CNBP controls IL-12 gene transcription and Th1 immunity

Chen, Yongzhi; Sharma, Satendra; Assis, Patrícia A.; Jiang, Zhaozhao; Elling, Roland; Olive, Andrew J.; Hang, Saiyu; Bernier, Jennifer; Huh, Jun R.; Sassetti, Christopher M.; Knipe, David M.; Gazzinelli, Ricardo T.; Fitzgerald, Katherine A.

doi:10.1084/jem.20181031

Cited by 36 publications

(49 citation statements)

References 63 publications

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“…It is tempting to speculate that recognition of the SARS-CoV-2 RNA by CNBP might contribute to establishing a specific cytokine response in infected cells. Intriguingly, the known CNBP-dependent cytokine expression signature 78,79 bears similarity to gene expression changes in SARS-CoV-2 infected cells [5][6][7] , which warrants future investigations. In addition to CNBP, we provide evidence that the interferon-induced protein RYDEN interacts with SARS-CoV-2 RNA and suppresses programmed ribosome frameshifting in a SARS-CoV-2 translational reporter.…”

Section: Rnamentioning

confidence: 92%

“…To further dissect these candidates and validate our RAP-MS results, we first focused on CNBP, which represents the most significantly enriched protein in SARS-CoV-2 purifications and was also induced upon infection. CNBP translocates to the nucleus upon immune stimulation and associates with an immune stimulatory DNA oligonucleotide, suggesting that it may be involved in foreign nucleic acid-sensing pathways 78 . Two recent studies showed that CNBP activates the innate immune response and induces the expression of several pro-inflammatory cytokines, including Il-6 and Cxcl10 in vivo 78,79 .…”

Section: The Transcriptional Regulator Cnbp Directly Engages the Sarsmentioning

confidence: 99%

“…CNBP translocates to the nucleus upon immune stimulation and associates with an immune stimulatory DNA oligonucleotide, suggesting that it may be involved in foreign nucleic acid-sensing pathways 78 . Two recent studies showed that CNBP activates the innate immune response and induces the expression of several pro-inflammatory cytokines, including Il-6 and Cxcl10 in vivo 78,79 . While our proteomics experiments did not yield peptides for these two CNBP-regulated cytokines, recent transcriptome studies demonstrated that IL-6 and CXCL10 were indeed induced in SARS-CoV-2 infected human cells [5][6][7] .…”

Section: The Transcriptional Regulator Cnbp Directly Engages the Sarsmentioning

confidence: 99%

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A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells

Schmidt

Lareau

Keshishian

et al. 2020

Preprint

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SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host defense mechanisms in infected cells. While SARS-CoV-2 co-opts cellular factors for viral translation and genome replication, a comprehensive map of the host cell proteome in direct contact with viral RNA has not been elucidated. Here, we use RNA antisense purification and mass spectrometry (RAP-MS) to obtain an unbiased and quantitative picture of the human proteome that directly binds the SARS-CoV-2 RNA in infected human cells. We discover known host factors required for coronavirus replication, regulators of RNA metabolism and host defense pathways, along with dozens of potential drug targets among direct SARS-CoV-2 binders. We further integrate the SARS-CoV-2 RNA interactome with proteome dynamics induced by viral infection, linking interactome proteins to the emerging biology of SARS-CoV-2 infections. Validating RAP-MS, we show that CNBP, a regulator of proinflammatory cytokines, directly engages the SARS-CoV-2 RNA. Supporting the functional relevance of identified interactors, we show that the interferon-induced protein RYDEN suppresses SARS-CoV-2 ribosomal frameshifting and demonstrate that inhibition of SARS-CoV-2-bound proteins is sufficient to manipulate viral replication. The SARS-CoV-2 RNA interactome provides an unprecedented molecular perspective on SARS-CoV-2 infections and enables the systematic dissection of host dependency factors and host defense strategies, a crucial prerequisite for designing novel therapeutic strategies.

