Proteomics Analysis of Gastric Epithelial AGS Cells Infected with Epstein-Barr Virus

Ding, Yong; Li, Xiaorong; Yang, Kang; Hu, Lihua; Hu, Guoqing; Gao, Kai

doi:10.7314/apjcp.2013.14.1.367

Cited by 11 publications

(9 citation statements)

References 31 publications

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“…GDF11 plays intensive roles in development, aging and disease (McPherron et al , ; Nakashima et al , ; Yokoe et al , ; Augusciak‐Duma & Sieron, ; Ding et al , ; Loffredo et al , ; Kaiser, ; Katsimpardi et al , ; Alvarez et al , ; Jamaiyar et al , ; Zhang et al , ), and was recently identified as a regulator of erythropoiesis, which maintains the survival of erythroid progenitors but inhibits further differentiation (Carrancio et al , ; Suragani et al , ). The beneficial effects of GDF11 inhibition were previously reported to be involved in activin receptor ligand traps on terminal erythropoietic differentiation in the mouse models of myelodysplastic syndrome and β‐thalassaemia (Dussiot et al , ; Suragani et al , ; Suragani et al , ).…”

Section: Discussionmentioning

confidence: 99%

GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1‐mediated BMP‐SMAD signalling suppression

et al. 2019

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Hepcidin (HAMP) synthesis is suppressed by erythropoiesis to increase iron availability for red blood cell production. This effect is thought to result from factors secreted by erythroid precursors. Growth differentiation factor 11 (GDF11) expression was recently shown to increase in erythroid cells of b-thalassaemia, and decrease with improvement in anaemia. Whether GDF11 regulates hepatic HAMP production has never been experimentally studied. Here, we explore GDF11 function during erythropoiesistriggered HAMP suppression. Our results confirm that exogenous erythropoietin significantly increases Gdf11 as well as Erfe (erythroferrone) expression, and Gdf11 is also increased, albeit at a lower degree than Erfe, in phlebotomized wild type and b-thalassaemic mice. GDF11 is expressed predominantly in erythroid burst forming unit-and erythroid colony-forming unit-cells during erythropoiesis. Exogeneous GDF11 administration results in HAMP suppression in vivo and in vitro. Furthermore, exogenous GDF11 decreases BMP-SMAD signalling, enhances SMAD ubiquitin regulatory factor 1 (SMURF1) expression and induces ERK1/2 (MAPK3/1) signalling. ERK1/2 signalling activation is required for GDF11 or SMURF1mediated suppression in BMP-SMAD signalling and HAMP expression. This research newly characterizes GDF11 in erythropoiesis-mediated HAMP suppression, in addition to ERFE.

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Section: Discussionmentioning

confidence: 99%

GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1‐mediated BMP‐SMAD signalling suppression

et al. 2019

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“…Advances in proteomic approaches have prompted several recent studies of different aspects of the EBV life cycle. Some of these studies have evaluated changes in expression levels of cellular proteins as well as interactions of the latency protein EBNA1 with the cellular proteins nucleophosmin and hnRNP in EBV-infected epithelial cell lines (32,33). Other studies have identified modifications of cellular proteins in response to EBV infection of B cells (34) and identified cellular proteins that are incorporated into herpesvirus virions (35).…”

Section: Discussionmentioning

confidence: 99%

Cellular STAT3 Functions via PCBP2 To Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes

