Biology subjects

Rehwinkel, J.

Publications and source records attributed to Rehwinkel, J..

At least 19 recordsLinked to original sources

bioRxiv2026

XRN1-dependent RNA homeostasis regulates hepatitis D virus

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis, yet the host mechanisms restricting HDV replication remain poorly understood. Although HDV infection activates the MDA5-LGP2 pathway and induces robust interferon (IFN) responses, these antiviral programs have limited impact on viral replication. Here we identify the 5-3 exoribonuclease XRN1 as a key regulator of HDV infection. Loss of XRN1 in hepatoma cells increased double-stranded RNA (dsRNA) levels and induced interferon-stimulated genes (ISGs), including MDA5 and MAVS, and limited HDV infection. XRN1 deficiency enhanced ADAR1-mediated RNA editing, revealing a dynamic interplay between endogenous dsRNA metabolism and antiviral sensing. Inhibition of type I IFN signaling restored MDA5 expression and rescued HDV replication in XRN1-deficient cells. To identify the downstream effectors responsible for this restriction, we combined transcriptomic profiling with functional siRNA screening and identified DUSP5 and SIRPA as previously unrecognized ISGs with anti-HDV activity. Together, our findings establish XRN1 as a gatekeeper of dsRNA homeostasis that controls HDV replication through innate immune activation and reveals host antiviral effectors that may provide therapeutic opportunities for chronic hepatitis D.

molecular biology↗

bioRxiv2026

TMEM33 deletion potentiates anti-tumor CD8+ T cell immunity

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8+ T cell responses. Constitutive Tmem33-/- mice exhibited delayed melanoma tumor growth and increased CD8+ T cell infiltration. Antigen-specific CD8+ compartments in tumors of Tmem33-/- mice showed TCF-1+PD-1+ progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8+ T cells ex vivo, (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of ex vivo-expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower TMEM33 expression in patient CD8+ T cells significantly correlated with improved survival and elevated TCF-7 (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8+ T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy. One sentence summaryTMEM33 intrinsically limits progenitor exhausted CD8+ T cells, scales anti-tumor responses and predicts melanoma patient survival.

immunology↗

bioRxiv2025

Annexin A2 mediates RIG-I-like receptor responses to viral infection

RIG-I and MDA5 are critical sensors of virus infection and detect many important human pathogens including SARS-CoV-2, influenza A virus (IAV), Zika virus and West Nile virus (WNV). MDA5 is activated by binding to double-stranded RNA generated during infection and induces strong pro-inflammatory and antiviral responses mediated largely via type I interferons. Activation of MDA5 is also implicated in monogenic (e.g. Aicardi-Goutieres syndrome) and complex polygenic (e.g. systemic lupus erythematosus) autoinflammatory diseases, demonstrating the importance of appropriate regulation of this pathway. Yet, how MDA5 is regulated is poorly defined. We employed SILAC-mass spectrometry to discover MDA5 binding partners in virus-infected cells. Our screen revealed Annexin A2 (ANXA2) as an interactor of MDA5 specifically during infection. Direct binding of ANXA2 and MDA5 was recapitulated in vitro and required Ca2+, and ANXA2 promoted MDA5 oligomerisation in cells. Loss of ANXA2 in human cells significantly blunted interferon responses to EMCV, WNV and IAV, demonstrating a role for ANXA2 in activation of both MDA5 and RIG-I. Using human induced pluripotent stem cells, we found that ANXA2 was required for potent neuronal cell responses to WNV infection and macrophage responses to multiple viral pathogens. Thus, we find that ANXA2 is a critical mediator of RIG-I-like receptor pathways.

immunology↗

bioRxiv2025

Hypoxia inducible factors regulate Pneumovirus replication by enhancing innate immune sensing

