Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways

Lai, Jenn‐Haung; Wu, De Wei; Wu, Chien‐Hsiang; Hung, Li-Wen; Huang, Chuan‐Yueh; Ka, Shuk‐Man; Chen, Ann; Chang, Zee-Fen; Ho, Ling‐Jun

doi:10.1016/j.isci.2021.102498

Cited by 36 publications

(44 citation statements)

References 30 publications

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“…In the current report, we first demonstrated that chCMPK2 inhibited the propagation of AIV H9N2 in a dose-dependent way, and chCMPK2 may also be an antiviral molecule against NDV. CMPK2 has been reported to be able to inhibit viral and bacterial infection, including SVCV, Dengue virus (DENV), Duck Tembusu virus (DTMUV), HIV-1 and Aeromonas hydrophila CCL1 ( El-Diwany et al, 2018 ; Liu et al, 2019 ; Xiang et al, 2020 ; Feng et al, 2021 ; Lai et al, 2021 ). Our analysis indicated that overexpression of chCMPK2 in DF-1 cells significantly inhibited H9N2 NP expression at the mRNA and protein levels, and knockdown of chCMPK2 had the opposite effects, which suggested that chCMPK2 was an important antiviral factor against AIV.…”

Section: Discussionmentioning

confidence: 99%

A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

Feng

Liu

et al. 2022

Front. Microbiol.

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Virus infection can lead to the production of interferon, which activates the JAK/STAT pathway and induces the expression of multiple downstream interferon-stimulated genes (ISGs) to achieve their antiviral function. Cytidine/uridine monophosphate kinase 2 (CMPK2) gene has been identified as an ISG in human and fish, and is also known as a rate-limiting enzyme in mitochondria to maintain intracellular UTP/CTP levels, which is necessary for de novo mitochondrial DNA synthesis. By mining previous microarray data, it was found that both Avian Influenza Virus (AIV) and Newcastle Disease Virus (NDV) infection can lead to the significant upregulation of chicken CMPK2 gene. However, little is known about the function of CMPK2 gene in chickens. In the present study, the open reading frame (ORF) of chicken CMPK2 (chCMPK2) was cloned from DF-1, a chicken embryo fibroblasts cell line, and subjected to further analysis. Sequence analysis showed that chCMPK2 shared high similarity in amino acid with CMPK2 sequences from all the other species, especially reptiles. A thymidylate kinase (TMK) domain was identified in the C-terminus of chCMPK2, which is highly conserved among all species. In vitro, AIV infection induced significant increases in chCMPK2 expression in DF-1, HD11, and the chicken embryonic fibroblasts (CEF), while obvious increase only detected in DF-1 cells and CEF cells after NDV infection. In vivo, the expression levels of chCMPK2 were up-regulated in several tissues from AIV infected chickens, especially the brain, spleen, bursa, kidney, intestine, heart and thymus, and notable increase of chCMPK2 was detected in the bursa, kidney, duodenum, lung, heart, and thymus during NDV infection. Here, using MDA5 and IFN-β knockdown cells, we demonstrated that as a novel ISG, chCMPK2 could be regulated by the MDA5/IFN-β pathway. The high expression level of exogenous chCMPK2 displayed inhibitory effects on AIV and NDV as well as reduced viral RNA in infected cells. We further demonstrated that Asp135, a key site on the TMK catalytic domain, was identified as critical for the antiviral activities of chCMPK2. Taken together, these data demonstrated that chCMPK2 is involved in the chicken immune system and may play important roles in host anti-viral responses.

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Section: Discussionmentioning

confidence: 99%

A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

Feng

Liu

et al. 2022

Front. Microbiol.

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“…CMPK2 played a critical role in dengue virus (DENV)-induced mitochondrial oxidative stress, cytokine release, and mitochondrial DNA (mtDNA) release to the cytosol. CMPK2 depletion could suppress the DENV-induced cell migration, TLR9 activation, and inflammasome pathway, and the increasing viral production ( 19 ). CMPK2 mediated the antiviral activity ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…CMPK2 depletion could suppress the DENV-induced cell migration, TLR9 activation, and inflammasome pathway, and the increasing viral production ( 19 ). CMPK2 mediated the antiviral activity ( 19 ). In the present study, CMPK2 was obviously up-regulated in chicken jejuna from LPC-treated groups which agree with the report that CMPK2 was involved in mtDNA synthesis and antiviral immunity in animals ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Lysophosphatidylcholine on Jejuna Morphology and Its Potential Mechanism

Abdel-Moneim

Mesalam

et al. 2022

Front. Vet. Sci.

