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# SARS CoV-2 E protein mechanisms
## Map description
This map focuses on interaction mechanisms between Envelope (E) protein and host proteins in different pathways. To allow a more detailed description of every possible phenotypes, E protein of both SARS-CoV-2 and SARS-CoV were used to built this diagram. In fact, E proteins (ORF4) from SARS CoV and SARS CoV-2 had a sequence identity 94.7% [10.1007/s10930-020-09901-4]. The activity of E protein was described in two compartments: in the nucleus and on plasmatic membrane. In the nucleus, strong inhibiting interactions were described between E protein with bromodomain proteins, BRD2 and BRD4 [10.1038/s41586-020-2286-9]. both bromodomain proteins were associated with acetylating of H3C15 histone protein to modulate chromatin accessibility [10.1038/nsmb.3228.; 10.1016/j.molcel.2008.01.018]. Moreover BRD4 plays an important role in the transcription, activating P-TEFb complex (Cyclin T1: CDK9) that phosphoriles RNA polymerase II [10.1038/emboj.2008.121]. On other hand, BRD2 allows to activate the TBP, transcription factor that start the gene transcription [10.1007/s11010-006-9223-6]. The inhibiting activity of E protein could acted negatively on c ell responce against viral infection.
On plasmatic membrane, the E protein interacts with PALS1 of human epithelial cells during SARS-CoV infection [10.1091/mbc.E10–04–0338]. PALS1 represents one of components of CRB3–Pals1–PATJ complex, the second major cell polarity protein complex at Tight Junctions [10.1146/annurev.cellbio.22.010305.104219]. Loss of PALS1 and the disruption of Tight Junctions allowed the progressive infiltration of SARS-CoV virions [10.1091/mbc.E10–04–0338]. Finally, E protein interacted negatively with two proteins involved in maintaining ionic homeostasis, Na+/K+ ATPase α-1 subunit and STOML3, which could reduce levels and activity of human epithelial sodium channels [10.1016/j.virol.2011.03.029].
## Cross-talk with other pathways (in the map, and in general)
Up to now, E protein involved following pathways: Chromatin organization, Gene transcription, Cell junction and Ion transport. In Apoptosis map reported in COVID19 Disease Maps, an important inhibiting interaction between anti-apoptotic protein B-cell lymphoma-extra-large (Bcl-xL) protein and E protein has been reported [10.1042/BJ20050698]. This inhibiting, enhanced by ORF7a, allows to activate Bax pathways inducing apoptotic cell death. Other diagram, where E protein plays a important role, is viral replication cycle. This diagram explained many steps of viral replication cycle, where E protein involved [10.1002/jmv.25693; 10.1080/22221751.2020.1719902].
## Creators
[Francesco Messina](https://fairdomhub.org/people/1592)
## Contributors and reviewers
[Francesco Nicola Lauria](https://fairdomhub.org/people/1593)
[Emanuela Giombini](https://fairdomhub.org/people/1588)
## Model at FairdomHub (https://fairdomhub.org/models/721)
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# SARS-CoV-2 Orf3a protein interactions
## Map description
ORF3a is the largest of the SARS-CoV accessory proteins at 274 amino acids in length with a native molecular weight of 31 kDa[1]. Orf3a with HOPS complex modify endomembrane compartments to favor coronavirus replication[2]IRF3, IL1A and TNFRSF1A receptor complex activate another complex which is containing IKBKG, IKBKB, and CHUK. For the activation of ininflammasome SARS-CoV unregulated the expression of pro-IL-1β transcription the result NF-κB activates. Two mechanisms introduce firstly Orf3a, and E proteins, leading to NLRP3 inflammasome assembly. ORF3a promotes ASC ubiquitination and consequent assembly of inflammasome. Second Orf8b interacts activates NLRP3 leads to proteolytic cleavage of pro-caspase 1 and pro-IL-1β[3]. TRAF3 also play a vital role to activate ininflammasome Orf3a interacts with TRAF3 to activate NF-kB, resulting in transcription of IL-1b. ORF3a interacts with TRAF3 to promote ASC ubiquitination, leading to activation of caspase 1 and IL-1b [4].TRIM59 regulate antiviral innate immune signaling and are usurped by Orf3a. TRIM59 negatively regulates NF-κB and IRF-3/7-mediated signal pathways[2]. TRAF6, activating protein (TAB) 2/3 recruits the critical kinase TAK1 to enable the active of NF-_kB essential modulator , the regulatory domain of inhibitor of NF-kB . Tripartite motifs (TRIMs) play an integral role in the positive and negative regulation of antiviral pathways[5].