The immune mechanisms responsible for protection and pathogenesis in pneumoviral infection are not well defined. We demonstrated that pharmacological activation of the hypoxic inducible factor (HIF) signalling axis using Daprodustat limited viral replication through enhanced immune signalling. Transcriptomic analysis revealed HIF augmented activation of innate immune response genes, including interferon-stimulated gene 15 (Isg15), in the lung and spleen of mice infected with pneumonia virus of mice (PVM). In human respiratory syncytial virus (hRSV) infected airway epithelial cells, Daprodustat inhibited viral replication and enhanced ISG15 expression in a HIF-dependent manner. Importantly, inhibition of type I interferon signalling or the RIG-I sensing pathway abrogated the antiviral activity of HIF. Moreover, Daprodustat increased interferon signalling in response to viral RNA, suggesting that HIF inhibits pneumovirus replication through enhancing viral RNA sensing. Mechanistically, Daprodustat reduced N6-methyladenosine modification of viral RNA through upregulation of RNA demethylases, promoting detection by innate immune sensors. This study highlights the intricate interplay between hypoxia and antiviral immunity and offers valuable insights into pneumovirus-host interactions and potential therapeutic interventions. SIGNIFICANCE STATEMENTThis study explores the role of the hypoxic inducible factor (HIF) signalling pathway in limiting pneumoviral infections, such as respiratory syncytial virus (hRSV) and pneumonia virus of mice (PVM). Using Daprodustat, a clinically approved activator of HIF signalling we demonstrated that stimulation of this pathway enhanced innate immune signalling and limited viral replication. Transcriptomic analysis showed that HIF promoted innate immune response genes in mice infected with PVM and human airway epithelial cells infected with hRSV. Importantly, inhibition of type I interferon signalling or the RIG-I sensing pathway abrogated the antiviral activity of HIF. We uncovered a role for HIF to regulate the levels of N6-methyladenosine modification of viral RNA transcripts, resulting in the increased activation of nucleic acid sensing.

microbiology↗

bioRxiv2025

Double-stranded RNA responses, neoantigen presentation and suppression of hepatocellular carcinoma through NMD inhibition via endonuclease SMG6

Nonsense-mediated mRNA decay (NMD) eliminates aberrant transcripts to maintain transcriptome integrity, yet its broader physiological roles remain incompletely defined. Here, using a liver-specific, inducible mouse model, we selectively inactivate the endonuclease SMG6 - the terminal effector of NMD - in a genetic model of hepatocellular carcinoma (HCC). SMG6 loss completely prevents tumour development and triggers robust innate and adaptive immune responses. Mechanistically, SMG6 inactivation causes the cytoplasmic accumulation of endogenous double-stranded RNAs (dsRNAs), leading to type I interferon induction via the dsRNA sensor MDA5 and revealing an unexpected physiological role for NMD in maintaining dsRNA homeostasis. In parallel, stabilisation and translation of normally degraded transcripts generate non-canonical MHC-I-presented peptides that elicit potent CD8+ T-cell responses. These findings identify SMG6-dependent NMD as a central gatekeeper that restrains dsRNA-driven antiviral signalling and suppresses immunogenic transcript expression. Our work establishes selective SMG6 inhibition as a promising strategy to enhance tumour immunogenicity and suggests that targeting terminal NMD activity could represent a conceptually distinct avenue for cancer immunotherapy.

cancer biology↗

bioRxiv2024

Iron deficiency causes aspartate-sensitive metabolic and proliferative dysfunction in CD8+ T cells

Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people, causing symptoms including anaemia and impaired immunity. Nevertheless, precisely how iron deprivation impacts immune cell function remains poorly characterised. We therefore interrogated how physiologically low iron availability affected activated CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation profoundly stalled proliferation without influencing cell viability, altered histone methylation status and disrupted mitochondrial membrane potential. Consistently, metabolism of glucose and glutamine in the TCA cycle was limited, indeed TCA cycle activity was partially reversed to a reductive trajectory. Previous studies have shown mitochondria-derived aspartate is crucial for proliferation of transformed cells. Surprisingly, we found aspartate was increased in stalled iron deficient CD8+ T-cells, but was not utilised cytosolically for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Conversely, exogenous aspartate, which directly accesses the cytosol, markedly rescued the clonal expansion of even severely iron-deficient CD8+ T-cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck impairing T-cells, which can be bypassed by resupplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.

