Parsing the role of NSP1 in SARS-CoV-2 infection

Fisher, Tal; Gluck, Avi; Narayanan, Krishna; Kuroda, Makoto; Nachshon, Aharon; Hsu, Jason C.; Halfmann, Peter; Yahalom-Ronen, Yfat; Tamir, Hadas; Finkel, Yaara; Schwartz, Michal; Weiss, Shay; Tseng, Chien-Te K.; Israely, Tomer; Paran, Nir; Kawaoka, Yoshihiro; Makino, Shinji; Rozman, Batsheva

doi:10.1016/j.celrep.2022.110954

Cited by 50 publications

(66 citation statements)

References 54 publications

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“…Therefore, it is possible that TIAR bound to RNA is co-exported from the nucleus through NXF1/NXT1 dependent RNA export pathway which is inhibited by CoV2 Nsp1 [ 84 ]. However, it appears that the RNA export inhibition by CoV2 Nsp1 is independent from ribosome binding or its RNA degradation activity [ 46 ], and therefore cannot be the main driver for nuclear accumulation of TIAR. Since RNA binding by RRMs 2 and 3 has different affinity and preferred RNA sequence composition [ 85 , 86 ], it is possible that depletion of a certain subset of RNAs through Nsp1-induced cleavage and degradation favors RRM2-dependent nuclear import.…”

Section: Discussionmentioning

confidence: 99%

“…Another viral protein that was shown to affect SG formation is Nsp1, a host shutoff factor encoded by the first N-terminal portion of ORF1ab of Betacoronaviruses [ 41 ]. The Nsp1-mediated host shutoff plays a key role in suppressing innate immune responses in infected cells, which has been demonstrated by comparing wild-type and recombinant Nsp1 mutant CoV infections with transmissible gastroenteritis virus (TGEV) [ 42 ], mouse hepatitis virus (MHV) [ 43 ], MERS-CoV [ 44 ], SARS [ 45 ], and CoV2 [ 46 ]. Nsp1 functions primarily through inhibition of host protein synthesis; for SARS and CoV2 Nsp1, this is accomplished through binding to the 43S small ribosomal subunit complex and blocking the mRNA entry channel of the mature 80S ribosome [ 41 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

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Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

et al. 2022

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Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the pandemic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress. Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause a decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear accumulation of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in virus replication compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

et al. 2022

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“…This is of particular importance when synthesis or degradation rates are not constant. Indeed, the reduced RNA half-lives observed for SARS-CoV-2 likely result from the general host shutoff protein nsp1 encoded by SARS-CoV-2 [28]. It is therefore very likely that degradation of cellular mRNAs depends on the abundance of nsp1, which increases substantially over the first few hours of infection.…”

Section: Discussionmentioning

confidence: 99%

grandR: a comprehensive package for nucleotide conversion sequencing data analysis

Rummel¹,

Sakellaridi²,

Erhard³

2022

Preprint

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Metabolic labeling of RNA is a powerful technique for studying the temporal dynamics of gene expression. Nucleotide conversion approaches greatly facilitate the generation of data but introduce challenges for their analysis. We here present grandR, a comprehensive package for quality control, differential gene expression analysis, kinetic modeling, and visualization of such data. We compare several existing methods for inference of RNA synthesis rates and half-lives using progressive labeling time courses. We demonstrate the need for recalibration of effective labeling times and introduce a Bayesian approach to study the temporal dynamics of RNA using snapshot experiments.

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“…Residues 1-117 and 122-130 of NSP1, which mediate these host-suppressive functions 27 are affected by the mutations G2A, H81C and R124C, fixed in sample S3. It has been reported that the induction of NSP1 mutations in the same locus as R124C (R124A and K125A) prevents NSP1 from accelerating the degradation of host mRNA and decreases its ribosome binding, while increasing its suppression of both host and viral mRNA translation 28 . Based on these observations, we estimate that at least one of the three NSP1 mutations significantly alters host-pathogen interaction; this alteration is likely beneficial, since all three mutations are fixed in sample S3.…”

Section: Mutations In Immunomodulatory Viral Proteins and Their Predi...mentioning

confidence: 99%

SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient

Shapira

Weiner

Sorek-Abramovich

et al. 2022

Preprint

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Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients may lead to accelerated viral mutation rate, immune evasion and persistent viral shedding over many months. Here we report the case of a severely immunocompromised cancer patient infected with the Delta variant of SARS-CoV-2 for over 8 months. Genome sequencing of samples taken after repeated monoclonal antibody treatments reveal the emergence and accumulation of mutations enabling escape from neutralization by antibodies. Mutations emerging in accessory and non-structural viral proteins target specific residues of immunomodulatory domains, potentially leading to loss of some functions, while preserving others. The mutated virus managed to completely overcome neutralization by monoclonal antibodies while remaining viable and infective. Our results suggest that the loss of specific immunomodulatory viral functions might confer a selective advantage in immunocompromised hosts. We also compare between mutations emerging in the presence and absence of neutralizing antibodies.

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Parsing the role of NSP1 in SARS-CoV-2 infection

Cited by 50 publications

References 54 publications

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

grandR: a comprehensive package for nucleotide conversion sequencing data analysis

SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient

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