## Cross-talk with other pathways
Trim59 pathway cross talk with other TRIM pathways used to inhibit the Nf-kb response in Orf3a COVID-19 Disease map.
TLR3, 7, 8 and 9, detect viral RNA and DNA in the endosome, whereas RLRs bind to viral RNA in the cytoplasm[6]. TLR7, TLR8 and TLR9, induces antiviral responses by producing interferon-α (IFN-α). Production of IFN-α is dependent on the Toll–interleukin-1 receptor domain–containing adaptor MyD88.[7] TRAF3 is required for TRIF-dependent activation. Internalized TLR4 recruits TRAF3 and TRAF6 to active endosomes via TRIF. TRAF6 mediates MyD88- and TRIF-induced activation of NF-κB1. TRAF6 bind to TAB2/3 to activate to NEMO to activate IKKα/β in the receptor complex[8]. TRIM23 knockdown decreased IFNβ production with SV infection in the cell.TRIM23-NEMO complexes is important for antiviral responses[9]. TRIM38 as a negative feedback regulator for TLR-induced production of proinflammatory cytokines by targeting TRAF6[10]. TRIM30α promoted the degradation of TAB2 and TAB3 and inhibited NF-κB activation induced by TLR signaling[11]. TRIM29 inhibited interferon-regulatory factors and signaling via the transcription factor NF-κB by degrading the adaptor NEMO and that TRIM29 directly bound NEMO and subsequently induced its ubiquitination and proteolytic degradation[12]. TRIM22 inhibits Tab2/3 complex independently of its E3 ubiquitin ligase activity and NF-κB responsive long terminal repeat elements[13]. TRIM27 inhibits VSV infection-induced type I IFN production by promoting TBK1 degradation[14]. Overexpression of TRIM21 inhibited the activity of the IFNB1[15]. TRIM14 as a Positive Regulator of the Type I IFN Response[16]. βTrCP E3 complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-κB[17]. TRIM39 negatively regulates the NFκB-mediated signaling pathway through stabilization of Cactin[18]
## References
[1] Molecular Biology of the SARS-Coronavirus. .
[2] “A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential DrugRepurposing.”
[3] “A Tug-Of-War Between Severe Acute Respiratory Syndrome Coronavirus 2 and Host Antiviral Defence: Lessons From Other Pathogenic Viruses.”
[4] “Siu, Kam-Leung et al. ‘Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC.’ FASEB journal : official publication of the Federation of American Societies for Experimental Biology vol. 33,8 (2019): 8865-8877. doi:10.1096/fj.201802418R.”
[5] “The TRIMendous Role of TRIMs in Virus–Host Interactions.”
[6] “MAVS Forms Functional Prion-Like Aggregates To Activate and Propagate Antiviral Innate Immune Response.”
[7] “Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.”
[8] “TRAF molecules in cell signaling and in human diseases.”
[9] “Polyubiquitin Conjugation to NEMO by Triparite Motif Protein 23 (TRIM23) Is Critical in Antiviral Defense.”
[10] “Tripartite Motif-Containing Protein 38 Negatively Regulates TLR3/4- And RIG-I-mediated IFN-β Production and Antiviral Response by Targeting NAP1.”
[11] “TRIM30α negatively regulates TLR-mediated NF-κB activation by targeting TAB2 and TAB3 for degradation.”
[12] “Identification of a Role for TRIM29 in the Control of Innate Immunity in the Respiratory Tract.”
[13] “TRIM22 Inhibits Influenza A Virus Infection by Targeting the Viral Nucleoprotein for Degradation.”
[14] “Zheng Q, Hou J, Zhou Y, Yang Y, Xie B, Cao X. Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27. Cell Res. 2015;25(10):1121-1136. doi:10.1038/cr.2015.108.”
[15] “Zhang Z, Bao M, Lu N, Weng L, Yuan B, Liu YJ. The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA. Nat Immunol. 2013;14(2):172-178. doi:10.1038/ni.2492.”
[16] “Zhou Z, Jia X, Xue Q, et al. TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I-like receptor-mediated innate immune response. Proc Natl Acad Sci U S A. 2014;111(2):E245-E254. doi:10.1073/pnas.1316941111.”
[17] “Liu S, Chen ZJ. Expanding role of ubiquitination in NF-κB signaling. Cell Res. 2011;21(1):6-21. doi:10.1038/cr.2010.170.”
[18] “Christian F, Smith EL, Carmody RJ. The Regulation of NF-κB Subunits by Phosphorylation. Cells. 2016;5(1):12. Published 2016 Mar 18. doi:10.3390/cells5010012.”