immunology↗

bioRxiv2023

Single-cell analysis of signalling and transcriptional responses to type I interferons

Type I interferons (IFNs) play crucial roles in antiviral defence, autoinflammation and cancer immunity. The human genome encodes 17 different type I IFNs that all signal through the same receptor. Non-redundant functions have been reported for some type I IFNs. However, whether different type I IFNs induce different responses remains largely unknown. We stimulated human peripheral blood mononuclear cells (PBMCs) with recombinant type I IFNs to address this question in multiple types of primary cells. We analysed signalling responses by mass cytometry and changes in gene expression by bulk and single-cell RNA sequencing. We found cell-type specific changes in the phosphorylation of STAT transcription factors and in the gene sets induced and repressed upon type I IFN exposure. We further report that the magnitude of these responses varied between different type I IFNs, whilst qualitatively different responses to type I IFN subtypes were not apparent. Taken together, we provide a rich resource mapping signalling responses and IFN-regulated genes in immune cells. HighlightsO_LIMass cytometry and scRNAseq analysis of human PBMCs stimulated with type I IFNs C_LIO_LICell type-specific phosphorylation of STAT proteins and induction of ISGs C_LIO_LIDifferent type I IFNs induce qualitatively similar responses that vary in magnitude C_LIO_LIIdentification of ten core ISGs, up-regulated by all cell types in response to all type I IFNs C_LI In briefRigby et al. provide a single-cell map of signalling and transcriptomic responses to type I IFNs in ex vivo stimulated human PBMCs. Different cell types responded in unique ways but differences between different type I IFNs were only quantitative. These rich datasets are available via an easy-to-use interactive interface (https://rehwinkellab.shinyapps.io/ifnresource/). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/547491v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@17e1e06org.highwire.dtl.DTLVardef@e53d81org.highwire.dtl.DTLVardef@290069org.highwire.dtl.DTLVardef@1da0c5a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Genome-wide association studies (GWAS) have identified risk loci, but some loci are associated with co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins; EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. Lung-specific eQTLs were identified from GTEx (v7) for each of the 332 host proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed an association between increased expression of EXOSC2 and higher risk of clinical COVID-19 which survived stringent multiple testing correction. EXOSC2 is a component of the RNA exosome and indeed, LC-MS/MS analysis of protein pulldowns demonstrated an interaction between the SARS-CoV-2 RNA polymerase and the majority of human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu-3 cells reduced EXOSC2 protein expression, impeded SARS-CoV-2 replication and upregulated oligoadenylate synthase (OAS) genes, which have been linked to a successful immune response against SARS-CoV-2. Reduced EXOSC2 expression did not reduce cellular viability. OAS gene expression changes occurred independent of infection and in the absence of significant upregulation of other interferon-stimulated genes (ISGs). Targeted depletion or functional inhibition of EXOSC2 may be a safe and effective strategy to protect at-risk individuals against clinical COVID-19.

genetics↗

bioRxiv2022

The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses

Host proteins sense viral products and induce defence mechanisms, particularly in immune cells. Using cell-free assays and quantitative mass spectrometry, we determined the interactome of capsid- host protein complexes of herpes simplex virus and identified the large dynamin-like GTPase myxovirus resistance protein B (MxB) as an interferon-inducible protein interacting with capsids. Electron microscopy analyses showed that cytosols containing MxB had the remarkable capability to disassemble the icosahedral capsids of herpes simplex viruses and varicella zoster virus into flat sheets of connected triangular faces. In contrast, capsids remained intact in cytosols with MxB mutants unable to hydrolyse GTP or to dimerize. Our data suggest that MxB senses herpesviral capsids, mediates their disassembly, and thereby restricts the efficiency of nuclear targeting of incoming capsids and/or the assembly of progeny capsids. The resulting premature release of viral genomes from capsids may enhance the activation of DNA sensors, and thereby amplify the innate immune responses.

