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Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations in the PKD1 (~85%) or PKD2 (~15%) gene which, respectively, encode polycystin-1 (PC1) and polycystin-2 (PC2). How PC1 regulates cell proliferation and apoptosis has been studied for decades but the underlying mechanisms remain controversial. Protein kinase RNA-activated (PKR) is activated by interferons or double-stranded RNAs, inhibits protein translation, and induces cell apoptosis. In a previous study, we found that PC1 reduces apoptosis through suppressing the PKR/eIF2α signaling. Whether and how PKR is involved in PC1-inhibited proliferation and protein synthesis remains unknown. Here we found that knockdown of PKR abolishes PC1-inhibited proliferation and translation. Because suppressed PKR-eIF2α signaling/activity by PC1 would stimulate, rather than inhibit, the proliferation and translation, we examined the effect of dominant negative PKR mutant K296R that has no kinase activity and found that it enhances the inhibition of proliferation and translation by PC1. Thus, our study showed that inhibition of cell proliferation and protein synthesis by PC1 is mediated by the total expression but not the kinase activity of PKR, possibly through physical association. [ABSTRACT FROM AUTHOR]

Pancreatic cancer belongs to lethal cancer with limited efficient treatment currently, and its main cause of death is rapid tumor growth and early metastasis. N6-methyladenosine (m6A) modification is a new method of epigenetic gene regulation involved in tumor progression, in which methyltransferase-like 3(METTL3) is the sole catalytic subunit. However, the role of METTL3 in pancreatic cancer remains to be explored. m6A level was measured using MeRIP assay, and RT-qPCR and western blot were applied to determine mRNA and protein expression, respectively. Cellular behaviors were detected using CCK-8, EdU, wound healing and transwell assays. Xenograft assays were conducted to further verify the roles of METTL3 in pancreatic cancer. METTL3 was highly expressed in pancreatic cancer. However, downregulation of METTL3 restrained the viability, migration and invasion of pancreatic cancer cells. Moreover, E2F5 was found to be positively regulated by METTL3. Intriguingly, the anti-tumor functions of METTL3 knockdown in the phenotype of pancreatic cancer cells were overturned by overexpression of E2F5. Silencing METTL3 resulted in the decreased stability of E2F5 by methylating E2F5. In conclusion, METTL3 can promote the malignant progression of pancreatic cancer by modifying E2F5 through m6A methylation to promote its stability. • METTL3 and E2F5 are elevated in pancreatic cancer. • E2F5 is positively related with METTL3 in pancreatic cancer. • Overexpression of E2F5 mitigated the potency of METTL3 knockdown on aggressiveness of pancreatic cancer cells. • METTL3 played an oncogenic role in the development of pancreatic cancer via promoting m6A-mediated E2F5 stability. [ABSTRACT FROM AUTHOR]

ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE−/−) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter. [ABSTRACT FROM AUTHOR]

