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

Abstract

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...

Redox regulation of T-cell receptor signaling

“…Blockade of mitochondrial complex-I in these cells reduced disease-associated hyper-expression of IL-4 (Kaminski et al, 2010(Kaminski et al, , 2013. In addition, a number of recent studies identified novel molecular players, which all affect mitochondrial ROS production and thereby T-cell activation as well as apoptosis (Kaminski et al, 2007(Kaminski et al, , 2013Silic-Benussi et al, 2010). In summary, it now clear that mitochondria have a complex and very important role in controlling T-cell function.…”

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

“…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.…”

Superoxide-Generating Nox5α Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype

“…Since the interaction of TRX-ASK1 is not affected by Nox isozyme-derived ROS (41), it is unlikely that Nox5␣ participates in the ADF/ASK1 pathway. p13, a HTLV-1-encoded protein located in mitochondria, also increases ROS generation and thereby induces the death of HTLV-1-infected cells, contributing to the turnover between normal and HTLV-1-transformed cells (42). However, Nox-dependent ROS generation is not affected by the mitochondrial oxidase inhibitor rotenone and appears to be functionally different from mitochondrial ROS production (14).…”