Structural basis for translation inhibition by MERS-CoV Nsp1 reveals a conserved mechanism for betacoronaviruses

Devarkar, Swapnil C.; Vetick, Michael; Balaji, Shravani; Lomakin, Ivan B.; Yang, Luojia; Jin, Danni; Gilbert, Wendy V.; Chen, Sidi; Xiong, Yong

doi:10.1016/j.celrep.2023.113156

Cited by 6 publications

(3 citation statements)

References 49 publications

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“…Because eukaryotic mRNA translation relies on recruiting the 40S ribosomal subunit to the template mRNA [ 2 ], Nsp1 suppresses the global translation of the host with direct consequences on viral propagation because the host cell translation machinery is employed to promote the production of viral proteins [ 20 , 22 ]. This strategy is shared among different Betacoronaviruses, as shown by structural and biochemical studies using Nsp1 from MERS [ 29 , 30 ] and the Bat-Hp-CoV_Zhejiang2013, referred to as Bat-Hp Coronavirus [ 30 ]. In all cases, the C-terminal end anchors Nsp1 with high affinity to the mRNA entry channel in a conformation that clashes with the translated mRNA.…”

Section: The Mechanism Of Host Translation Shutdownmentioning

confidence: 99%

The art of hijacking: how Nsp1 impacts host gene expression during coronaviral infections

Karousis

2024

Biochemical Society Transactions

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Non-structural protein 1 (Nsp1) is one of the first proteins produced during coronaviral infections. It plays a pivotal role in hijacking and rendering the host gene expression under the service of the virus. With a focus on SARS-CoV-2, this review presents how Nsp1 selectively inhibits host protein synthesis and induces mRNA degradation of host but not viral mRNAs and blocks nuclear mRNA export. The clinical implications of this protein are highlighted by showcasing the pathogenic role of Nsp1 through the repression of interferon expression pathways and the features of viral variants with mutations in the Nsp1 coding sequence. The ability of SARS-CoV-2 Nsp1 to hinder host immune responses at an early step, the absence of homology to any human proteins, and the availability of structural information render this viral protein an ideal drug target with therapeutic potential.

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Section: The Mechanism Of Host Translation Shutdownmentioning

confidence: 99%

The art of hijacking: how Nsp1 impacts host gene expression during coronaviral infections

Karousis

2024

Biochemical Society Transactions

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“…Unlike IAV that replicate within the nucleus of the host infected cell, SARS-CoV-2 lacks a nuclear replication step and replicates only in the cytoplasm of infected cells ( Cohen et al., 2011 ; Chen et al., 2022 ). Nevertheless, one of the known mechanisms by which SARS-CoV-2 Nsp1 inhibit host gene expression/translation occurs via hindering the nuclear transport complex NXF1/NXT1 to mediate the nuclear export of host mRNA from the nucleus to the cytoplasm of infected cells for translation ( Zhang et al., 2021 ; Devarkar et al., 2023 ). Although recent studies demonstrated that the SARS-CoV-2 Nsp1 is localized mainly in the cytoplasm of infected cells, a small portion colocalizes with the components of the nuclear pore complexes (NPCs) at the nuclear envelope, emphasizing that Nsp1 can indirectly displace NXF1/NXT1 complex from its NPC interactors ( Zhang et al., 2021 ; Devarkar et al., 2023 ).…”

Section: Iav Ns1 and Sars-cov-2 Nsp1 Post-translational Modifications...mentioning

confidence: 99%

“…Nevertheless, one of the known mechanisms by which SARS-CoV-2 Nsp1 inhibit host gene expression/translation occurs via hindering the nuclear transport complex NXF1/NXT1 to mediate the nuclear export of host mRNA from the nucleus to the cytoplasm of infected cells for translation ( Zhang et al., 2021 ; Devarkar et al., 2023 ). Although recent studies demonstrated that the SARS-CoV-2 Nsp1 is localized mainly in the cytoplasm of infected cells, a small portion colocalizes with the components of the nuclear pore complexes (NPCs) at the nuclear envelope, emphasizing that Nsp1 can indirectly displace NXF1/NXT1 complex from its NPC interactors ( Zhang et al., 2021 ; Devarkar et al., 2023 ). This finding confirm that SARS-CoV-2 Nsp1 can achieve this function at the interface between cytoplasmic and nuclear compartments of the host infected cell without localization into the nucleus.…”

