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Title: NF-κB Hyper-Activation by HTLV-1 Tax Induces Cellular Senescence, but Can Be Alleviated by the Viral Anti-Sense Protein HBZ}
Article:
Abstract:
Activation of I-κB kinases( IKKs) and NF-κB by the human T lymphotropic virus type 1( HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21CIP1/WAF1 and p27KIP1, which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21CIP1/WAF1-/p27KIP1-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induced by Tax in HeLa cells is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27KIP1 protein and p21CIP1/WAF1 mRNA respectively. Finally, we show that down-regulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyper-activation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis.
Introduction:
Human T-lymphotropic virus type 1( HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma( ATL), a malignancy of CD4+ T cells that develops in 2–5% of infected individuals over a course of several decades[1],[2]. HTLV-1 transactivator/oncoprotein, Tax, is thought to play a key role in ATL development. Tax is a potent activator of HTLV-1 transcription and NF-κB[2]. To promote viral mRNA synthesis, it acts as an adaptor that links three 21-bp Tax-responsive enhancer elements in the HTLV-1 long terminal repeats( LTRs) to transcription factors CREB/ATF-1 and transcriptional co-activators CBP/p300, p300-CBP-associated factor( PCAF) and transducers of regulated CREB( TORCs)[3]–[5]. Activation of NF-κB by Tax is mediated by direct binding of Tax to the regulatory subunit of I-κB kinase( IKK), NF-κB essential modulator( NEMO), also known as IKKγ. This interaction results in constitutive activation of IKKα and IKKβ, degradation of all I-κBs, and activation of both classical and alternative NF-κB pathways[6]–[8]. The oncogenic activity of Tax in cell culture and in transgenic mice is driven by NF-κB[9]–[13]. We have shown recently that Tax can activate the anaphase promoting complex/cyclosome( APC/C), an E3 ubiquitin ligase that controls metaphase to anaphase transition and mitotic exit[14]. APC/C activation by Tax leads to premature poly-ubiquitination and degradation of mitotic regulators including cyclin B and Skp2[14]. Skp2 is the substrate-recognition subunit of another E3 ubiquitin ligase known as SCFSkp2, which mediates the destruction of cyclin E/A-CDK2 inhibitor( CKI), p27Kip1( referred to as p27 henceforth) during S/G2[15],[16]. The premature degradation of Skp2 as induced by Tax leads to SCFSkp2 inactivation and p27 protein stabilization. The mRNA level of another CKI: p21CIP1/WAF1( referred to as p21 henceforth) also increases dramatically as a result of promoter activation and mRNA stabilization brought on by Tax[17]. The massive surge in p21 and p27 in turn leads to p53- and pRb-independent cellular senescence termed Tax-induced rapid senescence( Tax-IRS)[14]. Here we show that the p21-/27-mediated cellular senescence induced by Tax constitutes a cellular checkpoint response towards chronic NF-κB hyper-activation. We further demonstrate that RelA is the primary effector of this pathway and RelA acts upstream of the APC/C and RelB to stabilize p27 protein and p21 mRNA respectively. Our results suggest that Impairment to the p21-/27-mediated senescence checkpoint facilitates constitutive NF-κB activation and leukemia development. This is best evidenced by the loss of p27 expression and cytoplasmic localization of p21 in HTLV-1-transformed T cells[14],[18]. Importantly, we found that the HTLV-1 anti-sense RNA-encoded bZip protein, HBZ, could mitigate Tax-induced senescence by virtue of its ability to inhibit NF-κB[19]. HBZ has been shown previously to block trans-activation of viral mRNA expression by Tax[20],[21]. Thus, active HTLV-1 replication characterized by potent Tax-mediated LTR and NF-κB activation leads to senescence, while moderation of Tax activities and attenuation of viral replication by HBZ allow HTLV-1-infected T cells to proliferate, expand, and persist.
