Daxx interacts with HIV-1 integrase and inhibits lentiviral gene expression

Huang, Lu; Xu, Guan lan; Zhang, Jian Qi; Tian, Ling; Xue, Jing; Chen, Jin Zhong; Jia, William

doi:10.1016/j.bbrc.2008.06.017

Cited by 22 publications

(19 citation statements)

References 21 publications

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“…8). Similar roles for Daxx as part of an antiviral repressor complex have been documented in other viral systems (33,46,73). Furthermore, the observation that large DNA viruses encode proteins that disable Daxx (e.g., herpes simplex virus [HSV] pp71) (39,46,58) further supports our original proposal that Daxx complexes act as antiviral transcriptional repressors (17,18).…”

Section: Discussionsupporting

confidence: 78%

“…However, the fact that Daxx interacts with a large number of diverse viral proteins (33,39,(41)(42)(43)(44)(45)(46)58) indicates that functions relevant to host-virus interactions are prominent. This large collective of interactions between Daxx and viral proteins seem to highlight opposing strategies for the host and virus.…”

Section: Discussionmentioning

confidence: 99%

“…Daxx was first discovered as a cytoplasmic Fas death domain-associated protein (26). However, Daxx localization in promyelocytic nuclear bodies (PML-NBs) (27,28) and its association with numerous nuclear binding partners, including DNA-binding transcription factors and repressive epigenetic regulators (29)(30)(31)(32) and viral proteins (17,33,34), have suggested additional roles for Daxx (35).…”

mentioning

confidence: 99%

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Retroviral DNA Methylation and Epigenetic Repression Are Mediated by the Antiviral Host Protein Daxx

Shalginskikh

Poleshko

Skalka

et al. 2013

J Virol

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Integrated retroviral DNA is subject to epigenetic transcriptional silencing at different frequencies. This process is mediated by repressive DNA methylation and histone modifications on viral chromatin. However, the detailed mechanisms by which retroviral silencing is initiated and maintained are not well understood. Using a model system in which avian sarcoma virus (ASV) DNA is epigenetically repressed in mammalian cells, we previously found that a cellular scaffolding protein, Daxx, acts as an antiretroviral factor that promotes epigenetic repression through recruitment of histone deacetylases (HDACs). Here we show that human Daxx protein levels are increased in response to retroviral infection and that Daxx acts at the time of infection to initiate epigenetic repression. Consistent with a rapid and active antiviral epigenetic response, we found that repressive histone marks and long terminal repeat (LTR) DNA methylation could be detected within 12 h to 3 days postinfection, respectively. Daxx was also found to be required for long-term ASV silencing maintenance and full viral DNA methylation, and it was physically associated with both viral DNA and DNA methyltransferases (DNMTs). These findings support a model in which incoming retroviral protein-DNA complexes are detected by Daxx, and the integrated provirus is rapidly chromatinized and repressed by DNA methylation and histone modification as part of an antiviral response. These results uncover a possible direct and active antiviral mechanism by which DNMTs can be recruited to retroviral DNA. Retroviruses are important agents of disease and serve as valuable vectors for gene delivery, and their study has provided seminal insights into cellular functions. A defining feature of retroviral replication is the integration of a DNA copy of the retroviral RNA genome into host chromatin, a process that establishes the DNA provirus. Integration provides a permanent association of viral DNA with the host cell and all of its progeny, and it also allows the provirus to efficiently mobilize the cellular transcriptional machinery for synthesis of viral mRNAs and viral RNA genomes.DNA integration is an essential step in retroviral replication, and it is catalyzed by the virus-encoded integrase (IN) protein. However, establishment of the provirus does not guarantee its expression; transcriptional repression by epigenetic mechanisms (epigenetic silencing) is often observed in both natural and interspecies retroviral infections. Examples include the silencing of retroviruses in embryonic stem cells (1, 2), the progressive silencing of expression of genes transduced by retroviral vectors during long-term cell propagation (3), and HIV latency (4). Epigenetic mechanisms also repress the expression of endogenous retroviruses (5-9).Retroviral epigenetic silencing is mediated by the enzymatic placement, and subsequent reading, of DNA methylation marks (addition of a methyl group to position 5 of the cytosine pyrimidine [5MeCpG]) and repressive nucleosomal histone modifications. Th...

