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1.
J Biol Chem ; 297(1): 100856, 2021 07.
Article in English | MEDLINE | ID: covidwho-1283409

ABSTRACT

The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.


Subject(s)
Immunity, Innate/genetics , Nuclear Pore Complex Proteins/genetics , Nuclear Pore/genetics , Virus Diseases/genetics , Active Transport, Cell Nucleus/genetics , Active Transport, Cell Nucleus/immunology , DNA Viruses/genetics , DNA Viruses/pathogenicity , Humans , Immune Evasion/genetics , Immune Evasion/immunology , NF-kappa B/genetics , Nuclear Pore/immunology , Nuclear Pore Complex Proteins/immunology , RNA Viruses/genetics , RNA Viruses/pathogenicity , Viral Nonstructural Proteins/genetics , Virus Diseases/immunology , Virus Diseases/virology , Virus Replication/genetics , Virus Replication/immunology
2.
PLoS One ; 16(6): e0253089, 2021.
Article in English | MEDLINE | ID: covidwho-1282298

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic, infecting over 43 million people and claiming over 1 million lives, with these numbers increasing daily. Therefore, there is urgent need to understand the molecular mechanisms governing SARS-CoV-2 pathogenesis, immune evasion, and disease progression. Here, we show that SARS-CoV-2 can block IRF3 and NF-κB activation early during virus infection. We also identify that the SARS-CoV-2 viral proteins NSP1 and NSP13 can block interferon activation via distinct mechanisms. NSP1 antagonizes interferon signaling by suppressing host mRNA translation, while NSP13 downregulates interferon and NF-κB promoter signaling by limiting TBK1 and IRF3 activation, as phospho-TBK1 and phospho-IRF3 protein levels are reduced with increasing levels of NSP13 protein expression. NSP13 can also reduce NF-κB activation by both limiting NF-κB phosphorylation and nuclear translocation. Last, we also show that NSP13 binds to TBK1 and downregulates IFIT1 protein expression. Collectively, these data illustrate that SARS-CoV-2 bypasses multiple innate immune activation pathways through distinct mechanisms.


Subject(s)
Adaptor Proteins, Signal Transducing/immunology , COVID-19/immunology , Cell Nucleus/immunology , Interferon Regulatory Factor-3/immunology , RNA-Binding Proteins/immunology , SARS-CoV-2/immunology , Signal Transduction/immunology , Viral Nonstructural Proteins/immunology , Active Transport, Cell Nucleus/genetics , Active Transport, Cell Nucleus/immunology , Adaptor Proteins, Signal Transducing/genetics , COVID-19/genetics , Cell Nucleus/genetics , HeLa Cells , Humans , Interferon Regulatory Factor-3/genetics , NF-kappa B/genetics , NF-kappa B/immunology , Phosphorylation/genetics , Phosphorylation/immunology , /immunology , RNA-Binding Proteins/genetics , SARS-CoV-2/genetics , Signal Transduction/genetics , Viral Nonstructural Proteins/genetics
3.
Sci Adv ; 7(6)2021 02.
Article in English | MEDLINE | ID: covidwho-1066794

ABSTRACT

The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells.


Subject(s)
COVID-19/metabolism , Gene Expression , Host Microbial Interactions/genetics , RNA, Messenger/metabolism , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/metabolism , Virulence Factors/metabolism , Active Transport, Cell Nucleus/genetics , Animals , COVID-19/virology , Chlorocebus aethiops , HEK293 Cells , Humans , Nuclear Pore/metabolism , Nucleocytoplasmic Transport Proteins/genetics , Nucleocytoplasmic Transport Proteins/metabolism , RNA, Messenger/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , SARS-CoV-2/chemistry , Transfection , Vero Cells , Viral Nonstructural Proteins/genetics
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