scholarly journals Interplay of host regulatory network on SARS-CoV-2 binding and replication machinery

2020 ◽  
Author(s):  
Shiek SSJ Ahmed ◽  
Prabu Paramasivam ◽  
Kamal Raj ◽  
Vishal Kumar ◽  
Ram murugesan ◽  
...  
Keyword(s):  
Viral Replication ◽  
Intermediate Phase ◽  
Receptor Activation ◽  
Host Protein ◽  
Replication Machinery ◽  
Replication Process ◽  
Infection Pattern ◽  
Protein Interactome ◽  
Signaling Process

AbstractWe dissect the mechanism of SARS-CoV-2 in human lung host from the initial phase of receptor binding to viral replication machinery. We constructed two independent lung protein interactome to reveal the signaling process on receptor activation and host protein hijacking machinery in the pathogenesis of virus. Further, we test the functional role of the hubs derived from both interactome. Most hubs proteins were differentially regulated on SARS-CoV-2 infection. Also, the proteins of viral replication hubs were related with cardiovascular disease, diabetes and hypertension confirming the vulnerability and severity of infection in the risk individual. Additionally, the hub proteins were closely linked with other viral infection, including MERS and HCoVs which suggest similar infection pattern in SARS-CoV-2. We identified five interconnecting cascades between hubs of both networks that show the preparation of optimal environment in the host for viral replication process upon receptor attachment. Interestingly, we propose that seven potential miRNAs, targeting the intermediate phase that connects receptor and viral replication process a better choice as a drug for SARS-CoV-2.

scholarly journals Noroviruses Co-opt the Function of Host Proteins VAPA and VAPB for Replication via a Phenylalanine–Phenylalanine-Acidic-Tract-Motif Mimic in Nonstructural Viral Protein NS1/2

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Broc T. McCune ◽  
Wei Tang ◽  
Jia Lu ◽  
James B. Eaglesham ◽  
Lucy Thorne ◽  
...  
Keyword(s):  
Viral Replication ◽  
Function Analysis ◽  
Nonstructural Protein ◽  
Host Protein ◽  
Murine Norovirus ◽  
Human Pathogens ◽  
Host Proteins ◽  
Human Noroviruses ◽  
Murine Noroviruses

ABSTRACT The Norovirus genus contains important human pathogens, but the role of host pathways in norovirus replication is largely unknown. Murine noroviruses provide the opportunity to study norovirus replication in cell culture and in small animals. The human norovirus nonstructural protein NS1/2 interacts with the host protein VAMP-associated protein A (VAPA), but the significance of the NS1/2-VAPA interaction is unexplored. Here we report decreased murine norovirus replication in VAPA- and VAPB-deficient cells. We characterized the role of VAPA in detail. VAPA was required for the efficiency of a step(s) in the viral replication cycle after entry of viral RNA into the cytoplasm but before the synthesis of viral minus-sense RNA. The interaction of VAPA with viral NS1/2 proteins is conserved between murine and human noroviruses. Murine norovirus NS1/2 directly bound the major sperm protein (MSP) domain of VAPA through its NS1 domain. Mutations within NS1 that disrupted interaction with VAPA inhibited viral replication. Structural analysis revealed that the viral NS1 domain contains a mimic of the phenylalanine–phenylalanine-acidic-tract (FFAT) motif that enables host proteins to bind to the VAPA MSP domain. The NS1/2-FFAT mimic region interacted with the VAPA-MSP domain in a manner similar to that seen with bona fide host FFAT motifs. Amino acids in the FFAT mimic region of the NS1 domain that are important for viral replication are highly conserved across murine norovirus strains. Thus, VAPA interaction with a norovirus protein that functionally mimics host FFAT motifs is important for murine norovirus replication. IMPORTANCE Human noroviruses are a leading cause of gastroenteritis worldwide, but host factors involved in norovirus replication are incompletely understood. Murine noroviruses have been studied to define mechanisms of norovirus replication. Here we defined the importance of the interaction between the hitherto poorly studied NS1/2 norovirus protein and the VAPA host protein. The NS1/2-VAPA interaction is conserved between murine and human noroviruses and was important for early steps in murine norovirus replication. Using structure-function analysis, we found that NS1/2 contains a short sequence that molecularly mimics the FFAT motif that is found in multiple host proteins that bind VAPA. This represents to our knowledge the first example of functionally important mimicry of a host FFAT motif by a microbial protein.

scholarly journals SIRT5 is a proviral factor that interacts with SARS-CoV-2 Nsp14 protein

2022 ◽  
Author(s):  
Marius Walter ◽  
Irene P Chen ◽  
Albert Vallejo-Gracia ◽  
Ik-Jung Kim ◽  
Olga Bielska ◽  
...  
Keyword(s):  
Viral Replication ◽  
Catalytic Domain ◽  
Therapeutic Interventions ◽  
Stable Complex ◽  
Structural Protein ◽  
Knock Out ◽  
Protein Interactome ◽  
Lysine Residues ◽  
Dependent Protein

