Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13
            <sup>II</sup>
            Sensitizes Jurkat T Cells to Ras-Mediated Apoptosis

Hiraragi, Hajime; Michael, Bindhu; Nair, Amrithraj M.; Silic-Benussi, Micol; Ciminale, Vincenzo; Lairmore, Michael Dale

doi:10.1128/jvi.79.15.9449-9457.2005

Cited by 42 publications

(38 citation statements)

References 39 publications

(40 reference statements)

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“…induced by ceramide and FasL [17,18]. These findings are consistent with the hypothesis that p13 may act by lowering the threshold of PTP opening, as observed in isolated mitochondria.…”

Section: Effects Of P13 On Cell Turnover and Transformationsupporting

confidence: 90%

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K⁺ permeability: A new member of the viroporin family?

et al. 2010

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a b s t r a c tHuman T-cell leukemia virus type-1 (HTLV-1) encodes a mitochondrial protein named p13. p13 mediates an inward K + current in isolated mitochondria that leads to mitochondrial swelling, depolarization, increased respiratory chain activity and reactive oxygen species (ROS) production. These effects trigger the opening of the permeability transition pore and are dependent on the presence of K + and on the amphipathic alpha helical domain of p13. In the context of cells, p13 acts as a sensitizer to selected apoptotic stimuli. Although it is not known whether p13 influences the activity of endogenous K + channels or forms a channel itself, it shares some structural and functional analogies with viroporins, a class of small integral membrane proteins that form pores and alter membrane permeability.

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“…induced by ceramide and FasL [17,18]. These findings are consistent with the hypothesis that p13 may act by lowering the threshold of PTP opening, as observed in isolated mitochondria.…”

Section: Effects Of P13 On Cell Turnover and Transformationsupporting

confidence: 90%

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K⁺ permeability: A new member of the viroporin family?

et al. 2010

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“…[31][32][33] Furthermore, the p13 protein has been reported to suppress cell growth in vitro, tumorigenicity in vivo, and to sensitize Jurkat T cells to Ras-mediated apoptosis. 34,35 In the present study, we describe a novel function for p13, demonstrating that it is a negative regulator of HTLV-1 replication in the presence of Tax. The p13 protein binds to Tax and interferes with Tax-CBP/ p300 complex formation, thereby decreasing Tax transcriptional activity.…”

Section: Introductionmentioning

confidence: 68%

Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

Andresen

Pise-Masison

Sinha-Datta

et al. 2011

Blood

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IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) 1-3 and the neurologic disease HTLV-1-associated myelopathy/tropical spastic paresis (HAM/TSP). 4,5 In addition to the Gag, Pol, and Env proteins, HTLV-1 encodes through alternative splicing mRNAs for at least 7 additional viral proteins. The 2 essential positive regulators of HTLV-1 replication, the Tax and Rex proteins, are encoded by a unique, double-spliced mRNA and are expressed through ribosomal leaky scanning in orf-III and orf-IV, respectively. 6 Tax is an enhancer of viral transcription by its interaction with CREB/ATF, CBP/p300, and the Tax response element (TRE) located within the viral promoter. 7 In addition, Tax has been reported to interact with more than 100 different cellular proteins that affect gene expression, cell signaling, and proliferation. 8 Tax is also thought to be a promoter of T-cell transformation, because Tax expression immortalizes T cells in vitro and induces tumors in transgenic animals. 8,9 Rex interacts with a viral mRNA secondary structure, designated Rex responsive element (RxRE) located at the 3Ј-long terminal repeat (3Ј-LTR). Rex controls viral production by regulating the transport of unspliced and incompletely spliced viral mRNAs from the nucleus to the cytoplasm. 10 HTLV-1 also encodes 2 negative regulators of viral expression. The first, the p30 protein, is encoded by orf-II, interacts with tax/rex mRNA, and retains it in the nucleus. 11,12 At low concentrations, p30 also represses HTLV-1 LTR-driven transcription, whereas at high concentrations, 13,14 it activates transcription. The second negative regulator of HTLV-1 expression is the HTLV-1 basic zipper factor (HBZ) that is encoded by the antisense strand of the HTLV-1 genome. 15,16 HBZ interacts with CREB and CBP/p300, thereby blocking Tax-dependent transcription and viral expression. 17,18 HBZ also inhibits the activity of JunB and c-Jun by sequestering them in transcriptional inactive nuclear bodies and affects activating protein 1 (AP-1)-dependent cellular and viral transcription. 19,20 More recently, the HBZ antisense mRNA has been shown to induce T-cell proliferation. 21,22 p13 23,24 is a mitochondrial protein encoded by a distinct, singly spliced mRNA from orf-II. It accumulates in the inner membrane of the mitochondria and modulates K ϩ permeability and reactive oxygen species, thereby altering the morphology and function of mitochondria. [25][26][27] Evidence of p13 expression in HTLV-1-infected cells is indirect, because only the presence of mRNA has been demonstrated in both in vitro and ex vivo studies. [28][29][30] orf -II appears to be dispensable for viral infection and transformation of T cells in vitro; however, its requirement in HTLV-1 infection of rabbits remains uncertain because the mutation introduced into the HTLV-1 molecular clone to ablate p13 also affected the HBZ gene. [31][32][33] Furthermore, the p13 protein has been reported to suppress cell growth in vitro, tumorigeni...

