Human Immunodeficiency Virus Type 1 Vpr Links Proteasomal Degradation and Checkpoint Activation

DeHart, Jason L.; Planelles, Vicente

doi:10.1128/jvi.01628-07

Cited by 47 publications

(46 citation statements)

References 69 publications

(109 reference statements)

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“…Vpr is well known to induce apoptosis when a high concentration of Vpr is supplemented in culture or is exogenously expressed in cells (26,27,39,41). It has been shown recently that Vpr induces cell cycle arrest following its binding to a large complex consisting of DDB1, Cul4A E3 ubiquitin ligase, and DDB1-Cul4A-associated factor 1 (8,12,13,24,33,56,59). Furthermore, synthetic Vpr peptides are found to directly bind to ANT, a component of the mPTP located on the inner mitochondrial membrane.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that Vpr causes many cellular dysfunctions, including cell cycle arrest at the G 2 phase caused by the induction of the damage-specific DNA-binding protein 1 (DDB1) and the Cullin 4A (Cul4A) E3 ubiquitin ligase pathway (8,12,13,24,33,51,56,59) and the induction of caspase-dependent apoptosis (39). It is thought that HIV-1 Vpr is a potentially toxic molecule to mature neurons.…”

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confidence: 99%

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Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

Kitayama

Miura

Ando

et al. 2008

J Virol

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Human immunodeficiency virus type 1 (HIV-1)-infected macrophages damage mature neurons in the brain, although their effect on neuronal development has not been clarified. In this study, we show that HIV-1-infected macrophages produce factors that impair the development of neuronal precursor cells and that soluble viral protein R (Vpr) is one of the factors that has the ability to suppress axonal growth. Cell biological analysis revealed that extracellularly administered recombinant Vpr (rVpr) clearly accumulated in mitochondria where a Vpr-binding protein adenine nucleotide translocator localizes and also decreased the mitochondrial membrane potential, which led to ATP synthesis. The depletion of ATP synthesis reduced the transportation of mitochondria within neurites. This mitochondrial dysfunction inhibited axonal growth even when the frequency of apoptosis was not significant. We also found that point mutations of arginine (R) residues to alanine (A) residues at positions 73, 77, and 80 rendered rVpr incapable of causing mitochondrial membrane depolarization and axonal growth inhibition. Moreover, the Vpr-induced inhibition was suppressed after treatment with a ubiquinone analogue (ubiquinone-10). Our results suggest that soluble Vpr is a major viral factor that causes a disturbance in neuronal development through the induction of mitochondrial dysfunction. Since ubiquinone-10 protects the neuronal plasticity in vitro, it may be a therapeutic agent that can offer defense against HIV-1-associated neurological disease.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

Kitayama

Miura

Ando

et al. 2008

J Virol

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“…This discovery was the first of several describing the ability of viral proteins to modulate the ubiquitin proteasome system (UPS). The list of viral proteins that can manipulate the UPS now includes the paramyxovirus V protein, the hepatitis B virus protein X, and the HIV-1 proteins, Vpu and Vif (Horvath, 2004;Leupin et al, 2005;Margottin et al, 1998;Mehle et al, 2004;Sheehy et al, 2003;Sitterlin et al, 2000;Yu et al, 2003), and as its most recent addition, HIV-1 Vpr (reviewed in (Dehart and Planelles, 2007)) After years of searching for a mechanism to explain Vpr-induced G 2 arrest, it is somewhat perplexing that the most informative Vpr-binding partner was discovered in 1994 when a protein of unknown function was co-precipitated with Vpr (Zhao et al, 1994). This protein was originally named Vpr-interacting protein (RIP) or Vpr binding protein (VprBP; see Figure 1), and its cellular function remained enigmatic until 2006 when several groups identified a family of proteins, of which RIP/VprBP is a member, associated with damaged-DNA specific binding protein 1 (DDB1; see Figure 1) (Angers et al, 2006;He et al, 2006;Higa et al, 2006;Jin et al, 2006).…”