Koganti

Clark

Zhi

et al. 2015

J Virol

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A major hurdle to killing Epstein-Barr virus (EBV)-infected tumor cells using oncolytic therapy is the presence of a substantial fraction of EBV-infected cells that does not support the lytic phase of EBV despite exposure to lytic cycle-promoting agents. To determine the mechanism(s) underlying this refractory state, we developed a strategy to separate lytic from refractory EBV-positive (EBV ؉ ) cells. By examining the cellular transcriptome in separated cells, we previously discovered that high levels of host STAT3 (signal transducer and activator of transcription 3) curtail the susceptibility of latently infected cells to lytic cycle activation signals. The goals of the present study were 2-fold: (i) to determine the mechanism of STAT3-mediated resistance to lytic activation and (ii) to exploit our findings to enhance susceptibility to lytic activation. We therefore analyzed our microarray data set, cellular proteomes of separated lytic and refractory cells, and a publically available STAT3 chromatin immunoprecipitation sequencing (ChIP-Seq) data set to identify cellular PCBP2 [poly(C)-binding protein 2], an RNA-binding protein, as a transcriptional target of STAT3 in refractory cells. Using Burkitt lymphoma cells and EBV ؉ cell lines from patients with hypomorphic STAT3 mutations, we demonstrate that single cells expressing high levels of PCBP2 are refractory to spontaneous and induced EBV lytic activation, STAT3 functions via cellular PCBP2 to regulate lytic susceptibility, and suppression of PCBP2 levels is sufficient to increase the number of EBV lytic cells. We expect that these findings and the genome-wide resources that they provide will accelerate our understanding of a longstanding mystery in EBV biology and guide efforts to improve oncolytic therapy for EBV-associated cancers. IMPORTANCE Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and the effectiveness of oncolytic therapy for EBV ؉ cancers. To identify the mechanisms that underlie susceptibility to EBV lytic activation, we used host gene and protein expression profiling of separated lytic and refractory cells. We find that STAT3, a transcription factor overactive in many cancers, regulates PCBP2, a protein important in RNA biogenesis, to regulate susceptibility to lytic cycle activation signals. These findings advance our understanding of EBV persistence and provide important leads on devising methods to improve viral oncolytic therapies.

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“…Epstein-Barr virus (EBV) is a member of the gamma herpesviruses and was the first confirmed human tumor virus (Ding et al, 2013;Lu et al, 2017). EBV ubiquitously infects more than 90% of the global population and is closely associated with the development of several malignancies, including Burkitt's lymphoma and nasopharyngeal carcinoma (NPC) (Shair et al, 2008;Yu et al, 2012;Young, 2014;Young and Dawson, 2014;Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus Nuclear Antigen 1 Recruits Cyclophilin A to Facilitate the Replication of Viral DNA Genome

Xin

Liu

et al. 2019

Front. Microbiol.

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Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)-mediated DNA episomal genome replication and persistence are essential for the viral pathogenesis. Cyclophilin A (CYPA) is upregulated in EBV-associated nasopharyngeal carcinoma (NPC) with unknown roles. In the present approach, cytosolic CYPA was found to be bound with EBNA1 into the nucleus. The amino acid 376-459 of the EBNA1 domain was important for the binding. CYPA depletion attenuated and ectopic CYPA expression improved EBNA1 expression in EBV-positive cells. The loss of viral copy number was also accelerated by CYPA consumption in daughter cells during culture passages. Mechanistically, CYPA mediated the connection of EBNA1 with oriP (origin of EBV DNA replication) and subsequent oriP transcription, which is a key step for the initiation of EBV genome replication. Moreover, CYPA overexpression markedly antagonized the connection of EBNA1 to Ubiquitinspecific protease 7 (USP7), which is a strong host barrier with a role of inhibiting EBV genome replication. The PPIase activity of CYPA was required for the promotion of oriP transcription and antagonism with USP7. The results revealed a strategy that EBV recruited a host factor to counteract the host defense, thus facilitating its own latent genome replication. This study provides a new insight into EBV pathogenesis and potential virus-targeted therapeutics in EBV-associated NPC, in which CYPA is upregulated at all stages.

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Proteomics Analysis of Gastric Epithelial AGS Cells Infected with Epstein-Barr Virus

Cited by 11 publications

References 31 publications

GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1‐mediated BMP‐SMAD signalling suppression

GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1‐mediated BMP‐SMAD signalling suppression

Cellular STAT3 Functions via PCBP2 To Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes

Epstein-Barr Virus Nuclear Antigen 1 Recruits Cyclophilin A to Facilitate the Replication of Viral DNA Genome

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