Discussion:
The data reported herein have revealed constitutive IKK activation and NF-κB hyper-activation to be the cause for Tax-induced cellular senescence. These results have further established RelA to be the major driver of cellular senescence. Because NF-κB activation is often associated with cell survival and proliferation, we previously thought that a mechanism distinct from IKK/NF-κB activation is responsible for the cellular senescence induced by Tax[31]. Present data show unequivocally that the potentially deleterious IKK/NF-κB hyper-activation by Tax( or other means) immediately triggers a checkpoint mediated by p21 and p27, which act independently of pRb and p53 to induce cellular senescence[14]. We have previously reported that the stabilization of p27 by Tax is a result of premature activation of the APC/C, which brings about degradation of Skp2 and inactivation of SCFSkp2, the E3 ligase that targets p27 for degradation[14]. Present data indicate that hyper-activated NF-κB acts upstream of APC/C to stabilize p27. How NF-κB( RelA specifically) affects unscheduled activation of the APC/C remains to be elucidated. In agreement with our results, the loss of Skp2 has been shown recently to facilitate p21-/p27-mediated and Arf/p53-independent senescence in Skp2-/p19Arf-null mice[32]. The dramatic induction of p21 mRNA by Tax is a result of both promoter trans-activation and mRNA stabilization[17]. The increase in p21 mRNA stability is now shown to be RelB-dependent. Since RelB expression is up-regulated by RelA[29]( also see Fig. 5A), repression or knockdown of RelA effectively prevents p21 mRNA increase. How RelB increases p21 mRNA stability is not clear at present. It may promote the expression of a cellular factor crucial for blocking p21 mRNA degradation. We think p21-/p27-mediated senescence constitutes a checkpoint for blocking potentially oncogenic IKK-NF-κB hyper-activation. Since NF-κB is constitutively active in many human cancers, especially leukemia, present data would suggest that cellular changes that disable this senescence pathway must accompany NF-κB de-regulation in human cancers. Indeed, impairments of p21 and p27 function and expression have been observed in most if not all HTLV-1-transformed T cells previously[14],[33]. Studies of human breast cancers also show a correlation between the over-expression of IKK( i. e. chronic NF-κB activation) and the cytoplasmic localization of p21, in support this conclusion[34]. We think Tax-induced cell cycle aberrations such as DNA damage, and chromosome instability is likely to be NF-κB-mediated. That HeLa-G/ΔN-I-κBα/Tax cell lines are largely normal in their growth and division is consistent with this conclusion. Cellular signaling pathways activated by oxidative stress, inflammation, and DNA damage are known to cause aging and shortened lifespan, and these pathways impact NF-κB activation[35]. Earlier studies have also implicated NF-κB/Rel in aging, cell cycle arrest, or senescence[36]–[39]. Senescent cells are known to secret chemo-attractants for macrophages and NK cells[40], which are responsible for their eventual elimination. Whether senescent HTLV-1-infected cells may use this mechanism for virus transmission and spread, especially to macrophages, can only be speculated upon at this point. Our results also show that NF-κB activation caused by the over-expression of RelA, RelB, or c-Rel, however potent it may be, occurs transiently and leads rapidly to a steep surge in I-κBα and p100( and possibly other I-κB proteins), which promptly dampen NF-κB activity and prevent drastic p21/p27 up-regulation and senescence. This contrasts with the NF-κB hyper-activation by Tax that is mediated by the destruction of I-κBα and I-κB-like molecules via activated IKKs. How does HTLV-1 infection lead to adult T-cell leukemia when the expression of Tax causes senescence? Based on our results, moderation of Tax activities by HBZ, especially at the level of NF-κB activation, is obligatory for the proliferation and expansion of infected cells. Thus, the balance between Tax and HBZ expression, determined by the sites of proviral integration and the availability of cellular transcription factors, can modulate the extent of viral replication and NF-κB activation during infection. This, in turn, may determine the fate of infected cells, which likely ranges from robust viral replication and senescence, oligoclonal expansion, to viral latency and persistence( Fig. 7). Recently, Tax has been shown to up-regulate the expression of HBZ and this up-regulation is influenced by the HTLV-1 integration sites[41]. Furthermore, HBZ has been found to enhance viral infectivity and persistence, and facilitate proliferation of HTLV-1-infected lymphocytes[42],[43]. Finally, HBZ mRNA expression has been shown to correlate with HTLV-1 proviral load while Tax expression was found to decline over time after HTLV-1-infection in a rabbit model[44]. These results are consistent with the notion that HBZ plays a critical role in viral persistence in part by down-regulating the senescence-inducing activity of Tax( Fig. 7). Finally, Tax-induced senescence should be considered as a precancerous condition. While HBZ may either delay or prevent the onset of senescence by attenuating the expression of Tax and NF-κB activation by Tax, cellular changes that inactivate the senescence checkpoint may ultimately facilitate potent and persistent NF-κB activation by Tax to promote leukemia development. ATL cells often cease to express Tax, but continue to produce HBZ mRNA and, presumably, HBZ protein[45]. Whereas Tax, in association with HBZ, may facilitate cell proliferation and survival in the early stage of HTLV-1 infection, at a later time, cytotoxic T lymphocyte killing of Tax-expressing cells likely select for loss of Tax expression. It is conceivable that defects in the senescence checkpoint that develop during the evolution of the infected cells then facilitate the emergence of Tax-independent NF-κB activation( Fig. 7). Finally, the mitogenic activity of HBZ mRNA[46] may also play a role in leukemia maintenance.
Transcription factors of the NF-κB/Rel family are critical for the proliferation of lymphocytes and the expression of genes that mediate inflammatory and immune responses . They are often aberrantly activated in human cancers , especially leukemia , where they confer survival and proliferation advantages . Through the study of the trans-activator/oncoprotein , Tax , of the human T-lymphotropic virus type 1 ( HTLV-1 ) , we have found that persistent and potentially oncogenic activation of NF-κB triggers a defense mechanism that commits cells into senescence , an irreversible state of cell cycle arrest . This checkpoint is turned on by hyper-activated p65/RelA and is mediated by two cyclin-dependent kinase inhibitors , p21 and p27 , in a p53- and pRb-independent manner . It is often impaired in cancer cells with constitutively active NF-κB . Our results anticipate that the anti-sense protein of HTLV-1 , HBZ , which down-regulates NF-κB and HTLV-1 trans-activation by Tax , would mitigate or prevent Tax-induced senescence . This prediction has been borne out experimentally . Thus , Tax promotes robust HTLV-1 replication , potent NF-κB activation and senescence , while HBZ attenuates Tax-driven viral replication and NF-κB activation to allow proliferation of infected cells and persistent infection . Finally , our data support the notion that inactivation of the senescence checkpoint facilitates chronic NF-κB hyper-activation , a critical step in leukemia development .