scholarly journals Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

2021 ◽  
Vol 7 (6) ◽  
pp. eabe7386 ◽  
Author(s):  
Ke Zhang ◽  
Lisa Miorin ◽  
Tadashi Makio ◽  
Ishmael Dehghan ◽  
Shengyan Gao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Export ◽  
Messenger Rna ◽  
Mrna Export ◽  
Host Gene ◽  
Nuclear Pore ◽  
Host Gene Expression ◽  
Host Interactions ◽  
Inhibitory Function ◽  
Cellular Mrnas

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.

scholarly journals Distinct Basket Nucleoporins roles in Nuclear Pore Function and Gene Expression: Tpr is an integral component of the TREX-2 mRNA export pathway

2019 ◽  
Author(s):  
Vasilisa Aksenova ◽  
Hang Noh Lee ◽  
Alexandra Smith ◽  
Shane Chen ◽  
Prasanna Bhat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Export ◽  
Protein Modification ◽  
Mrna Export ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Nucleocytoplasmic Trafficking ◽  
Pore Complexes ◽  
Slow Turnover

AbstractNuclear pore complexes (NPCs) are important for many processes beyond nucleocytoplasmic trafficking, including protein modification, chromatin remodeling, transcription, mRNA processing and mRNA export. The multi-faceted nature of NPCs and the slow turnover of their components has made it difficult to understand the role of basket nucleoporins (Nup153, Nup50 and Tpr) in these diverse processes. To address this question, we used anAuxin-InducedDegron (AID) system to distinguish roles of basket nucleoporins: Loss of individual nucleoporins caused distinct alteration in patterns of nucleocytoplasmic trafficking and gene expression. Importantly, Tpr elimination caused rapid and pronounced changes in transcriptomic profiles within two hours of auxin addition. These changes were dissimilar to shifts observed after loss of Nup153 or Nup50, but closely related to changes after depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. Moreover, GANP association to NPCs was specifically disrupted upon TPR depletion. Together, our findings demonstrate a unique and pivotal role of Tpr in regulating gene expression through GANP- and/or NXF1-dependent mRNA nuclear export.

scholarly journals The Great Escape: mRNA Export through the Nuclear Pore Complex

2021 ◽  
Vol 22 (21) ◽  
pp. 11767
Author(s):  
Paola De Magistris
Keyword(s):  
Conformational Changes ◽  
Nuclear Pore Complex ◽  
Nuclear Export ◽  
Messenger Rna ◽  
Mrna Export ◽  
Protein Translation ◽  
Nuclear Pore ◽  
Body Of Knowledge ◽  
Transport Receptors ◽  
Basic Characteristics

Nuclear export of messenger RNA (mRNA) through the nuclear pore complex (NPC) is an indispensable step to ensure protein translation in the cytoplasm of eukaryotic cells. mRNA is not translocated on its own, but it forms ribonuclear particles (mRNPs) in association with proteins that are crucial for its metabolism, some of which; like Mex67/MTR2-NXF1/NXT1; are key players for its translocation to the cytoplasm. In this review, I will summarize our current body of knowledge on the basic characteristics of mRNA export through the NPC. To be granted passage, the mRNP cargo needs to bind transport receptors, which facilitate the nuclear export. During NPC transport, mRNPs undergo compositional and conformational changes. The interactions between mRNP and the central channel of NPC are described; together with the multiple quality control steps that mRNPs undergo at the different rings of the NPC to ensure only proper export of mature transcripts to the cytoplasm. I conclude by mentioning new opportunities that arise from bottom up approaches for a mechanistic understanding of nuclear export.

scholarly journals Nuclear Pore Complex Acetylation Regulates mRNA Export and Cell Cycle Commitment in Budding Yeast

2021 ◽  
Author(s):  
Mercè Gomar-Alba ◽  
Vasilisa Pozharskaia ◽  
Celia Schaal ◽  
Arun Kumar ◽  
Basile Jacquel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Export ◽  
Mrna Export ◽  
Cell Types ◽  
Nuclear Pore ◽  
Specific Cell ◽  
Nuclear Pore Complexes ◽  
Daughter Cells ◽  
Associated Proteins ◽  
Pore Complexes