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“…Studies of p13 II have focused primarily on its biochemical properties (11) and in vitro functions, such as suppression of cell proliferation (38) and sensitization to Ras-dependent apop- (19). In addition, we showed that expression of p13 II in HeLa cells was associated with a significant suppression of the tumorigenicity of c-myc-and Ha-rascotransfected rat embryonal fibroblasts in a nude mouse model (12,38).…”

Section: Discussionmentioning

confidence: 87%

“…p13 II localizes and accumulates in the inner membranes of mitochondria, and when ectopically expressed, it causes alteration of mitochondrial morphology and function (7,12). We recently reported the suppressive effect of p13 II on both cell growth in vitro and tumorigenicity in a murine model (12,38) and the sensitization of lymphocytes to apoptosis in a Ras-dependent fashion (19). Collectively, these observations indicate a distinct role for p13 II in HTLV-1 infection and a potential role in HTLV-1-mediated lymphocyte transformation.…”

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confidence: 99%

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 ^II Is Required for Viral Infectivity In Vivo

Hiraragi¹,

Kim²,

Phipps³

et al. 2006

J Virol

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Human T-lymphotropic virus type 1 (HTLV-1) is classified as a complex retrovirus and a member of the genus Deltaretrovirus. The HTLV-1 genome consists of long terminal repeats; genes encoding the structural and enzymatic proteins Gag, Pol, and Env; and a pX region located between env and the 3Ј long terminal repeat that encodes the regulatory proteins Tax and Rex, as well as several nonstructural "accessory" proteins, p12 II (12,16,28,30). HTLV-1 is the etiological agent of adult T-cell leukemia/lymphoma (ATL), a highly aggressive T-cell malignancy (reviewed in reference 43). The virus is also associated with lymphocyte-mediated inflammatory diseases, such HTLV-1-associated myelopathy-tropical spastic paraparesis (16,24,27). There are an estimated 15 to 25 million persons persistently infected by HTLV-1, and approximately 3 to 5% of these infected subjects will develop HTLV-1-associated diseases (27). The underlying mechanisms by which HTLV-1 establishes a persistent infection and transforms lymphocytes has been extensively investigated but incompletely understood. Based on the long period of latency and the low percentage of individuals who develop ATL, transformation of infected lymphocytes is believed to be initiated through the induction of cellular genes and alterations in cellular activation and death pathways by HTLV-1 proteins (18,35).Recent studies indicate a significant role for HTLV-1 accessory proteins in the life cycle of HTLV-1, particularly during the early phase of the viral infection of lymphocytes (reviewed in references 12, 28, and 32). Less is known about the accessory protein p13II , a singly spliced product of the second open reading frame (ORF II) of the pX gene region. p13II mRNA is expressed in various HTLV-1-infected cell lines isolated from clinical patients of ATL and HTLV-1-associated myelopathytropical spastic paraparesis (5, 36), and circulating cytotoxic lymphocytes specific to ORF II products (i.e., p13 II and p30 II ) have been detected both in HTLV-1-infected ATL patients and in asymptomatic persons (34). p13 II localizes and accumulates in the inner membranes of mitochondria, and when ectopically expressed, it causes alteration of mitochondrial morphology and function (7,12). We recently reported the suppressive effect of p13 II on both cell growth in vitro and tumorigenicity in a murine model (12,38) and the sensitization of lymphocytes to apoptosis in a Ras-dependent fashion (19). Collectively, these observations indicate a distinct role for p13 II in HTLV-1 infection and a potential role in HTLV-1-mediated lymphocyte transformation. Although initial studies reported that HTLV-1 ORF II was dispensable for viral infection in vitro (15, 37), disruption of pX ORF II in an HTLV-1 proviral clone that blocks expression of full-length p30 II alone or both p30 II and p13 II dramatically reduced viral infectivity and host humoral response in rabbits (2, 39). These studies, * Corresponding author. Mailing address: Department of Veterinary Biosciences, The Ohio State University, 1925 C...

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Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 ^II Sensitizes Jurkat T Cells to Ras-Mediated Apoptosis

Abstract: II 's influence on lymphocyte survival. Our data are the first to demonstrate that p13 II alters Ras-mediated apoptosis in T lymphocytes, and they reveal a potential mechanism by which HTLV-1 alters lymphocyte proliferation.

Cited by 42 publications

References 39 publications

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K⁺ permeability: A new member of the viroporin family?

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K⁺ permeability: A new member of the viroporin family?

Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 ^II Is Required for Viral Infectivity In Vivo

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Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 II Sensitizes Jurkat T Cells to Ras-Mediated Apoptosis

Abstract: II 's influence on lymphocyte survival. Our data are the first to demonstrate that p13 II alters Ras-mediated apoptosis in T lymphocytes, and they reveal a potential mechanism by which HTLV-1 alters lymphocyte proliferation.

Cited by 42 publications

References 39 publications

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K+ permeability: A new member of the viroporin family?

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K+ permeability: A new member of the viroporin family?

Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 II Is Required for Viral Infectivity In Vivo

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Resources

About

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 ^II Sensitizes Jurkat T Cells to Ras-Mediated Apoptosis

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K⁺ permeability: A new member of the viroporin family?

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K⁺ permeability: A new member of the viroporin family?

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13 ^II Is Required for Viral Infectivity In Vivo