Guanylate-Binding Proteins 2 and 5 Exert Broad Antiviral Activity by Inhibiting Furin-Mediated Processing of Viral Envelope Proteins

Braun, Elisabeth; Hotter, Dominik; Koepke, Lennart; Zech, Fabian; Groß, Rüdiger; Sparrer, Konstantin M. J.; Müller, Janis A.; Pfaller, Christian K.; Heusinger, Elena; Wombacher, Rebecka; Sutter, Kathrin; Dittmer, Ulf; Winkler, Michael; Simmons, Graham; Jakobsen, Martin R.; Conzelmann, Karl‐Klaus; Pöhlmann, Stefan; Münch, Jan; Fackler, Oliver T.; Kirchhoff, Frank; Sauter, Daniel

doi:10.1016/j.celrep.2019.04.063

Cited by 135 publications

(176 citation statements)

References 81 publications

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“…Zhang et al 33 first found that GBP2 inhibits cell metastasis and mitochondrial fission in breast cancer cells not only in vitro but in vivo and another study found an interesting result that GBP2 related to a recently generally T cell signature, suggesting tumor infiltration with T cells in breast cancer 34 . Other study found GPB2/5 shown wide antiviral activity by suppressing the activation of the virus-dependency factor furin 35 . GBP2 was similarly relocalized in cells in which autophagy was impaired 36 .…”

Section: Discussionmentioning

confidence: 91%

Comprehensive Analysis of the Expression and Prognosis for GBPs in Head and neck squamous cell carcinoma

Cai

Zhong

2020

Sci Rep

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Guanylate binding proteins (GBPs) belongs to the interferons (ifns) induced guanylate-bindingprotein family (Guanosine triphosphatases, GTPases) consisting of seven homologous members, termed GBP1 to GBP7. We used multidimensional survey ways to explore GBPs expression, regulation, mutations, immune infiltration and functional networks in head and neck squamous cell carcinoma (HnScc) patient data based on various open databases. the study provides staggered evidence for the significance of GBPs in HnScc and its potential role as a novel biomarker. our results showed that over expressions of 7 GBPs members and multivariate analysis suggested that N-stage, high expressions of GBP1 and low expression of GBP6/7 were linked to shorter OS in HNSCC patients. In addition, B cells of immune infiltrates stimulant the prognosis and might have a medical prognostic significance linked to GBPs in HnScc. We assume that GBPs play a synergistic role in the viral related HnScc. our results show that data mining efficiently reveals information about GBPs expression in HnScc and more importance lays a foundation for further research on the role of GBPs in cancers.Head and Neck Squamous Cell Carcinoma (HNSCC) is a common head and neck malignancy that originates from lips, mouth, paranasal sinuses, oropharynx, larynx, nasopharynx, and other pharyngeal cancers 1 . As the sixth most common type of malignant tumors, with more than 655,000 new cases and 90,000 deaths every year 2 . Currently, smoking, drinking, and human papillomavirus (HPV) infection are considered risk factors for HNSCC occurrence and prognosis 3 . Unfortunately, the 5-year survival rate is still below 50% due to the usual lack of early symptoms when HNSCC is detected early, while the survival rate is reduced to 35% due to local recurrence and metastasis 4 .Once in advanced stages, treatment can notably effect organ function and harm the structures involved in speaking and swallowing, causing devastating results in patient's quality of life 5,6 . Studies reported that lots of HNSCC not only has experienced epithelial-to-mesenchymal transition (EMT) but also presents a mesenchymal-like (ML) phenotype and thus effect the drug resistance, tumor migration or tumor growth 7 . The incidence and development of HNSCC is a complex process involving multiple molecules. Guan et al. found long non-coding RNA H19 and its mature miR-675 were significantly high level in two HNSCC cell lines as well as a cohort of 65 primary tumor samples 8 . Wu et al. reported that SUZ12 protein was particularly overexpression in primary HNSCC samples and is up-regulated significantly associated with cervical node metastasis, overall survival and disease-free survival 9 . Reed et al. believed that inactivation of the p16 tumor suppressor gene is a common event in HNSCC 10 . In spite of advances in combine chemotherapy, radiation, and surgery during the past decades have fundamentally improved survival rate of the HNSCC patients, many patients increase secondary tumors, recurrences or metastasis after ...

