RNA granules are cytoplasmic, microscopically visible, non-membrane ribo-nucleoprotein structures and are important posttranscriptional regulators in gene expression by controlling RNA translation and stability. TIA/G...RNA granules are cytoplasmic, microscopically visible, non-membrane ribo-nucleoprotein structures and are important posttranscriptional regulators in gene expression by controlling RNA translation and stability. TIA/G3BP/PABP-specific stress granules(SG) and GW182/DCP-specific RNA processing bodies(PB) are two major distinguishable RNA granules in somatic cells and contain various ribosomal subunits, translation factors, scaffold proteins, RNA-binding proteins, RNA decay enzymes and helicases to exclude m RNAs from the cellular active translational pool. Although SG formation is inducible due to cellular stress, PB exist physiologically in every cell. Both RNA granules are important components of the host antiviral defense. Virus infection imposes stress on host cells and thus induces SG formation. However, both RNA and DNA viruses must confront the hostile environment of host innate immunity and apply various strategies to block the formation of SG and PB for their effective infection and multiplication. This review summarizes the current research development in the field and the mechanisms of how individual viruses suppress the formation of host SG and PB for virus production.展开更多
Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E...Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E6 ORF integrity and produces a spliced E6*I RNA for efficient E7 translation. Here we report that the E6 intron has two overlapped branch point sequences(BPS) upstream of its 30 splice site, with an identical heptamer AACUAAC, for E6*I splicing. One heptamer has a branch site adenosine(underlined) at nt 384 and the other at nt 388. E6*I splicing efficiency correlates to the expression level of E6 and E7 proteins and depends on the selection of which branch site. In general, E6*I splicing prefers the 30 ss-proximal branch site at nt 388 over the distal branch site at nt 384. Inactivation of the nt 388 branch site was found to activate a cryptic acceptor site at nt 636 for aberrant RNA splicing. Together, these data suggest that HPV18 modulates its production ratio of E6 and E7 proteins by alternative selection of the two mapped branch sites for the E6*I splicing, which could be beneficial in its productive or oncogenic infection according to the host cell environment.展开更多
Human papillomavirus(HPV)infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers.Up to 38%–80%of head and neck squamous cell carcinoma(HN...Human papillomavirus(HPV)infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers.Up to 38%–80%of head and neck squamous cell carcinoma(HNSCC)in oropharyngeal location(OPSCC)and nearly all cervical cancers contain the HPV genome which is implicated in causing cancer through its oncoproteins E6 and E7.Given by the biologically distinct HPV-related OPSCC and a more favorable prognosis compared to HPV-negative tumors,clinical trials on de-escalation treatment strategies for these patients have been studied.It is therefore raised the questions for the patient stratification if treatment de-escalation is feasible.Moreover,understanding the crosstalk of HPV-mediated malignancy and immunity with clinical insights from the proportional response rate to immune checkpoint blockade treatments in patients with HNSCC is of importance to substantially improve the treatment efficacy.This review discusses the biology of HPV-related HNSCC as well as successful clinically findings with promising candidates in the pipeline for future directions.With the advent of various sequencing technologies,further biomolecules associated with HPV-related HNSCC progression are currently being identified to be used as potential biomarkers or targets for clinical decisions throughout the continuum of cancer care.展开更多
Dear Editor,Human papillomaviruses(HPV)are a large group(>200genotypes)of small double-stranded DNA viruses(https://pave.niaid.nih.gov/).Although infections by most HPV types are asymptomatic,persistent infections ...Dear Editor,Human papillomaviruses(HPV)are a large group(>200genotypes)of small double-stranded DNA viruses(https://pave.niaid.nih.gov/).Although infections by most HPV types are asymptomatic,persistent infections in cervical and ano-genital epithelia by high-risk展开更多
Viral infections remain a global threat to world health in the twenty-first century. They are caused by both DNA and RNA viruses and can manifest as acute or chronic infections, in some cases causing epidemics or even...Viral infections remain a global threat to world health in the twenty-first century. They are caused by both DNA and RNA viruses and can manifest as acute or chronic infections, in some cases causing epidemics or even global pandemics.Persistent viral infections lead to host immunodeficiency and the development of ~12% of human cancers worldwide.展开更多
