The KH-type splicing regulatory protein (KSRP) regulates type III interferon expression post-transcriptionally

Schmidtke, Lisa; Schrick, Katharina; Saurin, Sabrina; Käfer, Rudolf; Gather, Fabian; Weinmann‐Menke, Julia; Kleinert, Hartmut; Pautz, Andrea

doi:10.1042/bcj20180522

Cited by 14 publications

(11 citation statements)

References 48 publications

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“…In fact, accumulating evidence suggests that RBPs regulate not only type I IFN, but also type II and type III IFNs. TTP has been shown to mediate IFNγ mRNA decay [56], and KSRP depletion enhances IFNλ3 mRNA stability [57]. These reports further underscore the importance of RBPs in regulating host IFN response.…”

Section: Discussionmentioning

confidence: 93%

The RNA binding protein Quaking represses host interferon response by downregulating MAVS

et al. 2019

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Quaking (QKI) is an RNA-binding protein (RBP) involved in multiple aspects of RNA metabolism and many biological processes. Despite a known immune function in regulating monocyte differentiation and inflammatory responses, the degree to which QKI regulates the host interferon (IFN) response remains poorly characterized. Here we show that QKI ablation enhances poly(I:C) and viral infection-induced IFNβ transcription. Characterization of IFN-related signalling cascades reveals that QKI knockout results in higher levels of IRF3 phosphorylation. Interestingly, complementation with QKI-5 isoform alone is sufficient to rescue this phenotype and reduce IRF3 phosphorylation. Further analysis shows that MAVS, but not RIG-I or MDA5, is robustly upregulated in the absence of QKI, suggesting that QKI downregulates MAVS and thus represses the host IFN response. As expected, MAVS depletion reduces IFNβ activation and knockout of MAVS in the QKI knockout cells completely abolishes IFNβ induction. Consistently, ectopic expression of RIG-I activates stronger IFNβ induction via MAVS-IRF3 pathway in the absence of QKI. Collectively, these findings demonstrate a novel role for QKI in negatively regulating host IFN response by reducing MAVS levels.

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Section: Discussionmentioning

confidence: 93%

The RNA binding protein Quaking represses host interferon response by downregulating MAVS

et al. 2019

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“…Gene set analysis revealed that mRNAs associated with the KH type-splicing regulatory protein (KHSRP) were specifically enriched in endodermal cells (Figure 3G). KHSRP is involved in post-transcriptional regulation of mRNA expression, including IFN λ3 [30]. This could explain the discrepancy between IFN λ2/3 protein and mRNA expression level.…”

Section: Resultsmentioning

confidence: 99%

Teratogenic Rubella Virus Alters the Endodermal Differentiation Capacity of Human Induced Pluripotent Stem Cells

Bilz

Willscher

Binder

et al. 2019

Cells

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The study of congenital virus infections in humans requires suitable ex vivo platforms for the species-specific events during embryonal development. A prominent example for these infections is rubella virus (RV) which most commonly leads to defects in ear, heart, and eye development. We applied teratogenic RV to human induced pluripotent stem cells (iPSCs) followed by differentiation into cells of the three embryonic lineages (ecto-, meso-, and endoderm) as a cell culture model for blastocyst- and gastrulation-like stages. In the presence of RV, lineage-specific differentiation markers were expressed, indicating that lineage identity was maintained. However, portrait analysis of the transcriptomic expression signatures of all samples revealed that mock- and RV-infected endodermal cells were less related to each other than their ecto- and mesodermal counterparts. Markers for definitive endoderm were increased during RV infection. Profound alterations of the epigenetic landscape including the expression level of components of the chromatin remodeling complexes and an induction of type III interferons were found, especially after endodermal differentiation of RV-infected iPSCs. Moreover, the eye field transcription factors RAX and SIX3 and components of the gene set vasculogenesis were identified as dysregulated transcripts. Although iPSC morphology was maintained, the formation of embryoid bodies as three-dimensional cell aggregates and as such cellular adhesion capacity was impaired during RV infection. The correlation of the molecular alterations induced by RV during differentiation of iPSCs with the clinical signs of congenital rubella syndrome suggests mechanisms of viral impairment of human development.

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“…All remaining reported rate constants were assumed to be identical in A549 and Huh7.5 cells). Among the newly introduced parameters, degradation rate constants were fixed based on reported half-lives whenever possible (µCCL5,mRNA, µCXCL10,mRNA, µIFNλ,mRNA, µMX1,mRNA, µIFIT1,mRNA, µMX1, µIFIT1) [93][94][95][96][97][98][99][100]. The degradation of IFN in the supernatant was assumed to be negligible and set to 0.…”

Section: Mathematical Modellingmentioning

confidence: 99%

High Resolution Kinetic Characterization and Dynamic Mathematical Modeling of the RIG-I Signaling Pathway and the Antiviral Responses

Burkart

Schweinoch

Frankish

et al. 2022

Preprint

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The pattern recognition receptor RIG I is essential for the recognition of viral dsRNA and the activation of a cell autonomous antiviral response. Upon stimulation, RIG I triggers a signaling cascade leading to the expression of cytokines, most prominently type I and III interferons (IFNs). IFNs are secreted and signal in an auto and paracrine manner to trigger the expression of a large variety of IFN stimulated genes, which in concert establish an antiviral state of the cell. While the topology of this pathway has been studied quite intensively, the dynamics, particularly of the RIG I mediated IFN induction, is much less understood. Here, we employed electroporation based transfection to synchronously activate the RIG I signaling pathway, enabling us to characterize the kinetics and dynamics of cell intrinsic innate immune signaling to virus infections. By employing an A549 IFNAR1/IFNLR deficient cell line, we could analyze the difference between the primary RIG I signaling phase and the secondary signaling phase downstream of the IFN receptors. We further used our quantitative data to set up and calibrate a comprehensive dynamic mathematical model of the RIG I and IFN signaling pathways. This model accurately predicts the kinetics of signaling events downstream of dsRNA recognition by RIG I as well as the feedback and signal amplification by secreted IFN and JAK/STAT signaling. We have furthermore investigated the impact of various viral immune antagonists on the signaling dynamics experimentally, and we utilized the here described modelling approach to simulate and in silico study these critical virus-host interactions. Our work provides a comprehensive insight into the signaling events occurring early upon virus infection and opens up new avenues to study and disentangle the complexity of the host-virus interface.

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The KH-type splicing regulatory protein (KSRP) regulates type III interferon expression post-transcriptionally

Cited by 14 publications

References 48 publications

The RNA binding protein Quaking represses host interferon response by downregulating MAVS

The RNA binding protein Quaking represses host interferon response by downregulating MAVS

Teratogenic Rubella Virus Alters the Endodermal Differentiation Capacity of Human Induced Pluripotent Stem Cells

High Resolution Kinetic Characterization and Dynamic Mathematical Modeling of the RIG-I Signaling Pathway and the Antiviral Responses

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