Commit 37066504 authored by Marek Ostaszewski's avatar Marek Ostaszewski
Browse files

Merge branch 'readme_replace' into 'master'

Nsp14 and Orf3a descriptions replaced

See merge request !235
parents cce1ad4b ffcbc90a
# SARS-CoV-2 Orf3a protein interactions # The impact of SARS CoV-2 Nsp14 on metabolism
## Map description ## 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]. The viral protein Nsp14 of the novel SARS-CoV-2 is known to interact with three human proteins: the ⍺-galactosidase A (GLA), sirtuin 5 (SIRT5), and the IMP dehydrogenase 2 (IMPDH2) [DOI 10.1038/s41586-020-2286-9]. GLA plays a central role in the galactose metabolism and catalyzes the hydrolysis of ⍺-D-galactopyranose residues [DOI 10.1016/j.jmb.2004.01.035]. SIRT5 is a NAD-dependent desuccinylase and demanlonylase [DOI 10.1126/science.1207861]. It is located in the mitochondria and plays a pivotal role in the oxidative metabolism and apoptosis initiation [DOI 10.1016/j.jmb.2008.07.048]. In liver cells, it controls the detoxification of ammonia [DOI 10.1080/15548627.2015.1009778]. It is furthermore associated with the human nicotinate and nicotinamide metabolism. The IMP dehydrogenase is the rate-limiting enzyme in the de novo synthesis of GTP [DOI 10.1186/s13008-018-0038-0]. This feature turns the IMPDH2 into an attractive target for the regulation of the purine metabolism. The purine metabolism contains potential antiviral-targets, including the IMPDH2, the guanylate kinase (GK1), and the adenylosuccinate lyase (ADSL) [DOI 10.5281/zenodo.3752641].
## Cross-talk with other pathways The map displays the three pathways (galactose metabolism, nicotinate and nicotinamide metabolism, and purine metabolism) that are affected by Nsp14. The modulating nature of Nsp14 on the three enzymes is currently not known.
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] ## Cross-talk with other pathways
The galactose metabolism, harboring the GLA enzyme, is interconnected with the amino sugar and nucleotide sugar metabolism, as well as further sugar metabolisms, such as fructose or mannose. The enzyme SIRT5 can desuccinylate the serine hydroxymethyltransferase SHMT2, leading to increased serine catabolism [DOI 10.1158/0008-5472.CAN-17-1912]. The IMPDH plays a crucial role in the metabolism and proliferation of cells [DOI 10.1186/s13008-018-0038-0]. It is a central human metabolism, connected to a variety of other pathways, such as the riboflavin or histidine metabolism, or the pentose phosphate pathway. Downstream of the purine metabolism, the nucelobases guanine and adenine are synthesized.
## References ## Creators
[1] Molecular Biology of the SARS-Coronavirus. . [Alina Renz](https://fairdomhub.org/people/1564)
[2] “A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential DrugRepurposing.” [Andreas Draeger](https://fairdomhub.org/people/1569)
[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.”
## Contributors and reviewers
[Marek Ostaszewski](https://fairdomhub.org/people/665)
## Creators ## Model at FairdomHub (https://fairdomhub.org/models/710)
[Muhammad Naveez](https://fairdomhub.org/people/1546)
## Model at FairdomHub (https://fairdomhub.org/models/720)
# The impact of SARS CoV-2 Nsp14 on metabolism # SARS-CoV-2 Orf3a protein interactions
## Map description ## Map description
The viral protein Nsp14 of the novel SARS-CoV-2 is known to interact with three human proteins: the ⍺-galactosidase A (GLA), sirtuin 5 (SIRT5), and the IMP dehydrogenase 2 (IMPDH2) [DOI 10.1038/s41586-020-2286-9]. GLA plays a central role in the galactose metabolism and catalyzes the hydrolysis of ⍺-D-galactopyranose residues [DOI 10.1016/j.jmb.2004.01.035]. SIRT5 is a NAD-dependent desuccinylase and demanlonylase [DOI 10.1126/science.1207861]. It is located in the mitochondria and plays a pivotal role in the oxidative metabolism and apoptosis initiation [DOI 10.1016/j.jmb.2008.07.048]. In liver cells, it controls the detoxification of ammonia [DOI 10.1080/15548627.2015.1009778]. It is furthermore associated with the human nicotinate and nicotinamide metabolism. The IMP dehydrogenase is the rate-limiting enzyme in the de novo synthesis of GTP [DOI 10.1186/s13008-018-0038-0]. This feature turns the IMPDH2 into an attractive target for the regulation of the purine metabolism. The purine metabolism contains potential antiviral-targets, including the IMPDH2, the guanylate kinase (GK1), and the adenylosuccinate lyase (ADSL) [DOI 10.5281/zenodo.3752641]. 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].
The map displays the three pathways (galactose metabolism, nicotinate and nicotinamide metabolism, and purine metabolism) that are affected by Nsp14. The modulating nature of Nsp14 on the three enzymes is currently not known.
## Cross-talk with other pathways ## Cross-talk with other pathways
The galactose metabolism, harboring the GLA enzyme, is interconnected with the amino sugar and nucleotide sugar metabolism, as well as further sugar metabolisms, such as fructose or mannose. The enzyme SIRT5 can desuccinylate the serine hydroxymethyltransferase SHMT2, leading to increased serine catabolism [DOI 10.1158/0008-5472.CAN-17-1912]. The IMPDH plays a crucial role in the metabolism and proliferation of cells [DOI 10.1186/s13008-018-0038-0]. It is a central human metabolism, connected to a variety of other pathways, such as the riboflavin or histidine metabolism, or the pentose phosphate pathway. Downstream of the purine metabolism, the nucelobases guanine and adenine are synthesized. Trim59 pathway cross talk with other TRIM pathways used to inhibit the Nf-kb response in Orf3a COVID-19 Disease map.
## Creators 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]
[Alina Renz](https://fairdomhub.org/people/1564)
[Andreas Draeger](https://fairdomhub.org/people/1569) ## 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.”
## Contributors and reviewers
[Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model at FairdomHub (https://fairdomhub.org/models/710) ## Creators
[Muhammad Naveez](https://fairdomhub.org/people/1546)
## Model at FairdomHub (https://fairdomhub.org/models/720)
Supports Markdown
0% or .
You are about to add 0 people to the discussion. Proceed with caution.
Finish editing this message first!
Please register or to comment