Modulation of mitochondrial K+ permeability and reactive oxygen species production by the p13 protein of human T-cell leukemia virus type 1

Silic-Benussi, Micol; Cannizzaro, Enrica; Venerando, Andrea; Cavallari, Ilaria; Petronilli, Valeria; Rocca, Nicoletta La; Marin, Oriano; Chieco‐Bianchi, Luigi; Lisa, Fabio Di; D’Agostino, Donna M.; Bernardi, Paolo; Ciminale, Vincenzo

doi:10.1016/j.bbabio.2009.02.001

Cited by 44 publications

(54 citation statements)

References 37 publications

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“…13 Additional in vitro assays carried out with full-length synthetic p13 and isolated mitochondria demonstrated that it triggers an inward K ϩ current that induces depolarization and activation of the electron transport chain; these changes are accompanied by increased mitochondrial ROS production, which along with membrane depolarization, lowers the opening threshold of the permeability transition pore. 14 In the present study, we show that p13 increases ROS production in living cells. We also provide evidence that this change may have a distinct impact on cell survival and proliferation depending on the cell's inherent ROS levels, with activation predominating in normal resting T-cells and death-promoting effects in transformed cells.…”

Section: Introductionmentioning

confidence: 63%

Redox regulation of T-cell turnover by the p13 protein of human T-cell leukemia virus type 1: distinct effects in primary versus transformed cells

Silic-Benussi¹,

Cavallari²,

Vajente³

et al. 2010

Blood

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The present study investigated the function of p13, a mitochondrial protein of human T-cell leukemia virus type 1 (HTLV-1). Although necessary for viral propagation in vivo, the mechanism of function of p13 is incompletely understood. Drawing from studies in isolated mitochondria, we analyzed the effects of p13 on mitochondrial reactive oxygen species (ROS) in transformed and primary T cells. In transformed cells (Jurkat, HeLa), p13 did not affect ROS unless the cells were subjected to glucose deprivation, which led to a p13-dependent increase in ROS and cell death. Using RNA interference we confirmed that expression of p13 also influences glucose starvation-induced cell death in the context of HTLV-1-infected cells. ROS measurements showed an increasing gradient from resting to mitogenactivated primary T cells to transformed T cells (Jurkat). Expression of p13 in primary T cells resulted in their activation, an effect that was abrogated by ROS scavengers. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels; in the context of the HTLV-1 propagation strategy, p13 could increase the pool of "normal" infected cells while culling cells acquiring a transformed phenotype, thus favoring lifelong persistence of the virus in the host. (Blood. 2010;116(1): 54-62) IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects an estimated 20 million people worldwide. HTLV-1 is the causative agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4ϩ T cells that is refractory to current therapies. ATLL arises in approximately 3% of HTLV-1-infected persons and is preceded by a decades-long clinical latency.Many aspects of HTLV-1 replication, persistence, and pathogenesis remain incompletely understood (reviewed in Verdonck et al 1 ). Studies so far have been focused primarily on the transcriptional activator Tax, which is essential for expression from the viral promoter, and the posttranscriptional factor Rex, which is required for expression of incompletely spliced viral transcripts. Tax also plays a critical role in T-cell transformation through its ability to deregulate the expression of a vast array of cellular genes and interfere with cell-cycle checkpoints, producing major alterations in cell proliferation and survival and promoting genetic instability (reviewed in Lairmore et al 2 ). Indeed, expression of Tax in mouse thymocytes is sufficient for induction of T-cell leukemia/ lymphoma. 3 However, the contrast between the powerful oncogenic properties of Tax and the low prevalence and long latency of ATLL suggests the existence of mechanisms that limit the transforming potential of the virus and favor its lifelong persistence in the host in the absence of disease.Recent studies indicate that the viral accessory proteins p12, p21, p30, HBZ, and p13 may also contribute to HTLV-1 replication and pathogenesis (reviewed in Nicot et al 4 ). The present study is focused on p13, an 87-amino acid accessory prote...

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Section: Introductionmentioning

confidence: 63%

Redox regulation of T-cell turnover by the p13 protein of human T-cell leukemia virus type 1: distinct effects in primary versus transformed cells

Silic-Benussi¹,

Cavallari²,

Vajente³

et al. 2010

Blood

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“…Moreover, virus replication might also promote the overproduction of ROS. Indeed, in vitro studies have suggested that the HTLV-1 tax protein induces the production of ROS (Silic-Benussi et al, 2009;Chlichlia and Khazaie 2010;Kinjo et al, 2010). The excessive ROS production results in excessive usage of available antioxidants leading to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Serum total antioxidant capacity status of HTLV-1 infected patients

Shomali¹,

Avval²,

Boostani³

et al. 2015

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Summary. -Many aspects of the pathogenesis of Human T-cell lymphotropic virus type 1 (HTLV-1) still need further elucidations. Previous studies have indicated that oxidative stress occurs during infection with the other retrovirus, human immunodeficiency virus 1 (HIV-1). Similar results have been observed in some other chronic viral infections including hepatitis B (HBV) and hepatitis C (HCV). In order to reveal possible oxidative stress in HTLV-1-infected patients, we evaluated serum total antioxidant capacity (TAC) as an indicator of oxidative stress in these patients. Forty-four HTLV-1-seropositive individuals were included in this study, consisting of 12 symptomatic and 32 asymptomatic (carrier) cases. Controls consisted of 36 apparently healthy, HTLV-1-, HIV-and hepatitis-seronegative individuals. All symptomatic patients had HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). Serum TAC levels in patients and healthy individuals were measured using a quantitative TAC assay. The antioxidant capacity in HTLV-1-seropositive cases was significantly reduced compared to control group (P = 0.001). In addition, TAC was lower in patients with more than 5 years history of HAM/TSP compared to those with ≤5 years duration of the myelopathy (P = 0.03). Our results show a depletion of TAC during HTLV-1 infection, which intensifies along with the disease progress. This finding indicates a role of the oxidative stress in pathogenesis of HTLV-1. These results may prompt further research to evaluate any possible therapeutic effect of antioxidant dietary supplements for HTLV-1 infected individuals.Keywords: HTLV-1; oxidative stress; total antioxidant capacity (TAC) * Corresponding author. E-mail: youssefim@mums.ac.ir; phone: +98-511-8525007. Abbreviations: HAM/TSP = HTLV-1-associated myelopathy/tropical spastic paraparesis; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HTLV-1 = human T-lymphotropic virus type 1; ROS = reactive oxygen species; TAC = total antioxidant capacity

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“…A truncated form of p30, p13 localises in mitochondria and alters membrane potential as well as reactive oxygen species (ROS) production (Silic-Benussi et al, 2009). On the other hand, p13 binds to farnesyl pyrophosphate synthase (FPPS), an enzyme required for the prenylation of Ras (Lefebvre et al, 2002).…”

Section: Rex P12 P13 and P30mentioning

confidence: 99%