AbstractNuclear pore complexes (NPCs) mediate communication between the nucleus and the cytoplasm and regulate gene expression by interacting with transcription and mRNA export factors. Lysine acetyl-transferases (KATs) promote transcription through acetylation of chromatin-associated proteins. We find that Esa1, the KAT subunit of the yeast NuA4 complex, also acetylates the nuclear pore basket component Nup60 to promote mRNA export. Acetylation of Nup60 recruits mRNA export factors to the nuclear basket, including the scaffolding subunit of the Transcription and Export 2 (TREX-2) complex, Sac3. Esa1-dependent nuclear export of mRNAs promotes entry into S phase, and is inhibited by the Hos3 deacetylase in G1 daughter cells to restrain their premature commitment to a new cell division cycle. This mechanism also inhibits expression of the nutrient-regulated GAL1 gene specifically in daughter cells. These results reveal how acetylation contributes to the functional plasticity of NPCs in specific cell types, and demonstrate how the evolutionarily conserved NuA4 complex regulates gene expression dually at the level of transcription and mRNA export, by modifying the nucleoplasmic entrance to nuclear pores.

SARS coronavirus protein nsp1 disrupts localization of Nup93 from the nuclear pore complex

2019 ◽  
Vol 97 (6) ◽  
pp. 758-766 ◽  
Author(s):  
Garret N. Gomez ◽  
Fareeha Abrar ◽  
Maya P. Dodhia ◽  
Fabiola G. Gonzalez ◽  
Anita Nag
Keyword(s):  
Gene Expression ◽  
Nuclear Pore Complex ◽  
Rna Binding ◽  
Nonstructural Protein ◽  
Nuclear Lamina ◽  
Host Gene ◽  
Nuclear Pore ◽  
Host Gene Expression ◽  
Nonstructural Protein 1 ◽  
Cytoplasmic Transport

Severe acute respiratory syndrome coronavirus nonstructural protein 1 (nsp1) is a key factor in virus-induced down-regulation of host gene expression. In infected cells, nsp1 engages in a multipronged mechanism to inhibit host gene expression by binding to the 40S ribosome to block the assembly of translationally competent ribosome, and then inducing endonucleolytic cleavage and the degradation of host mRNAs. Here, we report a previously undetected mechanism by which nsp1 exploits the nuclear pore complex and disrupts the nuclear–cytoplasmic transport of biomolecules. We identified members of the nuclear pore complex from the nsp1-associated protein assembly and found that the expression of nsp1 in HEK cells disrupts Nup93 localization around the nuclear envelope without triggering proteolytic degradation, while the nuclear lamina remains unperturbed. Consistent with its role in host shutoff, nsp1 alters the nuclear–cytoplasmic distribution of an RNA binding protein, nucleolin. Our results suggest that nsp1, alone, can regulate multiple steps of gene expression including nuclear–cytoplasmic transport.

Host gene expression profiling in pathogen–host interactions

2006 ◽  
Vol 18 (4) ◽  
pp. 422-429 ◽  
Author(s):  
Hamid Hossain ◽  
Svetlin Tchatalbachev ◽  
Trinad Chakraborty
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Host Gene ◽  
Host Gene Expression ◽  
Host Interactions

scholarly journals Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

2017 ◽  
Author(s):  
Mandy Muller ◽  
Britt A. Glaunsinger
Keyword(s):  
Gene Expression ◽  
Messenger Rna ◽  
Rna Binding ◽  
Regulatory Element ◽  
Mrna Degradation ◽  
Host Gene ◽  
Host Gene Expression ◽  
Kshv Infection ◽  
Ribonucleoprotein Complexes ◽  
Rna Elements

ABSTRACTDuring lytic Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, the viral endonu-clease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3’ UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.AUTHOR SUMMARYThe ability of viruses to control the host gene expression environment is crucial to promote viral infection. Many viruses express factors that reduce host gene expression through widespread mRNA decay. However, some mRNAs escape this fate, like the transcript encoding the immunoregulatory cytokine IL-6 during KSHV infection. IL-6 escape relies on an RNA regulatory element located in its 3’UTR and involves the recruitment of a protective protein complex. Here, we show that this escape extends beyond KSHV to a variety of related and unrelated viral endonucleases. However, the IL-6 element does not protect against cellular endonucleases, revealing for the first time a virus-specific nuclease escape element. We identified a related escape element in the GADD45B mRNA, which displays several similarities with the IL-6 element. However, these elements assemble a largely distinct complex of proteins, leading to differences in the breadth of their protective capacity. Collectively, these findings reveal how a putative new class of RNA elements function to control RNA fate in the background of widespread mRNA degradation by viral endonucleases.

scholarly journals Rhinovirus 2A is the predominant protease responsible for instigating the early block to gene expression encountered in infected cells