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Section: Discussionmentioning

confidence: 91%

Comprehensive Analysis of the Expression and Prognosis for GBPs in Head and neck squamous cell carcinoma

Cai

Zhong

2020

Sci Rep

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“…Thus, HIV-1 might be particularly susceptible to further reductions in Env expression due to the degradation of single-spliced or unspliced HIV-1 RNAs. We have previously shown that increased Env expression due to vpu inactivation allows HIV-1 to partly evade restriction by GBP5, which impairs virion infectivity by interfering with furin-mediated Env processing (38)(39)(40). However, data obtained using a chimeric virus that differs only in the env coding region (Fig.…”

Section: Discussionmentioning

confidence: 98%

CpG Frequency in the 5′ Third of the env Gene Determines Sensitivity of Primary HIV-1 Strains to the Zinc-Finger Antiviral Protein

Kmieć

Nchioua

Sherrill-Mix

et al. 2020

mBio

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CpG dinucleotide suppression has been reported to allow HIV-1 to evade inhibition by the zinc-finger antiviral protein (ZAP). Here, we show that primate lentiviruses display marked differences in CpG frequencies across their genome, ranging from 0.44% in simian immunodeficiency virus SIVwrc from Western red colobus to 2.3% in SIVmon infecting mona monkeys. Moreover, functional analyses of a large panel of human and simian immunodeficiency viruses revealed that the magnitude of CpG suppression does not correlate with their susceptibility to ZAP. However, we found that the number of CpG dinucleotides within a region of ∼700 bases at the 5′ end of the env gene determines ZAP sensitivity of primary HIV-1 strains but not of HIV-2. Increased numbers of CpGs in this region were associated with reduced env mRNA expression and viral protein production. ZAP sensitivity profiles of chimeric simian-human immunodeficiency viruses (SHIVs) expressing different HIV-1 env genes were highly similar to those of the corresponding HIV-1 strains. The frequency of CpGs in the identified env region correlated with differences in clinical progression rates. Thus, the CpG frequency in a specific part of env, rather than the overall genomic CpG content, governs the susceptibility of HIV-1 to ZAP and might affect viral pathogenicity in vivo. IMPORTANCE Evasion of the zinc-finger antiviral protein (ZAP) may drive CpG dinucleotide suppression in HIV-1 and many other viral pathogens but the viral determinants of ZAP sensitivity are poorly defined. Here, we examined CpG suppression and ZAP sensitivity in a large number of primate lentiviruses and demonstrate that their genomic frequency of CpGs varies substantially and does not correlate with ZAP sensitivity. We further show that the number of CpG residues in a defined region at the 5′ end of the env gene together with structural features plays a key role in HIV-1 susceptibility to ZAP and correlates with differences in clinical progression rates in HIV-1-infected individuals. Our identification of a specific part of env as a major determinant of HIV-1 susceptibility to ZAP restriction provides a basis for future studies of the underlying inhibitory mechanisms and their potential relevance in the pathogenesis of AIDS.

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“…One hypothesis is that acquisition of a PCSK cleavage site would expand the number of cell types that can be directly infected by SARS-CoV-2. A recent report has started to address expression of FURIN in cells expressing SARS-CoV-2 host factors ACE2 or TMPRSS2 47 , and FURIN activity is inhibited by Guanylate-binding proteins (GBPs), a group of interferonstimulated genes, in order to restrict viral envelope processing 160 . However, the highly overlapping recognition sequence of PCSK family members (Extended Data Fig.…”

Section: Discussionmentioning

confidence: 99%

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Muus

Luecken

Eraslan

et al. 2020

Preprint

251

326

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The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2 + TMPRSS2 + cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.

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Guanylate-Binding Proteins 2 and 5 Exert Broad Antiviral Activity by Inhibiting Furin-Mediated Processing of Viral Envelope Proteins

Cited by 135 publications

References 81 publications

Comprehensive Analysis of the Expression and Prognosis for GBPs in Head and neck squamous cell carcinoma

Comprehensive Analysis of the Expression and Prognosis for GBPs in Head and neck squamous cell carcinoma

CpG Frequency in the 5′ Third of the env Gene Determines Sensitivity of Primary HIV-1 Strains to the Zinc-Finger Antiviral Protein

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

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