Plasmid DNA transfection is one of the fundamental tools of biomedical research.Here,we found that plasmid DNA transfection mediated by liposomes activates multiple innate immune responses in several widely used cell ...Plasmid DNA transfection is one of the fundamental tools of biomedical research.Here,we found that plasmid DNA transfection mediated by liposomes activates multiple innate immune responses in several widely used cell lines.Their activations were visible by the detection of stress granules(SG)and cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-DNA condensates(cGC)in the transfected cells in a plasmid DNA dose-dependent manner.The elevated levels of phosphorylated eukaryotic translation initiation factor 2 subunit alpha(eIF2a),interferon regulatory factor 3(IRF3),and signal transducer and activator of transcription 1(STAT1)were induced in plasmid DNAtransfected cells.The formation of SG but not cGC required active transcription and the formation of double-stranded RNA in transfected cells.Plasmid DNA-induced SG or cGC were mutually exclusive because they triggered two distinct pathways.Knockdown(KD)of protein kinase R(PKR)before plasmid DNA transfection led to abolishing SG without affecting cGC formation.Conversely,cGAS KD could prevent cGC without affecting SG formation.In addition,plasmid DNA-induced SG and cGC formation could be prevented,respectively,by co-expression of Kaposi’s sarcoma-associated herpesvirus proteins ORF57(PKR inhibitor)and ORF52(cGAS inhibitor).Inhibition of SG formation mediated by PKR KD,but not cGC KD,also led to increased expression of transgenes,indicating that PKR activation represents a major roadblock to gene expression.Together,these data indicate that plasmid DNA triggers innate immune responses in the transfected cells and causes a significant cellular perturbation that should be considered during experiment design and data interpretation.展开更多
基金supported by grants from the China Natural Science Foundation (81825015 and 31630086)the Natural Science Foundation of Hubei Province Innovation Group (2017CFA022)Intramural Research Program of NCI/NIH (1ZIASC010357 to ZMZ)
文摘RNA granules are cytoplasmic, microscopically visible, non-membrane ribo-nucleoprotein structures and are important posttranscriptional regulators in gene expression by controlling RNA translation and stability. TIA/G3BP/PABP-specific stress granules(SG) and GW182/DCP-specific RNA processing bodies(PB) are two major distinguishable RNA granules in somatic cells and contain various ribosomal subunits, translation factors, scaffold proteins, RNA-binding proteins, RNA decay enzymes and helicases to exclude m RNAs from the cellular active translational pool. Although SG formation is inducible due to cellular stress, PB exist physiologically in every cell. Both RNA granules are important components of the host antiviral defense. Virus infection imposes stress on host cells and thus induces SG formation. However, both RNA and DNA viruses must confront the hostile environment of host innate immunity and apply various strategies to block the formation of SG and PB for their effective infection and multiplication. This review summarizes the current research development in the field and the mechanisms of how individual viruses suppress the formation of host SG and PB for virus production.
基金fully supported by Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (1ZIASC010357 to ZMZ)a part of Brant AC Ph.D thesis being developed at the Post-graduate program in Genetics (PGGEN) of Rio de Janeiro Federal University (UFRJ), Rio de Janeiro, Brazil+2 种基金the National Cancer Institute of USAsupported by the PDSE program of Coordenacao de Aperfeicoamento de Pessoal de Nível Superior (Capes, Brazil)the National Cancer Institute of USA
文摘Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E6 ORF integrity and produces a spliced E6*I RNA for efficient E7 translation. Here we report that the E6 intron has two overlapped branch point sequences(BPS) upstream of its 30 splice site, with an identical heptamer AACUAAC, for E6*I splicing. One heptamer has a branch site adenosine(underlined) at nt 384 and the other at nt 388. E6*I splicing efficiency correlates to the expression level of E6 and E7 proteins and depends on the selection of which branch site. In general, E6*I splicing prefers the 30 ss-proximal branch site at nt 388 over the distal branch site at nt 384. Inactivation of the nt 388 branch site was found to activate a cryptic acceptor site at nt 636 for aberrant RNA splicing. Together, these data suggest that HPV18 modulates its production ratio of E6 and E7 proteins by alternative selection of the two mapped branch sites for the E6*I splicing, which could be beneficial in its productive or oncogenic infection according to the host cell environment.
