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SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171010 | GEO | 2021/12/17

REPOSITORIES: GEO

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SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (RNA-Seq)

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein is highly expressed upon infection and is essential for viral replication, making it a promising target for antiviral drug and vaccine development. Here, starting from a functional proteomics workflow, we catalogued the protein-protein interactions of 28 SARS-CoV-2 proteins in HEK293 cells, including an evolutionarily conserved specific interaction of N with the stress granule resident proteins G3BP1 and G3BP2. N protein localizes to stress granules and sequesters G3BP1 and G3BP2 away from their normal interaction partners, thus attenuating stress granule formation. N also binds directly to host mRNAs, with a preference for 3´ UTRs, and modulates target mRNA stability. We show that SARS-CoV-2 N protein rewires the G3BP1 mRNA-binding profile, thereby suppressing host gene expression changes induced in response to cellular stress.

2021-12-17 | GSE171009 | GEO

SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (iCLIP-Seq)

2021-12-17 | GSE171008 | GEO

SARS-CoV-2 nucleocapsid protein binds host mRNAs and attenuates stress granules to impair host stress response.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein is essential for viral replication, making it a promising target for antiviral drug and vaccine development. SARS-CoV-2 infected patients exhibit an uncoordinated immune response; however, the underlying mechanistic details of this imbalance remain obscure. Here, starting from a functional proteomics workflow, we cataloged the protein-protein interactions of SARS-CoV-2 proteins, including an evolutionarily conserved specific interaction of N with the stress granule resident proteins G3BP1 and G3BP2. N localizes to stress granules and sequesters G3BPs away from their typical interaction partners, thus attenuating stress granule formation. We found that N binds directly to host mRNAs in cells, with a preference for 3' UTRs, and modulates target mRNA stability. We show that the N protein rewires the G3BP1 mRNA-binding profile and suppresses the physiological stress response of host cells, which may explain the imbalanced immune response observed in SARS-CoV-2 infected patients.

| S-EPMC8642831 | biostudies-literature

SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response

Project description:SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response

| PRJNA718080 | ENA

SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (RNA-Seq)

Project description:SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (RNA-Seq)

| PRJNA718085 | ENA

SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (iCLIP-Seq)

Project description:SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (iCLIP-Seq)

| PRJNA718086 | ENA

Phase separation and stress granule association of SARS-CoV-2 Nucleocapsid protein

Project description:The current work identified the protein interactors of SARS-CoV-2 Nucleocapsid RNA binding protein (NCAP or N protein) in lung cancer A-549 cells, using a co-immunoprecipitation strategy, which is coupled with SILAC-based mass spec. A significant proportion of the identified NCAP interacting proteins included stress granule (SG) and immunoregulators. SG nucleator G3BP1 showed specific interaction wit NCAP in unstressed and oxidative- or heat-stressed cells. Following stress treatment, NCAP showed enhanced association with SGs. Recombinant NCAP exhibited in vitro liquid-liquid phase separation (LLPS)to form liquid droplets. RNA stimulated NCAP to develop droplets in vitro and SG assembly in cells, and RNase A treatment completely blocked both of these functions. An RNA intercalating mitoxantrone disrupted NCAP assembly in SGs invitro and in cells. This study provides insight into the biological processes and biophysical properties of the SARS-CoV-2 NCAP and identifies a candidate way to target this protein.

2021-11-25 | PXD023989 | Pride

SARS-CoV-2 nucleocapsid protein interacts with immunoregulators and stress granules and phase separates to form liquid droplets.

Project description:The current work investigated SARS-CoV-2 Nucleocapsid (NCAP or N protein) interactors in A549 human lung cancer cells using a SILAC-based mass spectrometry approach. NCAP interactors included proteins of the stress granule (SG) machinery and immunoregulators. NCAP showed specific interaction with the SG proteins G3BP1, G3BP2, YTHDF3, USP10 and PKR, and translocated to SGs following oxidative stress and heat shock. Treatment of recombinant NCAP with RNA isolated from A549 cells exposed to oxidative stress-stimulated NCAP to undergo liquid-liquid phase separation (LLPS). RNA degradation using RNase A treatment completely blocked the LLPS property of NCAP as well as its SG association. The RNA intercalator mitoxantrone also disrupted NCAP assembly in vitro and in cells. This study provides insight into the biological processes and biophysical properties of the SARS-CoV-2 NCAP.

| S-EPMC8652540 | biostudies-literature

SARS-CoV-2 nucleocapsid suppresses host pyroptosis by blocking Gasdermin D cleavage

Project description:SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by blocking Gasdermin D (GSDMD) cleavage. SARS-CoV-2-infected monocytes show enhanced cellular interleukin 1b (IL-1b) expression, but reduced IL-1b secretion. While SARS-CoV-2 infection promotes activation of the NLRP3 inflammasome and caspase-1, GSDMD cleavage and pyroptosis are inhibited in infected human monocytes. SARS-CoV-2 nucleocapsid protein associates with GSDMD in cells and inhibits GSDMD cleavage in vitro and in vivo. The nucleocapsid binds the GSDMD linker region and hinders GSDMD processing by caspase-1. These insights into how SARS-CoV-2 antagonizes cellular inflammatory responses may open new avenues for treating COVID-19 in the future.

| S-SCDT-EMBOJ-2021-108249 | biostudies-other

Arginine methylation of SARS-Cov-2 nucleocapsid protein regulates RNA binding, its ability to suppress stress granule formation, and viral replication.

Project description:Viral proteins are known to be methylated by host protein arginine methyltransferases (PRMTs) necessary for the viral life cycle, but it remains unknown whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins are methylated. Herein, we show that PRMT1 methylates SARS-CoV-2 nucleocapsid (N) protein at residues R95 and R177 within RGG/RG motifs, preferred PRMT target sequences. We confirmed arginine methylation of N protein by immunoblotting viral proteins extracted from SARS-CoV-2 virions isolated from cell culture. Type I PRMT inhibitor (MS023) or substitution of R95 or R177 with lysine inhibited interaction of N protein with the 5'-UTR of SARS-CoV-2 genomic RNA, a property required for viral packaging. We also defined the N protein interactome in HEK293 cells, which identified PRMT1 and many of its RGG/RG substrates, including the known interacting protein G3BP1 as well as other components of stress granules (SGs), which are part of the host antiviral response. Methylation of R95 regulated the ability of N protein to suppress the formation of SGs, as R95K substitution or MS023 treatment blocked N-mediated suppression of SGs. Also, the coexpression of methylarginine reader Tudor domain-containing protein 3 quenched N protein-mediated suppression of SGs in a dose-dependent manner. Finally, pretreatment of VeroE6 cells with MS023 significantly reduced SARS-CoV-2 replication. Because type I PRMT inhibitors are already undergoing clinical trials for cancer treatment, inhibiting arginine methylation to target the later stages of the viral life cycle such as viral genome packaging and assembly of virions may represent an additional therapeutic application of these drugs.

| S-EPMC8141346 | biostudies-literature

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