SARS-CoV-2 non-structural protein Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities. Protein-interactome studies identified human sirtuin 5 (SIRT5) as a putative binding partner of Nsp14. SIRT5 is an NAD-dependent protein deacylase critical for cellular metabolism that removes succinyl and malonyl groups from lysine residues. Here we investigated the nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection. We showed that SIRT5 stably interacts with Nsp14, but not with Nsp10, suggesting that SIRT5 and Nsp10 are parts of separate complexes. We found that SIRT5 catalytic domain is necessary for the interaction with Nsp14, but that Nsp14 does not appear to be directly deacylated by SIRT5. Furthermore, knock-out of SIRT5 or treatment with specific SIRT5 inhibitors reduced SARS-CoV-2 viral levels in cell-culture experiments. SIRT5 knock-out cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication, which opens novel avenues for therapeutic interventions.

scholarly journals Multiscale fragPIN Modularity

ISRN Genomics ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-10
Author(s):  
Enrico Capobianco
Keyword(s):  
Systems Biology ◽  
Comparative Assessment ◽  
Biological Processes ◽  
Central Theme ◽  
Topological Properties ◽  
Resolution Limit ◽  
Protein Interactome ◽  
Fluctuation Dynamics ◽  
Signaling Process

Modularity in protein interactome networks (PINs) is a central theme involving aspects such as the study of the resolution limit, the comparative assessment of module-finding algorithms, and the role of data integration in systems biology. It is less common to study the relationships between the topological hierarchies embedded within the same network. This occurrence is not unusual, in particular with PINs that are considered assemblies of various interactions depending on specialized biological processes. The integrated view offered so far by modularity maps represents in general a synthesis of a variety of possible interaction maps, each reflecting a certain biological level of specialization. The driving hypothesis of this work leverages on such network components. Therefore, subnetworks are generated from fragmentation, a process aimed to isolating parts of a common network source that are here called fragments, from which the acronym fragPIN is used. The characteristics of modularity in each obtained fragPIN are elucidated and compared. Finally, as it was hypothesized that different timescales may underlie the biological processes from which the fragments are computed, the analysis was centered on an example involving the fluctuation dynamics inherent to the signaling process and was aimed to show how timescales can be identified from such dynamics, in particular assigning the interactions based on selected topological properties.

scholarly journals Electrical induction hypothesis to explain enhancer-promoter communication

2015 ◽  
Author(s):  
Valentina Agoni
Keyword(s):  
Transcription Factors ◽  
Dna Replication ◽  
Induction Hypothesis ◽  
Unsolved Problem ◽  
Specific Binding ◽  
Replication Machinery ◽  
Replication Process ◽  
Electrical Induction ◽  
Binding Sequence

The steps of the DNA replication process remains to be clarified. Transcription factors are supposed to find their specific binding-sequence driven by epigenetic modifications and GpC islands. But then how can the replication machinery be able to find the promoters of exactly the genes that the cell needs to transcribe in that moment? Here we hypothesize a role of DNA conductance and electrical induction to give an explanation to this unsolved problem. Our hypothesis goes in accordance with the fact that many authors identified 3D loops in the genomes.

scholarly journals Mapping the host protein interactome of non-coding regions in SARS-CoV-2 genome

2021 ◽  
Author(s):  
Liuyiqi Jiang ◽  
Mu Xiao ◽  
Qing-Qing Liao ◽  
Luqian Zheng ◽  
Chunyan Li ◽  
...  
Keyword(s):  
Cell Lines ◽  
Protein Translation ◽  
Host Protein ◽  
Cell Type ◽  
Host Interactions ◽  
Coding Regions ◽  
Protein Interactome ◽  
Cell Type Specific ◽  
Negative Sense

A deep understanding of SARS-CoV-2-host interactions is crucial to the development of effective therapeutics. The role of non-coding regions of viral RNA (ncrRNAs) has not been scrutinized. We developed a method using MS2 affinity purification coupled with liquid chromatography-mass spectrometry (MAMS) to systematically map the interactome of SARS-CoV-2 ncrRNA in different human cell lines. Integration of the results defined the core and cell-type-specific ncrRNA-host protein interactomes. The majority of ncrRNA-binding proteins were involved in RNA biogenesis, protein translation, viral infection, and stress response. The 5′ UTR interactome is enriched with proteins in the snRNP family and is a target for the regulation of viral replication and transcription. The 3′ UTR interactome is enriched with proteins involved in the cytoplasmic RNP granule (stress granule) and translation regulation. We show that the ORF10 is likely to be a part of 3′ UTR. Intriguingly, the interactions between negative-sense ncrRNAs and host proteins, such as translation initiation factors and antiviral factors, suggest a pathological role of negative-sense ncrRNAs. Moreover, the cell-type-specific interactions between ncrRNAs and mitochondria may explain the differences of cell lines in viral susceptibility. Our study unveils a comprehensive landscape of the functional SARS-CoV-2 ncrRNA-host protein interactome, providing a new perspective on virus-host interactions and the design of future therapeutics.