基金This work was supported by grants from the Medical and the Health Science Project of Zhejiang Province(2019KY327)Guangji Talents Foundation Award(E)of Zhejiang Cancer Hospital。
文摘Human papillomavirus(HPV)infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers.Up to 38%–80%of head and neck squamous cell carcinoma(HNSCC)in oropharyngeal location(OPSCC)and nearly all cervical cancers contain the HPV genome which is implicated in causing cancer through its oncoproteins E6 and E7.Given by the biologically distinct HPV-related OPSCC and a more favorable prognosis compared to HPV-negative tumors,clinical trials on de-escalation treatment strategies for these patients have been studied.It is therefore raised the questions for the patient stratification if treatment de-escalation is feasible.Moreover,understanding the crosstalk of HPV-mediated malignancy and immunity with clinical insights from the proportional response rate to immune checkpoint blockade treatments in patients with HNSCC is of importance to substantially improve the treatment efficacy.This review discusses the biology of HPV-related HNSCC as well as successful clinically findings with promising candidates in the pipeline for future directions.With the advent of various sequencing technologies,further biomolecules associated with HPV-related HNSCC progression are currently being identified to be used as potential biomarkers or targets for clinical decisions throughout the continuum of cancer care.
基金supported by the Intramural Research Program of the National Institutes of HealthNational Cancer Institutethe Center for Cancer Research
文摘Dear Editor,Human papillomaviruses(HPV)are a large group(>200genotypes)of small double-stranded DNA viruses(https://pave.niaid.nih.gov/).Although infections by most HPV types are asymptomatic,persistent infections in cervical and ano-genital epithelia by high-risk
文摘Viral infections remain a global threat to world health in the twenty-first century. They are caused by both DNA and RNA viruses and can manifest as acute or chronic infections, in some cases causing epidemics or even global pandemics.Persistent viral infections lead to host immunodeficiency and the development of ~12% of human cancers worldwide.
基金supported by the Intramural Research Program of the National Institutes of Health,the National Cancer Institute,and the Center for Cancer Research(ZIASC010357 to Z.M.Z.).
文摘Plasmid DNA transfection is one of the fundamental tools of biomedical research.Here,we found that plasmid DNA transfection mediated by liposomes activates multiple innate immune responses in several widely used cell lines.Their activations were visible by the detection of stress granules(SG)and cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-DNA condensates(cGC)in the transfected cells in a plasmid DNA dose-dependent manner.The elevated levels of phosphorylated eukaryotic translation initiation factor 2 subunit alpha(eIF2a),interferon regulatory factor 3(IRF3),and signal transducer and activator of transcription 1(STAT1)were induced in plasmid DNAtransfected cells.The formation of SG but not cGC required active transcription and the formation of double-stranded RNA in transfected cells.Plasmid DNA-induced SG or cGC were mutually exclusive because they triggered two distinct pathways.Knockdown(KD)of protein kinase R(PKR)before plasmid DNA transfection led to abolishing SG without affecting cGC formation.Conversely,cGAS KD could prevent cGC without affecting SG formation.In addition,plasmid DNA-induced SG and cGC formation could be prevented,respectively,by co-expression of Kaposi’s sarcoma-associated herpesvirus proteins ORF57(PKR inhibitor)and ORF52(cGAS inhibitor).Inhibition of SG formation mediated by PKR KD,but not cGC KD,also led to increased expression of transgenes,indicating that PKR activation represents a major roadblock to gene expression.Together,these data indicate that plasmid DNA triggers innate immune responses in the transfected cells and causes a significant cellular perturbation that should be considered during experiment design and data interpretation.