Section: Iav Ns1 and Sars-cov-2 Nsp1 Post-translational Modifications...mentioning

confidence: 99%

Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1

Khalil,

Nogales,

Martínez-Sobrido

et al. 2024

Front. Cell. Infect. Microbiol.

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Following virus recognition of host cell receptors and viral particle/genome internalization, viruses replicate in the host via hijacking essential host cell machinery components to evade the provoked antiviral innate immunity against the invading pathogen. Respiratory viral infections are usually acute with the ability to activate pattern recognition receptors (PRRs) in/on host cells, resulting in the production and release of interferons (IFNs), proinflammatory cytokines, chemokines, and IFN-stimulated genes (ISGs) to reduce virus fitness and mitigate infection. Nevertheless, the game between viruses and the host is a complicated and dynamic process, in which they restrict each other via specific factors to maintain their own advantages and win this game. The primary role of the non-structural protein 1 (NS1 and Nsp1) of influenza A viruses (IAV) and the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively, is to control antiviral host-induced innate immune responses. This review provides a comprehensive overview of the genesis, spatial structure, viral and cellular interactors, and the mechanisms underlying the unique biological functions of IAV NS1 and SARS-CoV-2 Nsp1 in infected host cells. We also highlight the role of both non-structural proteins in modulating viral replication and pathogenicity. Eventually, and because of their important role during viral infection, we also describe their promising potential as targets for antiviral therapy and the development of live attenuated vaccines (LAV). Conclusively, both IAV NS1 and SARS-CoV-2 Nsp1 play an important role in virus–host interactions, viral replication, and pathogenesis, and pave the way to develop novel prophylactic and/or therapeutic interventions for the treatment of these important human respiratory viral pathogens.

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SARS-CoV2 Nsp1 is a metal-dependent DNA and RNA endonuclease

Salgueiro,

Saramago,

Tully

et al. 2024

Biometals

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Over recent years, we have been living under a pandemic, caused by the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). One of the major virulence factors of Coronaviruses is the Non-structural protein 1 (Nsp1), known to suppress the host cells protein translation machinery, allowing the virus to produce its own proteins, propagate and invade new cells. To unveil the molecular mechanisms of SARS-CoV2 Nsp1, we have addressed its biochemical and biophysical properties in the presence of calcium, magnesium and manganese. Our findings indicate that the protein in solution is a monomer and binds to both manganese and calcium, with high affinity. Surprisingly, our results show that SARS-CoV2 Nsp1 alone displays metal-dependent endonucleolytic activity towards both RNA and DNA, regardless of the presence of host ribosome. These results show Nsp1 as new nuclease within the coronavirus family. Furthermore, the Nsp1 double variant R124A/K125A presents no nuclease activity for RNA, although it retains activity for DNA, suggesting distinct binding sites for DNA and RNA. Thus, we present for the first time, evidence that the activities of Nsp1 are modulated by the presence of different metals, which are proposed to play an important role during viral infection. This research contributes significantly to our understanding of the mechanisms of action of Coronaviruses.

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Structural basis for translation inhibition by MERS-CoV Nsp1 reveals a conserved mechanism for betacoronaviruses

Cited by 6 publications

References 49 publications

The art of hijacking: how Nsp1 impacts host gene expression during coronaviral infections

The art of hijacking: how Nsp1 impacts host gene expression during coronaviral infections

Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1

SARS-CoV2 Nsp1 is a metal-dependent DNA and RNA endonuclease

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