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Retroviral DNA Methylation and Epigenetic Repression Are Mediated by the Antiviral Host Protein Daxx

Shalginskikh

Poleshko

Skalka

et al. 2013

J Virol

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“…These findings suggest that Daxx/HDAC/Dmnt1 complexes play a role in initiating epigenetic silencing, possibly as part of an antiviral response against retroviruses (87,89). Daxx knockdown was also shown to increase HIV-1-derived lentiviral reporter gene expression (90). Daxx associates with lentiviral DNA by interacting with the HIV-1 integrase, and like ASV HDACs, is recruited to viral DNA, resulting in lentiviral gene repression (90).…”

Section: Daxx Impairment By Virion Proteins: a Role In Latency And Simentioning

confidence: 97%

Virion Factors That Target Daxx To Overcome Intrinsic Immunity

Schreiner

Wodrich

2013

J Virol

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bPML nuclear bodies and their associated functions are part of an intrinsic cellular mechanism aimed at maintaining transcriptional control over viral gene expression and preventing replication of invading viruses. To overcome these barriers, many viruses express early nonstructural, multifunctional proteins to support the viral replication cycle or modulate host immune responses. Virion proteins constituting the invading particle are traditionally investigated for their role in transport during entry or egress and in the assembly of new virions. The additional functions of virion proteins have largely been ignored, in contrast to those of their nonstructural counterparts. A number of recent reports suggest that several virion proteins may also play vital roles in gene activation processes, in particular by counteracting intrinsic immune mechanisms mediated by the PML nuclear body-associated cellular factors Daxx, ATRX, and Sp100. These virion proteins share several features with their more potent nonstructural counterparts, and they may serve to bridge the gap in the early phase of an infection until immediate early viral gene expression is established. In this review, we discuss how virion proteins are an integral part of gene regulation among several viral families and to what extent structural proteins of incoming virions may contribute to species barrier, latency, and oncogenesis.W hen viral genetic information is transferred from cell to cell, it must be compacted and transcriptionally inactivated for storage in the viral capsid during transport. This process needs to be actively reversed upon infection against cellular transcriptional repression through intrinsic antiviral mechanisms. An important factor in the cellular control of viral gene expression is death domain-associated protein (Daxx). Daxx was initially described as a modulator of apoptotic signaling (1), but recent reports suggest that Daxx plays an active role in gene regulation by repressing or modulating transcription through chromatin remodeling (2, 3). Daxx mainly cooperates with alpha-thalassemia retardation syndrome x-linked (ATRX), a putative member of the SNF2 family of ATP-dependent chromatin-remodeling proteins. In this repressive complex, ATRX acts as the core ATPase subunit, while Daxx is the targeting factor, leading to histone deacetylase (HDAC) recruitment (4-6).Daxx is found associated with the promyelocytic leukemia protein nuclear body (PML-NB) or chromatin. Association with PML-NB alleviates gene repression and activates apoptosis, while chromatin-bound Daxx represses transcription (7-9). It has been long established that PML-NBs are nuclear structures with antiviral activity, accumulating an expanding number of transient or constitutive cellular factors involved in transcriptional control, chromatin remodeling, genome integrity, apoptosis, and tumor suppression (10). Moreover, several PML-NB constituents can be induced by type I and II interferon (IFN), resulting in increased antiviral activity by attenuating viral gene exp...

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“…33 As a novel histone chaperone and a product of an interferon-c-induced gene, Daxx has been extensively implicated in virus infection and T-cell activation. [34][35][36][37][38][39][40][41][42][43] Recent studies demonstrated that MST1 and Daxx interact with each other to mediate interferon-c-induced apoptosis in microglia, which plays a critical role during inflammation. 44 In this process, Daxx directly binds to MST1 and regulates its homooligomerization, activation and nuclear translocation.…”

Section: Gck-ii Kinases Regulate Lymphocyte Adhesion Migration Prolmentioning

confidence: 99%