microbiology↗

bioRxiv2021

ZBP1 induces inflammatory signaling via RIPK3 and promotes SARS-CoV-2-induced cytokine expression

COVID-19 caused by the SARS-CoV-2 virus remains a threat to global health. The disease severity is mediated by cell death and inflammation, which regulate both the antiviral and the pathological innate immune responses. ZBP1, an interferon-induced cytosolic nucleic acid sensor, facilitates antiviral responses via RIPK3. Although ZBP1-mediated cell death is widely described, whether and how it promotes inflammatory signaling is unclear. Here, we report a ZBP1-induced inflammatory signaling pathway that depends on ubiquitination and RIPK3s scaffolding ability independently of cell death. In human cells, ZBP1 associates with RIPK1 and RIPK3 as well as ubiquitin ligases cIAP1 and LUBAC. RIPK1 and ZBP1 are ubiquitinated to promote TAK1- and IKK-mediated inflammatory signaling. Additionally, RIPK1 recruits the p43/41-caspase-8-p43-FLIP heterodimer to suppress RIPK3 kinase activity, which otherwise promotes inflammatory signaling in a kinase activity-dependent manner. Lastly, we show that ZBP1 contributes to SARS-CoV-2-induced cytokine production. Taken together, we describe a ZBP1-RIPK1-RIPK3-mediated inflammatory signaling pathway relayed by the scaffolding role of RIPKs and regulated by caspase-8. Our results suggest the ZBP1 pathway contributes to inflammation in response to SARS-CoV-2 infection.

immunology↗

bioRxiv2021

The RNA sensor MDA5 detects SARS-CoV-2 infection

Human cells respond to infection by SARS-CoV-2, the virus that causes COVID-19, by producing cytokines including type I and III interferons (IFNs) and proinflammatory factors such as IL6 and TNF. IFNs can limit SARS-CoV-2 replication but cytokine imbalance contributes to severe COVID-19. We studied how cells detect SARS-CoV-2 infection. We report that the cytosolic RNA sensor MDA5 was required for type I and III IFN induction in the lung cancer cell line Calu-3 upon SARS-CoV-2 infection. Type I and III IFN induction further required MAVS and IRF3. In contrast, induction of IL6 and TNF was independent of the MDA5-MAVS-IRF3 axis in this setting. We further found that SARS-CoV-2 infection inhibited the ability of cells to respond to IFNs. In sum, we identified MDA5 as a cellular sensor for SARS-CoV-2 infection that induced type I and III IFNs.

immunology↗

bioRxiv2020

Fractional response analysis reveals logarithmic cytokine responses in cellular populations

Although we can now measure single-cell signaling responses with multivariate, high-throughput techniques our ability to interpret such measurements is still limited. Even interpretation of dose-response based on single-cell data is not straightforward: signaling responses can differ significantly between cells, encompass multiple signaling effectors, and have dynamic character. Here, we use probabilistic modeling and information-theory to introduce fractional response analysis (FRA), which quantifies changes in fractions of cells with given response levels. FRA can be universally performed for heterogeneous, multivariate, and dynamic measurements and, as we demonstrate, uncovers otherwise hidden patterns in single-cell data. In particular, we show that fractional responses to type I interferon in human peripheral blood mononuclear cells are very similar across different cell types, despite significant differences in mean or median responses and degrees of cell-to-cell heterogeneity. Further, we demonstrate that fractional responses to cytokines scale linearly with the log of the cytokine dose, which uncovers that cellular populations are sensitive to fold-changes in the dose, as opposed to additive changes.