Section: Vpr Binding Partners Involved In G 2 Arrestmentioning

confidence: 99%

HIV-1 Vpr: Mechanisms of G2 arrest and apoptosis

Andersen

Rouzic

Planelles

2008

Experimental and Molecular Pathology

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Since the first isolation of HIV-1 from a patient with generalized lymphadenopathy in 1983, great progress has been made in understanding the viral life cycle and the functional nuances of each of the nine genes encoded by HIV-1. Considerable attention has been paid to four small HIV-1 open reading frames, vif, vpr, vpu and nef. These genes were originally termed "accessory" because their deletion failed to completely disable viral replication in vitro. More than twenty years afte the cloning and sequencing of HIV-1, a great deal of information is available regarding the multiple functions of the accessory proteins and it is well accepted that, collectively, these gene products modulate the host cell biology to favor viral replication, and that they are largely responsible for the pathogenesis of HIV-1. Expression of Vpr, in particular, leads to cell cycle arrest in G 2 , followed by apoptosis.Here we summarize our current understanding of Vpr biology with a focus on Vpr-induced G 2 arrest and apoptosis.

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“…The human immunodeficiency virus-1 accessory protein Vpr has been shown to cause replication stress leading to G2 cell cycle arrest by interacting with the DDB1 E3 ligase complex. 31 Interestingly, strong evidence has been presented that Vpr binding to the E3 ligase is not sufficient to induce G2 arrest, thus leading to the prediction that Vpr functions as an adapter to target a yetunknown cell cycle regulator for ubiquitination by the DDB1 E3 ligase. [32][33][34][35] It is tempting to speculate that the same is true for HBx.…”

mentioning

confidence: 99%

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Lluesma¹,

Schaeffer²,

Robert³

et al. 2008

Hepatology

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Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but its role in the transformation process remains unclear. HBV encodes a small protein, known as HBx, which is required for infection and has been implicated in hepatocarcinogenesis. Here we show that HBx induces lagging chromosomes during mitosis, which in turn leads to formation of aberrant mitotic spindles and multinucleated cells. These effects require the binding of HBx to UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and cell cycle regulation, and are unexpectedly attributable to HBx interfering with S-phase progression and not directly with mitotic events. HBx also affects S-phase and induces lagging chromosomes when expressed from its natural viral context and, consequently, exhibits deleterious activities in dividing, but not quiescent, hepatoma cells. Conclusion: In addition to its reported role in promoting HBV replication, the binding of HBx to DDB1 may induce genetic instability in regenerating hepatocytes and thereby contribute to HCC development, thus making this HBV-host protein interaction an attractive target for new therapeutic intervention. (HEPATOLOGY 2008;48:1467-1476.)H epatocellular carcinoma (HCC) is the fifth most frequent cancer in humans, accounting for nearly 1 million deaths annually, and is mainly the consequence of chronic hepatitis B virus (HBV) infection. 1 HBV encodes a small regulatory protein, termed HBx, which is essential for virus replication in vivo and is expressed during chronic infection. 2 HBx has also been implicated in hepatocarcinogenesis. HBx is conserved among all mammalian hepatitis viruses that cause liver cancer in their hosts, whereas no counterpart exists in the non-oncogenic avian hepatitis viruses. Evidence derived from tumor sample analysis, cell culture, and transgenic animal studies collectively supports a role for HBx in HCC development. 3,4 However, the mechanism by which HBx may contribute to hepatocyte transformation remains obscure.In cell culture, HBx exhibits many activities, including an ability to stimulate HBV replication and to interfere with cell cycle progression, and it is believed to do so through interaction with cellular proteins. 2 Among these is UV-damaged DNA binding protein 1 (DDB1), a highly conserved 127-kDa protein that is also targeted by other viral regulatory proteins (see Discussion) and that functions as a subunit of an E3 ubiquitin ligase complex, in which it serves an adapter function to select specific targets for ubiquitin-dependent proteolysis. 5 Previous work demonstrated that HBx stimulates HBV genome replication by binding to DDB1 in the nuclear compartment of cells. 6 A nuclear interaction with DDB1 is also required for HBx to interfere with cell viability. 7 A similar DDB1-binding dependent cytotoxic activity has been re-

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Human Immunodeficiency Virus Type 1 Vpr Links Proteasomal Degradation and Checkpoint Activation

Cited by 47 publications

References 69 publications

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction

HIV-1 Vpr: Mechanisms of G2 arrest and apoptosis

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

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