scholarly journals Electrical induction hypothesis to explain enhancer-promoter communication

2015 ◽  
Author(s):  
Valentina Agoni
Keyword(s):  
Transcription Factors ◽  
Dna Replication ◽  
Induction Hypothesis ◽  
Unsolved Problem ◽  
Specific Binding ◽  
Replication Machinery ◽  
Replication Process ◽  
Electrical Induction ◽  
Binding Sequence

The steps of the DNA replication process remains to be clarified. Transcription factors are supposed to find their specific binding-sequence driven by epigenetic modifications and GpC islands. But then how can the replication machinery be able to find the promoters of exactly the genes that the cell needs to transcribe in that moment? Here we hypothesize a role of DNA conductance and electrical induction to give an explanation to this unsolved problem. Our hypothesis goes in accordance with the fact that many authors identified 3D loops in the genomes.

scholarly journals Enhanced Production of the Mical Redox Domain for Enzymology and F-actin Disassembly Assays

2021 ◽  
Vol 22 (4) ◽  
pp. 1991
Author(s):  
Jimok Yoon ◽  
Heng Wu ◽  
Ruei-Jiun Hung ◽  
Jonathan R. Terman
Keyword(s):  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Actin Dynamics ◽  
Specific Substrate ◽  
Actin Assembly ◽  
Redox Enzymes ◽  
Enhanced Production ◽  
Reversible Redox ◽  
Future Work ◽  
Signaling Process

To change their behaviors, cells require actin proteins to assemble together into long polymers/filaments—and so a critical goal is to understand the factors that control this actin filament (F-actin) assembly and stability. We have identified a family of unusual actin regulators, the MICALs, which are flavoprotein monooxygenase/hydroxylase enzymes that associate with flavin adenine dinucleotide (FAD) and use the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH) in Redox reactions. F-actin is a specific substrate for these MICAL Redox enzymes, which oxidize specific amino acids within actin to destabilize actin filaments. Furthermore, this MICAL-catalyzed reaction is reversed by another family of Redox enzymes (SelR/MsrB enzymes)—thereby revealing a reversible Redox signaling process and biochemical mechanism regulating actin dynamics. Interestingly, in addition to the MICALs’ Redox enzymatic portion through which MICALs covalently modify and affect actin, MICALs have multiple other domains. Less is known about the roles of these other MICAL domains. Here we provide approaches for obtaining high levels of recombinant protein for the Redox only portion of Mical and demonstrate its catalytic and F-actin disassembly activity. These results provide a ground state for future work aimed at defining the role of the other domains of Mical — including characterizing their effects on Mical’s Redox enzymatic and F-actin disassembly activity.

scholarly journals An autoantibody directed against human thrombin anion-binding exosite in a patient with arterial thrombosis: effects on platelets, endothelial cells, and protein C activation

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1843-1850 ◽  
Author(s):  
E Arnaud ◽  
M Lafay ◽  
P Gaussem ◽  
V Picard ◽  
M Jandrot-Perrus ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Receptor Activation ◽  
Anion Binding ◽  
Thrombin Receptor ◽  
Cell Functions ◽  
Human Thrombin

Abstract An autoantibody, developed by a patient with severe and recurrent arterial thrombosis, was characterized to be directed against the anion- binding exosite of thrombin, and inhibited all thrombin interactions requiring this secondary binding site without interfering with the catalytic site. The effect of the antibody was studied on thrombin interactions with platelets and endothelial cells from human umbilical veins (HUVEC). The autoantibody specifically and concentration- dependently inhibited alpha-thrombin-induced platelet activation and prostacyclin (PGI2) synthesis from HUVEC. It had no effect when gamma- thrombin or the thrombin receptor activation peptide SFLLR were the inducers. The effect of the antibody on protein C activation has been studied. The antibody blocked the thrombin-thrombomodulin activation of protein C. The inhibition of the activation was maximal with a low concentration of thrombomodulin. The fact that the autoantibody inhibited concentration-dependent alpha-thrombin-induced platelet and endothelial cell functions emphasizes the crucial role of the anion- binding exosite of thrombin to activate its receptor. In regard to the pathology, the antibody inhibited two vascular processes implicated in thrombin-antithrombotic functions, PGI2 secretion, and protein C activation, which could be implicated in this arterial thrombotic disease.

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