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Lysophosphatidylcholine (LPC) plays a vital role in promoting jejuna morphology in broilers. However, the potential mechanism behind LPC improving the chicken jejuna morphology is unclear. Therefore, the present study was designed to reveal the important genes associated with LPC regulation in birds' jejuna. Thus, GSE94622, the gene expression microarray, was obtained from Gene Expression Omnibus (GEO). GSE94622 consists of 15 broiler jejuna samples from two LPC-treated (LPC500 and LPC1000) and the control groups. Totally 98 to 217 DEGs were identified by comparing LPC500 vs. control, LPC1000 vs. control, and LPC1000 vs. LPC500. Gene ontology (GO) analysis suggested that those DEGs were mainly involved in the one-carbon metabolic process, carbon dioxide transport, endodermal cell differentiation, the positive regulation of dipeptide transmembrane transport, cellular pH reduction, and synaptic transmission. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated the DEGs were enriched in NOD-like receptor (NLR), RIG-I-like receptor (RILR), Toll-like receptor (TLR), and necroptosis signaling pathway. Moreover, many genes, such as RSAD2, OASL, EPSTI1, CMPK2, IFIH1, IFIT5, USP18, MX1, and STAT1 might be involved in promoting the jejuna morphology of broilers. In conclusion, this study enhances our understanding of LPC regulation in jejuna morphology.

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“…Regarding CMPK2, studies using murine genital tract epithelial cells have also shown an upregulation of CMPK2 mRNA upon C. muridarum infection [60]. The enzyme CMPK2 not only supplies deoxyribonucleotides for the synthesis of mitochondrial DNA (mtDNA) [61] but it also possesses immunomodulatory and antiviral activities: CMPK2 was shown to limit dengue virus infection of murine and human cells in an IFN-dependent and IFN-independent manner [62]. Taken together, the Ct-induced upregulation of interferon regulated genes in pOECs potentially not only limits Ct propagation within the infected cell, but it could also promote immunomodulation in the genital tract.…”

Section: Innate Immune Response Of Porcine Oviduct Epithelial Cells To Chlamydia Trachomatis Infectionmentioning

confidence: 99%

Host–Pathogen Interactions of Chlamydia trachomatis in Porcine Oviduct Epithelial Cells

et al. 2021

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Chlamydia trachomatis (Ct) causes the most prevalent bacterial sexually transmitted disease leading to ectopic pregnancy and infertility. Swine not only have many similarities to humans, but they are also susceptible to Ct. Despite these benefits and the ease of access to primary tissue from this food animal, in vitro research in swine has been underutilized. This study will provide basic understanding of the Ct host–pathogen interactions in porcine oviduct epithelial cells (pOECs)—the counterparts of human Fallopian tube epithelial cells. Using NanoString technology, flow cytometry, and confocal and transmission-electron microscopy, we studied the Ct developmental cycle in pOECs, the cellular immune response, and the expression and location of the tight junction protein claudin-4. We show that Ct productively completes its developmental cycle in pOECs and induces an immune response to Ct similar to human cells: Ct mainly induced the upregulation of interferon regulated genes and T-cell attracting chemokines. Furthermore, Ct infection induced an accumulation of claudin-4 in the Ct inclusion with a coinciding reduction of membrane-bound claudin-4. Downstream effects of the reduced membrane-bound claudin-4 expression could potentially include a reduction in tight-junction expression, impaired epithelial barrier function as well as increased susceptibility to co-infections. Thereby, this study justifies the investigation of the effect of Ct on tight junctions and the mucosal epithelial barrier function. Taken together, this study demonstrates that primary pOECs represent an excellent in vitro model for research into Ct pathogenesis, cell biology and immunity.

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Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways

Cited by 36 publications

References 30 publications

A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

A Role for the Chicken Interferon-Stimulated Gene CMPK2 in the Host Response Against Virus Infection

Effects of Lysophosphatidylcholine on Jejuna Morphology and Its Potential Mechanism

Host–Pathogen Interactions of Chlamydia trachomatis in Porcine Oviduct Epithelial Cells

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