1. HBZ protein has a variety of functions, including the suppression of apoptosis, the promotion of proliferation, and the impairment of anti-viral activity, through the interaction with several host cellular proteins including p300/CBP, Foxp3, and Foxo3a. These functions dramatically modify the transcriptional profiling of host T cells. HBZ mRNA also promotes T cell proliferation and viability. HBZ changes infected T cells to CCR4+TIGIT+CD4+ effector/memory T cells. This unique immunophenotype enables T cells to migrate into various organs and tissues and to survive in vivo. In this review, we summarize how HBZ hijacks the transcriptional networks and immune systems of host T cells to contribute to HTLV-1 pathogenesis on the basis of recent new findings about HBZ and tax.

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Correction: HTLV-1 bZIP Factor Enhances T-cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors

Cited by 33 publications

References 2 publications

Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP

Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP

HTLV-1 HBZ Viral Protein: A Key Player in HTLV-1 Mediated Diseases

HTLV-1 Alters T Cells for Viral Persistence and Transmission

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