systems biology↗

bioRxiv2020

Recognition of Z-RNA by ADAR1 limits interferon responses

Nucleic acids are powerful triggers of innate immunity and can adopt the unusual Z-conformation. The p150 isoform of adenosine deaminase acting on RNA 1 (ADAR1) prevents aberrant interferon (IFN) induction and contains a Z-nucleic acid binding (Z) domain. We report that knock-in mice bearing two point mutations in the Z domain of ADAR1, which abolish binding to Z-form nucleic acids, spontaneously induced type I IFNs and IFN-stimulated genes (ISGs) in multiple organs. This included the lung where both stromal and haematopoietic cells displayed ISG induction in Adar1mZ/mZ mice. Concomitantly, Adar1mZ/mZ mice showed improved control of influenza A virus. The spontaneous IFN response in Adar1mZ/mZ mice required MAVS, implicating cytosolic RNA sensing. Finally, analysis of A-to-I changes revealed a specific requirement of ADAR1s Z domain in editing of a subset of RNAs. In summary, our results reveal that endogenous RNAs in Z-conformation have immunostimulatory potential that is curtailed by ADAR1.

immunology↗

bioRxiv2020

Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This was HIF1/2-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reaveal a mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.

cancer biology↗

bioRxiv2020

Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence SummaryNRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

microbiology↗

bioRxiv2020

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signalling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1 deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterised by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17-driven inflammatory skin conditions such as psoriasis. SummaryDevos, Tanghe et al. find that the recognition of endogenous nucleic acids by the nucleic acid sensor ZBP1 causes necroptosis of RIPK1-deficient keratinocytes. This process drives the development of an inflammatory skin disease characterised by an IL-17 immune response.

immunology↗

bioRxiv2020

SAMHD1 limits the efficacy of forodesine in leukaemia by protecting cells against cytotoxicity of dGTP

The anti-leukaemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphates (dNTPs), protected cells against the effects of dNTP imbalances. SAMHD1-deficient cells induced intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine acted synergistically to kill cells lacking SAMHD1. Using mass cytometry, we found that these compounds killed SAMHD1-deficient malignant cells from patients with chronic lymphocytic leukaemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation were unaffected. We therefore propose to use forodesine as a precision medicine for leukaemia, stratifying patients by SAMHD1 genotype or expression. O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/951517v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@69c367org.highwire.dtl.DTLVardef@19be007org.highwire.dtl.DTLVardef@91156corg.highwire.dtl.DTLVardef@1158ec6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOSupplementary Figure 5.C_FLOATNO Graphical Abstract C_FIG Highlights O_LISAMHD1-deficient cells die upon exposure to deoxyribonucleosides (dNs) C_LIO_LIDeoxyguanosine (dG) is the most toxic dN, inducing apoptosis in cells lacking SAMHD1 C_LIO_LISAMHD1-mutated leukaemic cells can be killed by dG and the PNP-inhibitor forodesine C_LI In BriefSAMHD1 degrades deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. Davenne et al. found that SAMHD1 protects cells against dNTP imbalances. Exposure of SAMHD1-deficient cells to deoxyguanosine (dG) results in increased intracellular dGTP levels and subsequent apoptosis. This can be exploited to selectively kill cancer cells that acquired SAMHD1 mutations.

cancer biology↗

bioRxiv2020

Varicella-Zoster Virus ORF9 Is an Antagonist of the DNA Sensor cGAS

Varicella-Zoster virus (VZV) causes chickenpox and shingles. Although infection is associated with severe morbidity in some individuals, molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was required for type I interferon (IFN) induction during VZV infection and that recognition of VZV by cGAS restricted its replication. Viral gene overexpression screening identified the essential VZV tegument protein ORF9 as a cGAS antagonist. Ectopically and virally expressed ORF9 bound to endogenous cGAS. Confocal microscopy revealed co-localisation of cGAS and ORF9, which reduced the type I IFN response to transfected DNA. ORF9 and cGAS also interacted directly in a cell-free system and phase-separated together with DNA. Furthermore, ORF9 inhibited cGAMP production by cGAS. Taken together, we uncovered the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identified a VZV immune antagonist that directly interferes with DNA sensing via cGAS.

immunology↗