Expression of Murine Leukemia Virus Envelope Protein Is Sufficient for the Induction of Apoptosis

Zhao, Xiaoqing; Yoshimura, Fayth K.

doi:10.1128/jvi.02291-07

Cited by 11 publications

(10 citation statements)

References 35 publications

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“…Indeed, this toxicity is the basis for the mink cell focus assay used to quantitate MCF viruses (9). It was proposed previously that this death is due to virus superinfection and the subsequent buildup of the Env protein, resulting in endoplasmic reticulum (ER) stress (41). However, given the similarities between this phenomenon and XMRV toxicity to SY5Y cells, we hypothesized that MCF virus might kill cells via a similar cAMP-mediated mechanism.…”

Section: Xmrv Induces Apoptosis In Sy5y Neuroblastoma Cellsmentioning

confidence: 96%

Xpr1 Is an Atypical G-Protein-Coupled Receptor That Mediates Xenotropic and Polytropic Murine Retrovirus Neurotoxicity

Vaughan

Mendoza

Aranda

et al. 2012

J Virol

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Xenotropic murine leukemia virus-related virus (XMRV) was first identified in human prostate cancer tissue and was later found in a high percentage of humans with chronic fatigue syndrome (CFS). While exploring potential disease mechanisms, we found that XMRV infection induced apoptosis in SY5Y human neuroblastoma cells, suggesting a mechanism for the neuromuscular pathology seen in CFS. Several lines of evidence show that the cell entry receptor for XMRV, Xpr1, mediates this effect, and chemical cross-linking studies show that Xpr1 is associated with the G␤ subunit of the G-protein heterotrimer. The activation of adenylate cyclase rescued the cells from XMRV toxicity, indicating that toxicity resulted from reduced G-protein-mediated cyclic AMP (cAMP) signaling. Some proteins with similarity to Xpr1 are involved in phosphate uptake into cells, but we found no role of Xpr1 in phosphate uptake or its regulation. Our results indicate that Xpr1 is a novel, atypical G-protein-coupled receptor (GPCR) and that xenotropic or polytropic retrovirus binding can disrupt the cAMP-mediated signaling function of Xpr1, leading to the apoptosis of infected cells. We show that this pathway is also responsible for the classic toxicity of the polytropic mink cell focus-forming (MCF) retrovirus in mink cells. Although it now seems clear that the detection of XMRV in humans was the result of sample contamination with a recombinant mouse virus, our findings may have relevance to neurologic disease induced by MCF retroviruses in mice.

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Section: Xmrv Induces Apoptosis In Sy5y Neuroblastoma Cellsmentioning

confidence: 96%

Xpr1 Is an Atypical G-Protein-Coupled Receptor That Mediates Xenotropic and Polytropic Murine Retrovirus Neurotoxicity

Vaughan

Mendoza

Aranda

et al. 2012

J Virol

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“…However, as overexpression of MLV Env protein is already sufficient to induce apoptosis (Fig. 6D) and to trigger UPR (Zhao and Yoshimura, 2008), our data strongly suggest that UPR activation is a major cause for apoptosis in Setdb1…”

Section: Discussionmentioning

confidence: 65%

“…6D). Interestingly, expression of MLV Env protein from exogenous MLV retroviruses also results in increased apoptosis (Zhao and Yoshimura, 2008) and infection with MLV retroviruses results in impaired B cell development in vivo (Finstad et al, 2007). Furthermore, it is possible that transcripts/proteins produced from other upregulated repeat elements contribute to the phenotype.…”

Section: Discussionmentioning

confidence: 99%

Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells

et al. 2016

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The H3K9me3-specific histone methyltransferase Setdb1 impacts on transcriptional regulation by repressing both developmental genes and retrotransposons. How impaired retrotransposon silencing may lead to developmental phenotypes is currently unclear. Here, we show that loss of Setdb1 in pro-B cells completely abrogates B cell development. In pro-B cells, Setdb1 is dispensable for silencing of lineage-inappropriate developmental genes. Instead, we detect strong derepression of endogenous murine leukemia virus (MLV) copies. This activation coincides with an unusual change in chromatin structure, with only partial loss of H3K9me3 and unchanged DNA methylation, but strongly increased H3K4me3. Production of MLV proteins leads to activation of the unfolded protein response pathway and apoptosis. Thus, our data demonstrate that B cell development depends on the proper repression of retrotransposon sequences through Setdb1.

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“…In fact, expression of gPr80 env is sufficient to induce apoptosis in gPr80 env transfected cells (Yu et al 1991; Yu et al 1997; Zhao & Yoshimura 2008) and neuropathological lesion in ts 1 env gene transgenic mice (Yu et al 1997). Based on the above data accumulation of gPr80 env is thought to be the primary insult in ts 1-induced astrocyte dysfunction and neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice

Kuang¹,

Hu²,

Yan³

et al. 2010

Neurochemistry International

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Many neurodegenerative diseases are associated with accumulation of misfolded proteins in cells of the central nervous system (CNS). We have previously reported that accumulation of the precursor envelope protein gPr80env of ts1, a mutant of Moloney murine leukemia virus (MoMuLV), in the endoplasmic reticulum (ER) of infected astrocytes, results in ER stress, oxidative stress and cell death, subsequently leading to ts1-mediated neurodegeneration in infected mice. In the present study, we assessed whether treatments that reduce the accumulation of gPr80env in the ER of ts1-infected astrocytes provided a protective effect against ER stress and cell death. We show that treatment with phenylbutyric acid (PBA) can prevent the unfolded protein response (UPR), ER stress and cell death in cultured ts1-infected astrocytes. The protective effect of PBA is associated with its ability to reduce gPr80env accumulation and to increase the expression of proteins involved in protein folding in the ER, such as protein disulfide isomerase (PDI) and ERp44, rather than by decrease mRNA levels of gPr80env or alter the proteasomal degradation process for gPr80env. In infected mice treated with PBA we also noted a reduction in the severity of the neuropathology in brainstem tissues and a delayed onset of paralysis. These results show that PBA is a potentially effective drug for the treatment of neurodegeneration caused by protein accumulation in cells of the CNS.

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Expression of Murine Leukemia Virus Envelope Protein Is Sufficient for the Induction of Apoptosis

Cited by 11 publications

References 35 publications

Xpr1 Is an Atypical G-Protein-Coupled Receptor That Mediates Xenotropic and Polytropic Murine Retrovirus Neurotoxicity

Xpr1 Is an Atypical G-Protein-Coupled Receptor That Mediates Xenotropic and Polytropic Murine Retrovirus Neurotoxicity

Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells

Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice

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