The purpose of this study is to determine whether IL-27 regulates macrophage ABCA1 expression, foam cell formation, and also explore the underlying mechanisms. Here, we revealed that IL-27 decreased lipid accumulation in THP-1 derived macrophages through markedly enhancing cholesterol efflux and increasing ABCA1 expression at both protein and mRNA levels. Our study further demonstrated that IL-27 increased ABCA1 level via activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of Janus kinase 2, (JAK2)/STAT3 suppressed the stimulatory effects of IL-27 on ABCA1 expression. The present study concluded that IL-27 reduces lipid accumulation of foam cell by upregulating ABCA1 expression via JAK2/STAT3. Therefore, targeting IL-27 may offer a promising strategy to treat atherosclerotic vascular disease. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do assisted reproduction techniques (ARTs) affect DNA methylation of imprinted genes and does aberrant methylation of imprinted genes account for the incidence of human spontaneous abortion (SA)? SUMMARY ANSWER Our results show that imprinting errors of imprinted genes may contribute to human SA, and the occurrence of aberrant methylation of imprinted genes in ART pregnancies was comparable with that in natural pregnancies. WHAT IS KNOWN ALREADY Animal data and human studies demonstrated that in vitro culture of embryos can cause methylation defects in individual genes, which might affect subsequent embryonic development and contribute to SA. However, our previous studies showed an abnormal methylation pattern of PEG1 in human aborted chrionic villus samples (CVS) but an increased occurrence of aberrant methylation in CVS from ART-derived pregnancies was not observed. STUDY DESIGN, SIZE AND DURATION CVS were collected from women who underwent abortion procedures in the Department of Gynecology and Obstetrics in Nanfang Hospital from May 2008 to July 2011. Muscle samples (MS) were obtained from aborted fetuses and stillbirths. The samples were divided into four experimental groups: (A) SA/stillbirth after ART (n= 75), (B) multi-fetal reduction after ART (n=73), (C) SA/stillbirth of natural pregnancies (n=90) and (D) induced abortion (IA) of natural pregnancies (n=82). PARTICIPANTS/MATERIALS, SETTING AND METHODS The mean±SD age of patients was 31.0±4.1 (range: 18–45 years). The DNA methylation patterns of one paternally methylated (H19) and two maternally methylated (LIT1 and SNRPN) genes were analyzed in CVS and MS using pyrosequencing and bisulfite sequencing PCR. MAIN RESULTS AND THE ROLE OF CHANCE Clear hypo-methylation (<10%) or hyper-methylation (>90%) were not detected in LIT1 and SNRPN but two regions of hyper-methylation (91.7 and 91.4%) were observed in H19. The mean percentage of methylation in the SA samples (groups A and C) was higher than that in the IA samples (groups B and D; P<0.05). Box plot analyses showed that in the 165 SA samples, methylation values for 40/495 (8.1%) differentially methylated regions of the three genes represented outliers. The incidence of outlier was highest for LIT1 (13.3%, 22/165). In contrast, no outliers were found in the 155 IA samples. The receiver operating characteristic curve analyses showed a positive correlation between percentage methylation of all three genes and incidence of SA (P<0.05). In addition, the conception modes (natural versus ART) and the fertilization methods used in ART (IVF and ICSI) did not affect the methylation patterns of the imprinted genes. No increase in the rate of abnormal methylation was found in the ART samples. LIMITATIONS AND REASONS FOR CAUTION The studied loci represent only a small fraction of developmentally important genes. Further studies are needed to evaluate changes in the expression and the methylation status of other genes that may lead to SA. WIDER IMPLICATIONS OF THE FINDINGS The findings provide new insights into the etiology of human SA. The possibility that the abnormal methylation seen is a consequence of the defect that led to the SA cannot be excluded. STUDY FUNDING/COMPETING INTEREST(S) None of the authors has any competing interest. This study was supported by National Natural Science Foundation of China (81170574), The National Key Basic Research Development Plan of China (973 Program) (2007CB948104), Comprehensive strategic sciences cooperation projects of Guangdong Province and Chinese Academy (04020416) and Guangzhou Science and Technology Program key projects (11C22120737). [ABSTRACT FROM PUBLISHER]

Phosphodiesterase (PDE) 3B, a major isoform of PDE in adipocytes, mediates the antilipolytic action of insulin. PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. An increased fat cell size, a common feature of obesity, could account for this reduction. Insulin receptor substrate-1 (IRS-1) (−/−) mice are lean with a reduced fat cell size and have insulin resistance due to a primary defect of insulin signaling. To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (−/−) mice. In IRS-1 (−/−) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (−/−) mice. Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. [Copyright &y& Elsevier]

Xyloglucan endotransglycosylase/hydrolase (XTH) genes play an important role in plant resistance to abiotic stress. However, systematic studies of the response of Boehmeria nivea (ramie) XTH genes (BnXTHs) to cadmium (Cd) stress are lacking. We sought to identify the BnXTH-family genes in ramie through bioinformatics analyses and to investigate their responses to Cd stress. We identified 19 members of the BnXTH gene family from the ramie genome, referred to as BnXTH1-19, among which BnXTH18 and BnXTH19 were located on no chromosomes and the remaining genes were unevenly distributed across 11 chromosomes. The 19 members were divided into four groups, Groups I/II/IIIA/IIIB, according to their phylogenetic relationships, and these groups were supported by analyses of intron–exon structure and conserved motif composition. A highly conserved catalytic site (HDEIDFEFLG) was observed in all BnXTH proteins. Additionally, three gene pairs (BnXTH6–BnXTH16, BnXTH8–BnXTH9, and BnXTH17–BnXTH18) were obtained with a fragment and tandem-repeat event analysis of the ramie genome. An analysis of cisregulatory elements revealed that BnXTH expression might be regulated by multiple hormones and abiotic and biotic stress responses. In particular, 17 cisregulatory elements related to abiotic and biotic stress responses and 11 cisregulatory elements related to hormone responses were identified. We also found that most BnXTH genes responded to Cd stress, and BnXTH1, BnXTH3, BnXTH6, and BnXTH15 were most likely to contribute to the Cd tolerance of ramie, as evidenced by the substantial increases in expression under Cd treatment. Heterologous expression of BnXTH1, BnXTH6, and BnXTH15 significantly enhanced the Cd tolerance of transgenic yeast cells. These results suggest that the BnXTH gene family is involved in Cd stress responses, laying a theoretical foundation for functional studies of BnXTH genes and the innovative breeding of Cd-tolerant ramie. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 3B (PDE3B) gene expression is generally reduced in large adipocytes of obese, insulin-resistant mice. This reduced gene expression is restored by peroxisome proliferator-activated receptor (PPAR) γ ligands accompanied by a reduced fat cell size. To determine whether PDE3B gene expression is regulated by PPARγ itself, we analyzed lean PPARγ (+/−) mice with adipocyte size comparable to control PPARγ (+/+) mice. In adipocytes of PPARγ (+/−) mice, PDE3B mRNA and protein were both reduced to 63% of wild-type levels. Basal PDE activity tended to be decreased to 70% of wild-type levels, and, similarly, insulin-induced PDE activity was significantly decreased to 70%. Thus, PPARγ is required for PDE3B gene expression independent of adipocyte size. [Copyright &y& Elsevier]