## Creators
[Muhammad Naveez](https://fairdomhub.org/people/1546)
## Model at FairdomHub (https://fairdomhub.org/models/720)
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Authors:
Arnau Montagud, Miguel Ponce de Leon (miguel.ponce@bsc.es) from Barcelona Supercomputing Center, Spain
Description:
Molecular mechanisms affected by Nsp4 and Nsp6 proteins of SARS-CoV-2</body>
Authors:
Arnau Montagud, Miguel Ponce de Leon (miguel.ponce@bsc.es) from Barcelona Supercomputing Center, Spain
Description:
Molecular mechanisms affected by Nsp4 and Nsp6 proteins of SARS-CoV-2
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# SARS CoV-2 Nsp4 and Nsp6 interactions with human and viral proteins
## Map description
The map is centred on the interactions of Nsp4 and Nsp6 proteins and the host human proteins. Nsp4 and Nsp6 are part of the 16 non-structural proteins (Nsp1-16) that form the replicase/transcriptase complex (RTC) [PMID 32353859]. The RTC consists of multiple enzymes, notably including the papain-like protease (Nsp3) with whom both Nsp4 and Nsp6 interact to induce rearrangement of the cellular membrane to form double-membrane vesicles or spherules, where the coronavirus replication transcription complex (RTC) is assembled and anchored in SARS-COV-1 [PMID 31226023].
Nsp4 interacts with several proteins (TIMM9, 10, 10B and 29) of the TIM complex, the mitochondrial transporters that regulates import of transmembrane proteins into the inner mitochondrial membrane [PMID 32353859]. Nsp4 also interacts with: ALG11, a mannosyltransferase involved in the synthesis of core oligosaccharide on the cytoplasmic face of the endoplasmic reticulum [DOI 10.1093/hmg/ddq016]; IDE, a zinc metallopeptidase that degrades intracellular insulin [DOI 10.1210/mend-4-8-1125] involved in antigen presentation via MHC class I; NUP210, a nucleoporin essential for nuclear pore assembly and fusion, [DOI 10.1091/mbc.e03-04-0260]; and DNAJC11, required for mitochondrial inner membrane organization [PMID 25997101].
Nsp6, whose alleged function is limiting autophagasome expansion [PMID 32353859], interacts with several ATPases that are considered located in different cellular membranes: ATP5MG, mitochondrial ATP synthase membrane subunit g [PMID 11230166]; ATP6AP1, subunit of the vacuolar ATP synthase protein pump [PMID 27231034]; and ATP13A3, a probable cation-transporting ATPase 13A3 allegedly in the cytoplasmic membrane [PMID 11867234]. Additionally, Nsp6 also interacts with SIGMAR1, which functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane [DOI 10.1074/jbc.272.43.27107]; and also with a member of the solute carrier superfamily SLC6A15 although this interaction fell below the authors’ scoring thresholds [PMID 32353859]. Interestingly, SLC6A15 also interacts with SARS-CoV-2 proteins Orf9c and M, even though below the authors’ scoring thresholds [PMID 32353859].
No tissue or cell-type specificity that we know of, even though most functional descriptions were taken from SARS-CoV-1.
## Cross-talk with other pathways (in the map, and in general)
The map is located at the level of the functions of Nsp4 and Nsp6. On the horizontal dimension, these proteins interact together with Nsp3 to rearrange the plasma membrane into double-membrane vesicles. Additionally, Nsp6 has common human proteins targets with Orf9c and M SARS-CoV-2 viral proteins.
On the vertical dimension, these interactions are downstream the entering, decapsulation and translation of the viral RNAs (we have depicted the latter, but just as placeholders) and they are upstream of the different pathways from all the human proteins connected by those. These would mainly be mitochondrial transport through the TIM complex for Nsp4 and different ion pumping and oxidative phosphorylation pathways for Nsp6.
This map will connect with these other maps from the consortium: Virus replication cycle, RTC and transcription, PAMP signalling (as Orf9 and M proteins affect it) and HCoVs autophagy (for Nsp6).
## Creators
[Arnau Montgud](https://fairdomhub.org/people/1537)
[Miguel Ponce de Leon](https://fairdomhub.org/people/1536)
## Contributors and reviewers
[Alfonso Valencia](https://fairdomhub.org/people/61)
## Model at FairdomHub (https://fairdomhub.org/models/708)
This diff is collapsed.
