A cytomegaloviral protein reveals a dual role for STAT2 in IFN-γ signaling and antiviral responses

Zimmermann, Albert; Trilling, Mirko; Wagner, Markus; Wilborn, Manuel; Bubić, Ivan; Jonjić, Stipan; Koszinowski, Ulrich H.; Hengel, Hartmut

doi:10.1084/jem.20041401

Cited by 139 publications

(213 citation statements)

References 49 publications

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“…When analysing an MCMV mutant lacking M27, a gene encoding an inhibitor of STAT2-mediated IFN signalling, an increased sensitivity of replication to exogenously added type I IFN was observed, whereas DM27-MCMV replication was wt-like in the presence of endogenously produced IFN (Zimmermann et al, 2005). Based on this observation we hypothesized that MCMV induces only very low amounts of endogenous type I IFN in fibroblast cultures and may be able to avoid IFN gene induction.…”

Section: Shuts Down Ifn-a/b Gene Expression After An Initial Phamentioning

confidence: 94%

“…Cells were infected and washed before being lysed and analysed as described previously (Zimmermann et al, 2005). Nuclear lysates were incubated with 1 ng 32 P-labelled probe (kB-consensus: 59-AGTTGAGGGACTTT-CCCAGGC-39; Santa Cruz).…”

Section: Methodsmentioning

confidence: 99%

“…Given the usually asymptomatic course of primary and reactivated CMV replication in immunocompetents, limiting the amount of type I IFN secretion in productively infected tissues may indeed contribute to host health and establish a suitable condition for host-virus coexistence. Albeit type I IFNs are relatively poor inhibitors of MCMV replication on their own, they can reach sufficient antiviral priming of neighbouring cells even at low concentrations in combination with synergistic cytokines like lymphotoxins and IFNc (Benedict et al, 2001;Zimmermann et al, 2005).…”

Section: T K Le and Othersmentioning

confidence: 99%

“…For cytomegaloviruses (CMV), a number of genes were reported to code for inhibitors counteracting IFN responses. The mouse cytomegalovirus (MCMV) M27 protein downregulates STAT2 to disrupt IFN-a/b and IFN-c signal transduction, resulting in a dramatic attenuation of viral replication in vivo (Khan et al, 2004;Zimmermann et al, 2005). The human CMV (HCMV) immediate-early 1 (ie1)-encoded protein pp72 was described as a STAT-interacting protein that diminishes ISGF3-dependent transcription (Paulus et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

Trilling

Zimmermann

et al. 2008

Journal of General Virology

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We have investigated beta interferon (IFN-b) and IFN-a4 gene expression and activation of related transcription factors in mouse cytomegalovirus (MCMV)-infected fibroblasts. mRNA analysis demonstrated an initial phase of IFN gene induction upon MCMV infection, which was followed by a sustained MCMV-mediated simultaneous downregulation of IFN-b and IFN-a4 gene expression. The induction of IFN transcription resulted from the activation of the components of the IFN-b enhanceosome, i.e. IFN regulatory factor (IRF) 3, nuclear factor (NF)-kB, activating transcription factor (ATF)-2 and c-Jun. Activation of the transcription factors occurred rapidly and in a sequential order upon infection, but only lasted a while. As a consequence, IFN-a/b gene expression became undetectable 6 h post-infection and throughout the MCMV replication cycle. This effect is based on an active interference since restimulation of IFN gene induction by further external stimuli (e.g. Sendai virus infection) was completely abolished. This inhibition required MCMV gene expression and was not observed in cells infected with UV-inactivated MCMV virions. The efficiency of inhibition is achieved by a concerted blockade of IkBa degradation and a lack of nuclear accumulation of IRF3 and ATF-2/c-Jun. Using an MCMV mutant lacking pM27, a signal transducer and activator of transcription (STAT) 2-specific inhibitor of Jak/STAT signalling, we found that the initial phase of IFN induction and the subsequent inhibition does not depend on the positive-IFN feedback loop. Our findings indicate that the MCMV-mediated downregulation of IFN transcription in fibroblasts relies on a large arsenal of inhibitory mechanisms targeting each pathway that contributes to the multiprotein enhanceosome complex. INTRODUCTIONUpon virus infection the type I interferon (IFN-a/b) response is one of the earliest innate host defence mechanisms, and many viruses have found means to avoid IFN gene expression Haller et al., 2006). Production of IFN-a/b is induced by the recognition of pathogen-associated molecular patterns (PAMP) (Medzhitov & Janeway, 2002) and initiates transcriptional upregulation of IFN-stimulated genes (ISGs) to establish an antiviral state. IFN-a/b synthesized by virus-infected cells bind to the IFN-a/b receptor complex, termed IFNAR, and activates the Jak/STAT signal transduction cascade, leading to the formation of the IFN-stimulated gene factor 3 (ISGF3). ISGF3 binds to IFN-stimulated response elements (ISRE), located in the promoter region of IFNinducible target genes mediating IFN effector functions (Darnell et al., 1994).Initiation of IFN transcription and its subsequent autocrine and paracrine amplification is a prerequisite for efficient IFN effector responses. IFN-b gene transcription is controlled by a higher order transcription enhancer complex, known as enhanceosome (Maniatis, 1986;Maniatis et al., 1998). The multi-component complex includes three distinct transcription factors binding cooperatively to the IFN-b promoter and the architectural high mobili...