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Section: Rnamentioning

confidence: 92%

Section: The Transcriptional Regulator Cnbp Directly Engages the Sarsmentioning

confidence: 99%

Section: The Transcriptional Regulator Cnbp Directly Engages the Sarsmentioning

confidence: 99%

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A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells

Schmidt

Lareau

Keshishian

et al. 2020

Preprint

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“…Similarly, NONO has a previously characterized anti-viral role in the context of HIV and poliovirus infection, where it acts as a sensor for viral DNA and activates cGAS to trigger innate immunity (Lahaye et al, 2018;Lenarcic et al, 2013) . CNBP is another factor that sensitizes host cells to infection and has also been shown to recognize diverse intracellular microbial products to drive inflammatory cytokine gene expression, particularly IL-12β (Chen et al, 2018) . Members of the SWI/SNF protein family, SMARCA4 and SMARCA5 were among the strongest genome-wide hits in either direction (Wei et al, 2020) .…”

Section: Intersection Of Chirp-ms and Crispr Perturbation Screens Assmentioning

confidence: 99%

Systematic discovery and functional interrogation of SARS-CoV-2 viral RNA-host protein interactions during infection

Flynn

Yasumoto

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a pandemic with growing global mortality. There is an urgent need to understand the molecular pathways required for host infection and anti-viral immunity. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with viral ChIRP-MS data from three other positive-sense RNA viruses defined pan-viral and SARS-CoV-2-specific host interactions. Functional interrogation of these factors with a genome-wide CRISPR screen revealed that the vast majority of viral RNA-binding proteins protect the host from virus-induced cell death, and we identified known and novel anti-viral proteins that regulate SARS-CoV-2 pathogenicity. Finally, our RNA-centric approach demonstrated a physical connection between SARS-CoV-2 RNA and host mitochondria, which we validated with functional and electron microscopy data, providing new insights into a more general virus-specific protein logic for mitochondrial interactions. Altogether, these data provide a comprehensive catalogue of SARS-CoV-2 RNA-host protein interactions, which may inform future studies to understand the mechanisms of viral pathogenesis, as well as nominate host pathways that could be targeted for therapeutic benefit.Highlights· ChIRP-MS of SARS-CoV-2 RNA identifies a comprehensive viral RNA-host protein interaction network during infection across two species· Comparison to RNA-protein interaction networks with Zika virus, dengue virus, and rhinovirus identify SARS-CoV-2-specific and pan-viral RNA protein complexes and highlights distinct intracellular trafficking pathways· Intersection of ChIRP-MS and genome-wide CRISPR screens identify novel SARS-CoV-2-binding proteins with pro- and anti-viral function· Viral RNA-RNA and RNA-protein interactions reveal specific SARS-CoV-2-mediated mitochondrial dysfunction during infection

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“…Inducible control of macrophage inflammatory response genes involves the concerted activities of multiple transcription factors and coregulators, including multiple NF-κB family members, IRF and AP-1 transcription factors, and other DNA-binding proteins, such as CNBP (56,(66)(67)(68). Individual genes likely have different levels of sensitivity to the loss of particular transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Caspase-8 promotes c-Rel–dependent inflammatory cytokine expression and resistance against Toxoplasma gondii

DeLaney

Berry

Christian

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Following engagement of tumor necrosis factor superfamily receptors or certain Toll-like receptors (TLRs), caspase-8 initiates cell-extrinsic apoptosis while inhibiting RIPK3-dependent programmed necrosis. In addition, caspase-8 has an important, albeit less well understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 or the adaptor FADD have defective inflammatory cytokine expression and inflammasome priming in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8–mediated gene regulation has a physiological role during infection, remain poorly defined. Here we demonstrate that both caspase-8 enzymatic activity and scaffolding functions contribute to inflammatory cytokine gene expression. Caspase-8 enzymatic activity was necessary for maximal expression of Il1b and Il12b, but caspase-8 deficient cells exhibited a further decrease in expression of these genes. Furthermore, the ability of TLR stimuli to induce optimal IκB kinase phosphorylation and nuclear translocation of the nuclear factor kappa light chain enhancer of activated B cells family member c-Rel required caspase activity. Interestingly, overexpression of c-Rel was sufficient to restore expression of IL-12 and IL-1β in caspase-8–deficient cells. Moreover, Ripk3−/−Casp8−/− mice were unable to control infection by the intracellular parasite Toxoplasma gondii, which corresponded to defects in monocyte recruitment to the peritoneal cavity, and exogenous IL-12 restored monocyte recruitment and protection of caspase-8–deficient mice during acute toxoplasmosis. These findings provide insight into how caspase-8 controls inflammatory gene expression and identify a critical role for caspase-8 in host defense against eukaryotic pathogens.

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CNBP controls IL-12 gene transcription and Th1 immunity

Cited by 36 publications

References 63 publications

A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells

A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells

Systematic discovery and functional interrogation of SARS-CoV-2 viral RNA-host protein interactions during infection

Caspase-8 promotes c-Rel–dependent inflammatory cytokine expression and resistance against Toxoplasma gondii

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