2019 ◽  
Author(s):  
David Smart ◽  
Irene Filippi ◽  
Benjamin Smalley ◽  
Donna Davies ◽  
Christopher J. McCormick
Keyword(s):  
Gene Expression ◽  
Nuclear Export ◽  
Cysteine Proteases ◽  
Host Gene ◽  
Host Gene Expression ◽  
Reporter System ◽  
Host Cell Response ◽  
Relative Contribution ◽  
Individual Ability ◽  
Viral Polyprotein

AbstractHuman rhinoviruses express 2 cysteine proteases, 2A and 3C, that are responsible for viral polyprotein processing. Both proteases also suppress host gene expression by inhibiting mRNA transcription, nuclear export and cap-dependent translation. However, the relative contribution that each makes in achieving this goal remains unclear. In this study we have compared both the combined and individual ability of the 2 proteases to shut downin cellulogene expression using a novel dynamic reporter system. Our findings show that 2A inhibits host gene expression much more rapidly than 3C. By comparing the activities of a representative set of proteases from the three different Human Rhinovirus (HRV) species, we also find variation in the speed at which host gene expression is suppressed. Our work highlights the key role that 2A plays in early suppression of the infected host cell response and shows that this can be influenced by natural variation in the activity of this enzyme.

scholarly journals Formation of Tap/NXT1 Heterodimers Activates Tap-Dependent Nuclear mRNA Export by Enhancing Recruitment to Nuclear Pore Complexes

2002 ◽  
Vol 22 (1) ◽  
pp. 245-256 ◽  
Author(s):  
Heather L. Wiegand ◽  
Glen A. Coburn ◽  
Yan Zeng ◽  
Yibin Kang ◽  
Hal P. Bogerd ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Mrna Export ◽  
Nuclear Accumulation ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Protein Functions ◽  
Cellular Mrnas ◽  
Pore Complexes

ABSTRACT The Tap protein has been shown to activate the nuclear export of mRNA species bearing retroviral constitutive transport elements and is also believed to play an essential role in the sequence nonspecific export of cellular mRNAs. However, it has remained unclear how Tap activity is regulated in vivo. Here, we report that the small NXT1/p15-1 protein functions as a critical cofactor for Tap-mediated mRNA export in both human and invertebrate cells. In the absence of NXT1 binding, the Tap protein is unable to effectively interact with components of the nuclear pore complex and both Tap nucleocytoplasmic shuttling and the nuclear export of mRNA molecules tethered to Tap are therefore severely attenuated. Formation of a Tap/NXT1 heterodimer enhances nucleoporin binding both in vitro and in vivo and induces the formation of a Tap/NXT1/nucleoporin ternary complex that is likely to be a key intermediate in the process of nuclear mRNA export. The critical importance of NXT1 for the nuclear export of poly(A)+ RNA is emphasized by the finding that specific inhibition of the expression of the Drosophila homolog of human NXT1, by using RNA interference, results in the nuclear accumulation of poly(A)+ RNA in cultured insect cells. These data suggest that NXT1 may act as a molecular switch that regulates the ability of Tap to mediate nuclear mRNA export by controlling the interaction of Tap with components of the nuclear pore.

scholarly journals Inhibition of Host Gene Expression by KSHV: Sabotaging mRNA Stability and Nuclear Export

2021 ◽  
Vol 11 ◽  
Author(s):  
Carissa Ikka Pardamean ◽  
Ting-Ting Wu
Keyword(s):  
Gene Expression ◽  
Nuclear Export ◽  
Kaposi Sarcoma ◽  
Open Reading Frame ◽  
Host Gene ◽  
Host Gene Expression ◽  
Direct Function ◽  
Reading Frame ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68

Viruses are known for their ability to alter host gene expression. Kaposi sarcoma-associated herpesvirus has two proteins that obstruct host gene expression. KSHV SOX, encoded by the open reading frame 37 (ORF37), induces a widespread cytoplasmic mRNA degradation and a block on mRNA nuclear export. The other KSHV protein, encoded by the open reading frame 10 (ORF10), was recently identified to inhibit host gene expression through its direct function on the cellular mRNA export pathway. In this review, we summarize the studies on both SOX and ORF10 in efforts to elucidate their mechanisms. We also discuss how the findings based on a closely related rodent virus, murine gammaherpesvirus-68 (MHV-68), complement the KSHV findings to decipher the role of these two proteins in viral pathogenesis.

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