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Section: Shuts Down Ifn-a/b Gene Expression After An Initial Phamentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: T K Le and Othersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

Trilling

Zimmermann

et al. 2008

Journal of General Virology

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“…Because the standard biological method to quantify interferons is with antiviral assays, we were concerned that the differential antiviral effects of the various interferon subtypes might produce aberrant results. Therefore, we developed a stable reporter cell line using human retinal pigment epithelial cells (ATCC CRL2302) transfected with a plasmid containing interferon-stimulated response element (ISRE) promoter/enhancer elements driving a luciferase reporter gene (pISRE; Stratagene) (40). Cells were grown for 24 h before adding serial dilutions of our recombinant IFN-␣ subtypes and commercially available IFN-␣ subtypes (PBL Assay Science, Piscataway, NJ) for 4 h. The cells were lysed with Bright Glo lysis buffer (Promega), and luciferase activity was measured 10 min later.…”

Section: Ethicsmentioning

confidence: 99%

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

Lavender¹,

Gibbert

Peterson³

et al. 2016

J Virol

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112

188

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circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer

Yang

Luo

Shao

et al. 2022

Cancer Communications

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Background Circular RNAs (circRNAs) generated by back‐splicing of precursor mRNAs (pre‐mRNAs) are often aberrantly expressed in cancer cells. Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers, including colorectal cancer (CRC). However, the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited. Here, we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis. Methods circRNA microarray was performed with three pairs of tumor and non‐tumor tissues from CRC patients. The expression of circRNAs were determined by quantitative PCR (qPCR) and in situ hybridization (ISH). The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs. The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array, RNA pull‐down/mass spectrometry, RNA immunoprecipitation assay, luciferase reporter assay, chromatin immunoprecipitation analysis, and fluorescence in situ hybridization (FISH). Results Among circRNAs, circCAPRIN1 was most significantly upregulated in CRC tissue specimens. circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients. Downregulation of circCAPRIN1 suppressed proliferation, migration, and epithelial‐mesenchymal transition of CRC cells, while circCAPRIN1 overexpression had opposite effects. RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism. Moreover, circCAPRIN1 promoted lipid synthesis by enhancing Acetyl‐CoA carboxylase 1 (ACC1) expression. Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2 (STAT2) to activate ACC1 transcription, thus regulating lipid metabolism and facilitating CRC tumorigenesis. Conclusions These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC. circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1. circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.

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A cytomegaloviral protein reveals a dual role for STAT2 in IFN-γ signaling and antiviral responses

Cited by 139 publications

References 49 publications

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer

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