Background: Flammulina filiformis (previously known as Asian F. velutipes) is a popular commercial edible mushroom. Many bioactive compounds with medicinal effects, such as polysaccharides and sesquiterpenoids, have been isolated and identified from F. filiformis, but their biosynthesis and regulation at the molecular level remains unclear. In this study, we sequenced the genome of the wild strain F. filiformis Liu355, predicted its biosynthetic gene clusters (BGCs) and profiled the expression of these genes in wild and cultivar strains and in different developmental stages of the wild F. filiformis strain by a comparative transcriptomic analysis. Results: We found that the genome of the F. filiformis was 35.01 Mb in length and harbored 10,396 gene models. Thirteen putative terpenoid gene clusters were predicted and 12 sesquiterpene synthase genes belonging to four different groups and two type I polyketide synthase gene clusters were identified in the F. filiformis genome. The number of genes related to terpenoid biosynthesis was higher in the wild strain (119 genes) than in the cultivar strain (81 genes). Most terpenoid biosynthesis genes were upregulated in the primordium and fruiting body of the wild strain, while the polyketide synthase genes were generally upregulated in the mycelium of the wild strain. Moreover, genes encoding UDP-glucose pyrophosphorylase and UDP-glucose dehydrogenase, which are involved in polysaccharide biosynthesis, had relatively high transcript levels both in the mycelium and fruiting body of the wild F. filiformis strain. Conclusions: F. filiformis is enriched in a number of gene clusters involved in the biosynthesis of polysaccharides and terpenoid bioactive compounds and these genes usually display differential expression between wild and cultivar strains, even in different developmental stages. This study expands our knowledge of the biology of F. filiformis and provides valuable data for elucidating the regulation of secondary metabolites in this unique F. filiformis strain. [ABSTRACT FROM AUTHOR]

HDGFRP2 (HRP-2) belongs to the Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) family, which are characterized by a conserved HATH/PWWP domain at a well-conserved region of the N-terminus. However, the cellular function of HRP-2 remains unknown. In this study, we showed for the first time that HRP-2 is frequently overexpressed in human HCC tissues at mRNA and protein levels. We further showed that HRP-2 can promote HCC cells growth in vitro and xenograft tumors in vivo. Using protein affinity purification methods, we searched for functional partners of HRP-2, and found that HRP-2 interacts with various proteins known to be involved in transcription elongation and processing. Furthermore, we demonstrate HRP-2 interacts and co-localizes with RNA processing regulator IWS1, and positively regulated the mRNA level of Cyclin D1. Together, our study suggests HRP-2 may act as an mRNA processing co-factor to promote cells growth by regulating the mRNA of key oncogenes, which can be explored further for cancer treatment. [ABSTRACT FROM AUTHOR]

Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial effects on cardiac function and ventricular remodeling. The present study aimed to investigate the expression of ghrelin and the growth hormone (GH) secretagogue receptor 1a (GHSR-1a), and the association with cardiac remodeling in rats with myocardial infarction (MI). Twenty-four hours after ligation of the anterior descending artery (LAD), adult male Sprague–Dawley rats were randomized to 3 d, 7 d and 28 d group. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. Expression of both ghrelin and GHSR-1a was assessed by means of immunohistochemistry and real-time PCR. Plasma ghrelin levels were measured by ELISA kit. In addition, cardiac remodeling was assessed by echocardiographic and hemodynamic measurements. Plasma and cardiac expression of ghrelin decreased on days 3, 7 and 28 compared with the sham group (P < 0.05). In contrast the GHSR-1a mRNA levels increased during the same days (P < 0.05). Decreased positive immunoreaction for ghrelin and increased positive GHSR-1a were also observed in the infarcted heart. Interestingly, plasma ghrelin correlated negatively with left ventricular end-diastolic pressure (r = − 0.59, P = 0.002) and left ventricular end-diastolic dimension (r = − 0.73, P < 0.01). The ghrelin system may play an important role regulating cardiac remodeling after MI and present as a potential significant target for pharmacological modulation and treating cardiac remodeling. [ABSTRACT FROM AUTHOR]

Highlights: [•] We observed that GDF-15 promotes cholesterol efflux in THP-1 macrophages. [•] GDF-15 induces ABCA1 expression via PI3K/PKCζ/SP1 signaling pathway. [•] The paper first time explains the regulation mechanism of GDF-15-induced ABCA1 expression. [ABSTRACT FROM AUTHOR]

Periodontitis is an inflammatory disease leading to the destruction of periodontal tissue. Vitamin D3 is an important hormone involved in the preservation of serum calcium and phosphate levels, regulation of bone metabolism and inflammatory response. Recent studies suggest that vitamin D3 metabolism might play a role in the progression of periodontitis. The aim of the present study was to examine the effects of 25(OH)D3, which is stable form of vitamin D3 in blood, and biologically active form 1,25(OH)2D3 on the production of interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) by cells of periodontal ligament. Commercially available human periodontal ligament fibroblasts (hPdLF) and primary human periodontal ligament cells (hPdLC) were used. Cells were stimulated with either Porphyromonas gingivalis lipopolysaccharide (LPS) or heat-killed P. ginigvalis in the presence or in the absence of 25(OH)D3 or 1,25(OH)2D3 at concentrations of 10–100 nM. Stimulation of cells with either P. gingivalis LPS or heat-killed P. gingivalis resulted in a significant increase of the expression levels of IL-6, IL-8, and MCP-1 in gene as well as in protein levels, measured by qPCR and ELISA, respectively. The production of these pro-inflammatory mediators in hPdLF was significantly inhibited by both 25(OH)D3 and 1,25(OH)2D3 in a dose-dependent manner. In primary hPdLCs, both 25(OH)D3 and 1,25(OH)2D3 inhibited the production of IL-8 and MCP-1 but have no significant effect on the IL-6 production. The effect of both 25(OH)D3 and 1,25(OH)2D3 was abolished by specific knockdown of vitamin D3 receptor by siRNA. Our data suggest that vitamin D3 might play an important role in the modulation of periodontal inflammation via regulation of cytokine production by cells of periodontal ligament. Further studies are required for better understanding of the extents of this anti-inflammatory effect and its involvement in the progression of periodontal disease. [ABSTRACT FROM AUTHOR]

ATP-binding cassette transporter A1 (ABCA1) is critical in exporting cholesterol from macrophages and plays a protective role in the development of atherosclerosis. The purpose of this study was to investigate the effects of betulinic acid (BA), a pentacyclic triterpenoid, on ABCA1 expression and cholesterol efflux, and to further determine the underlying mechanism. BA promoted ABCA1 expression and cholesterol efflux, decreased cellular cholesterol and cholesterol ester content in LPS-treated macrophages. Furthermore, we found that BA promoted ABCA1 expression via down-regulation of miR-33s. The inhibition of LPS-induced NF-κB activation further decreased miR-33s expression and enhanced ABCA1 expression and cholesterol efflux when compared with BA only treatment. In addition, BA suppressed IκB phosphorylation, p65 phosphorylation and nuclear translocation, and the transcription of NF-κB-dependent related gene. Moreover, BA reduced atherosclerotic lesion size, miR-33s levels and NF-κB activation, and promoted ABCA1 expression in apoE−/− mice. Taken together, these results reveal a novel mechanism for the BA-mediated ABCA1 expression, which may provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis. [ABSTRACT FROM AUTHOR]

Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(−), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether lipoxin A4 (LXA4) increases expression of heme oxygenase-1(HO-1) in cardiomyocytes, whether LXA4-induced HO-1 protects cardiomyocytes against hypoxia/reoxygenation (H/R) injury, and what are the mechanisms involved in the LXA4-induced HO-1 induction. Methods: Rat cardiomyocytes were exposed to H/R injury with or without preincubation with LXA4 or HO-1 inhibitor ZnPP-IX or various signal molecule inhibitors. Expressions of HO-1 protein and mRNA were analyzed by using Western blot and RT-PCR respectively. Activity of nuclear factor E2-related factor 2 (Nrf2) binding to the HO-1 E1 enhancer was assessed by chromatin immunoprecipitation. Nrf2 binding to the HO-1 antioxidant responsive element (ARE) were measured by using electrophoretic mobility shift assay. Results: Pretreatment of the cells undergoing H/R lesion with LXA4 significantly reduced the lactate dehydrogenase and creatine kinase productions, increased the cell viability, and increased the expressions of HO-1 protein and mRNA and HO-1 promoter activity. HO-1 inhibition abolished the protective role of LXA4 on the cells undergoing H/R lesion. LXA4 increased p38 mitogen-activated protein kinase (p38 MAPK) activation, nuclear translocation of Nrf2, Nrf2 binding to the HO-1 ARE and E1 enhancer in cardiomyocytes with or without H/R exposure. Conclusion: The protection role of LXA4 against H/R injury of cardiomyocytes is related to upregulation of HO-1, via activation of p38 MAPK pathway and nuclear translocation of Nrf2 and Nrf2 binding to the HO-1 ARE and E1 enhancer, but not via activation of phosphatidyinositol-3-kinase or extracellular signal-regulated kinase pathway. [ABSTRACT FROM AUTHOR]

Abstract: Kindlin-2, as a focal adhesion protein, has been found to regulate tumor progression. However, the mechanism underlying Kindlin-2 regulation of tumor progression is largely unknown. Here, we report that Kindlin-2 regulates breast cancer cell proliferation, apoptosis and chromosomal abnormalities in both gain and loss of function assays. Functionally, overexpression of Kindlin-2 promotes tumor formation in implanted xenograft while knockdown of Kindlin-2 inhibits tumor growth in mice. Mechanistically, an array-based comparative genomic hybridization and karyotype analyses indicate that ectopic expression of Kindlin-2 leads to genome instability in breast cancer cells. Our data suggest a novel mechanism that Kindlin-2 regulates breast cancer progression by inducing genome instability. [Copyright &y& Elsevier]

Abstract: Previous studies have shown that sinomenine possesses potent immunoregulatory properties. However, little is known about its exact mechanisms of action. Increasing recognition of the importance of renal tubular epithelial cells (TECs) in renal diseases raises the question whether sinomenine can regulate TEC activity. In this study, cultured human TECs were exposed to proinflammatory factors interferon-γ (IFN-γ) and tumor necrotic factor-α (TNF-α) in presence or absence of sinomenine for 72 h, followed by analysis of surface expression of costimulatory molecules. Flow cytometric analysis revealed that various costimulatory molecules were expressed on TECs and that they were significantly up-regulated by the simulation of IFN-γ and TNF-α. However, sinomenine especially down-regulated B7-H1 and B7-DC expression on TECs at both mRNA and protein levels. Moreover, the significant damping effect of sinomenine on B7-H1 and B7-DC signals could promote IL-2 and IFN-γ production by co-cultured CD4+ T cell. Our results indicated that sinomenine could regulate TECs activity via B7-H1 and B7-DC, in addition to previously reported its effects on some pro-inflammatory factors production by macrophages and peripheral blood mononuclear cells. [Copyright &y& Elsevier]

Enterovirus A71 (EVA71) is a human enterovirus belonging to the Picornaviridae family and mostly causes hand-foot-and-mouth disease in infants. Viperin is an important interferon-stimulated gene with a broad antiviral activity against various viruses. However, the effect of viperin on human enteroviruses and the interaction mechanism between EVA71 and viperin remains elusive. Here, we confirmed the EVA71-induced expression of viperin in a mouse model and cell lines and showed that viperin upregulation by EVA71 infection occurred on both the mRNA and protein level. Viperin knockdown and overexpression in EVA71-infected cells indicated that this protein can markedly inhibit EVA71 infection. Interestingly, immunofluorescent confocal microscopy and co-immunoprecipitation assays indicated that viperin interacts and colocalizes with the EVA71 protein 2C in the endoplasmic reticulum. Furthermore, amino acids 50–60 in the N-terminal domain of viperin were the key residues responsible for viperin interaction with 2C. More importantly, the N-terminal domain of viperin was found responsible for inhibiting EVA71 replication. Our findings can potentially aid future research on the prevention and treatment of nervous system damage caused by EVA71 and may provide a potential target for antiviral therapy. [ABSTRACT FROM AUTHOR]