# SARS CoV-2 Nsp9 binding proteins
## Map description
The non-structural protein 9 (Nsp9) has not yet identified its designated function but is estimated that it is essential forviral RNA synthesis for both transcription and translation. We included the binding proteins of Nsp9 in this map [1] with further functional partners especially relating with transcription and translation. We also involved the other Nsps which are suggested to bind with Nsp9 in recent literatures, and the binding proteins of those other Nsps. We chose the proteins which bind poly-RNA, and work for transportation between nucleus and cytoplasm. We also added the other virus-relating processes which those binding proteins are reported their contribution. The map contains the medicines which affect to the proteins in the map.
### How they are related to the COVID-19
These processes may contribute for the COVID-19 replication by recruiting the working complexes via Nsp9 and the other Nsps [2]. In this scenario, the complex with Nsp8 may play significant role. Nsp9 and 10 complex is a candidate which can activate immune system of patients via neutrophil. The complex with Nsp14 may work transportation between nucleus and cytoplasm. There exist the other several possibilities that Nsp9 works more as a competitive/uncompetitive/noncompetitive inhibitor of the binding proteins than a cooperator. We may test and predict this possibility by simulating the time-course fluctuation of the reactants among possible several scenarios.
### What are the key molecular mechanisms
Transcription factors which directly bind Nsp9 may have significant role to replicate viral RNA. Another COVID-19 protein Nsp8 is expected to cooperate with Nsp9 for RNA replication [3]. Some of the binding proteins are known which cooperate with the other viral proteins for such as recruiting virus proteins into cellular nuclei, etc. These processes are expected as the part of critical function of Nsp9, but have not yet confirmed with experiments.
There exist at least two therapeutic candidates of medicines in this map; one is Remdesivir, which was found originally for Ebola, now is supposed to work against Nsps complex, and Ribavirin[4], which was a candidate medicine for HCV infection, and is supposed to inhibit nucleus-cytoplasm transporting process.
### What is the physiological context
The processes in this map are about general function of a cell.
All the processes in this map are composed with the proteins in human cells.
### References
[1] Gordon DE, et al. A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing. Nature. 2020 Apr 30. doi: 10.1038/s41586-020-2286-9. PMID: 32353859.
[2] Jingjiao Li, Mingquan Guo, Xiaoxu Tian, Chengrong Liu, Xin Wang, Xing Yang, Ping Wu, Zixuan Xiao, Yafei Qu, Yue Yin, Joyce Fu, Zhaoqin Zhu, Zhenshan Liu, Chao Peng, Tongyu Zhu, Qiming Liang. Virus-host interactome and proteomic survey of PMBCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis.
bioRxiv 2020.03.31.019216; doi: https://doi.org/10.1101/2020.03.31.019216
[3] Shengjie Dong, Jiachen Sun, Zhuo Mao, Lu Wang, Yi-Lin Lu, Jiesen Li. A Guideline for Homology Modeling of the Proteins From Newly Discovered Betacoronavirus, 2019 Novel Coronavirus (2019-nCoV). J Med Virol. 2020 Mar 17;10.1002/jmv.25768. doi: 10.1002/jmv.25768, PMID: 32181901.
[4] Ivan Fan-Ngai Hung, Kwok-Cheung Lung, Eugene Yuk-Keung Tso, Raymond Liu, Tom Wai-Hin Chung, Man-Yee Chu, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet, VOL 395, ISSUE 10238, P1695-1704, MAY 30, 2020. DOI:https://doi.org/10.1016/S0140-6736(20)31042-4
## Cross-talk with other pathways
This map connect with the following diagrams.
SARS-CoV-2 and COVID-19 Pathway, nsp9/nsp10-mediated SARS-CoV-2 pathogenesis in Wiki Pathway, Nsp9 is involved the processes of viral proteins replication in a Human cell, homo-dimer formation, and heterodimerization with Nsp10.
In Reactome SARS-CoV-2 Infection also include Nsp9 dimerization process.
In individual diagrams, RTC and transcription map, Virus replication cycle map include Nsp9 and the other Nsps(Nsp7, 8, 10, 12, 14, and 16). Additionally to the above two maps, ETC map has overlaps via Nsp7 and Nsp8. Nsp14 and metabolism map overlaps via Nsp14.
## Creators
[Noriko Hiroi](https://fairdomhub.org/people/1534)
[Yusuke Hiki](https://fairdomhub.org/people/1655)
[Takahiro G. Yamada](https://fairdomhub.org/people/1645)
[Akira Funahashi](https://fairdomhub.org/people/1561)
## Model at FairdomHub (https://fairdomhub.org/models/736)
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