SARS-CoV-2 and COVID-19 pathway (Homo sapiens)

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1818surfaceglycoprotein S301616162913, 336103229271162933163, 123316323217162911616341683216119, 26314, 28, 31cell membranecholesterol depletionProtein expressionVirionHuman cellType I interferoninduction andsignalingSCARB1HDL40SActivation of NLRP3inflammasomeFURINTLR7Integrative stressresponsetrimerheparan sulfatecomplexTMPRSS4nsp1CTSLNSP3-NSP4-NSP6complexViral RNA synthesisHijack ofubiquitinationACATpolymerasecomplexSLC6A19Pathogenesis25HCsphingosine624227S2 subunitSARS-CoV-2proteinsorf1a15TMPRSS225, 31orf1abACE2dimerORF3aORF6ORF7aORF8nucleocapsidprotein22membraneglycoprotein22envelopeprotein22surfaceglycoprotein22, 23SARS-CoV-2RNAorf1ORF3aORF6ORF7aORF8ORF10nucleocapsidphosphoproteinmembraneglycoproteinenvelopeproteinsurfaceglycoproteinsurfaceglycoprotein Ssurfaceglycoprotein S22, 23membraneglycoprotein M22orf1abnsp2PL2-PRO3CL-PRO20nsp4nsp7nsp8nsp95nsp10nsp127, 14, 20nsp13ExoN14nsp15nsp16nsp6nsp5SARS-CoV-2RNAnucleocapsidprotein N22envelopeprotein E22ORF10nsp9nsp9orf1ORF7bORF7bnsp16nsp10surfaceglycoprotein Ssurfaceglycoprotein Ssurfaceglycoprotein SACE2recognition complexVirionPL2-PROnsp4nsp6ACE2VirionORF3ansp9nsp10nsp1-40Scomplexnsp1ORF149S2 subunitnsp8NRP13, 12EndocytosisVirionorf1nsp7nsp8nsp127, 14, 20orf1aborf1abcomplexType I interferoninduction andsignaling21surfaceglycoprotein Ssurfaceglycoprotein Ssurfaceglycoprotein Srecognition complexACE2surfaceglycoprotein Ssurfaceglycoprotein Ssurfaceglycoprotein SVirionsurfaceglycoprotein Ssurfaceglycoprotein Ssurfaceglycoprotein SVirionHDLACE2Virionsurfaceglycoprotein Ssurfaceglycoprotein Ssurfaceglycoprotein Srecognition complexSCARB1HDLMembranefusioncholesterolcholesterol


Collaborative project for curation biological processes involved in the COVID-19 disease after SARS-Cov-2 infection. It focuses on experimental evidence and plays with improved annotation of complexes and with the Evidence and Conclusion Ontology. The complexes link to EBI's Complex Portal, resulting from a collaboration with that database at the recent online ELIXIR biohackathon. Editing this pathway is (at this moment) coordinated via the #sarscov2 channel. Additionally, please feel free to add suggestions to the discussion page (see the tab at the top of this page). The large viral Spike protein (S or surface glycoprotein) forms trimers. It interacts with the host's ACE2 receptor to establish binding (Hoffmann et al 2020). There are suggestions for more than one cell entry mechanism, with the evidence for ACE2/TMPRSS2 entry being most clear now. Lack of expression of TMPRSS2 may explain age differences in COVID19 severity. In this mechanism, to enter the virus needs to be primed by the host protease TMPRSS2 that splits the Spike protein into 2 peptides S1 and S2. S1 contains the ACE2 receptor binding site, S2 binds to the host cell membrane which leads to membrane fusion, the start of the uptake process. The ACE2 receptor interaction was also suggested as the start of specific lung-damaging effects. Other human genes that may be involved in alternative cell uptake mechanisms include CTSL and SLC6A19.

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  1. ''Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by depleting membrane cholesterol.''; EMBO J, 2020 PubMed Europe PMC Scholia
  2. ''TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.''; Sci Immunol, 2020 PubMed Europe PMC Scholia
  3. ''Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity.''; Science, 2020 PubMed Europe PMC Scholia
  4. ''Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.''; Intensive Care Med, 2020 PubMed Europe PMC Scholia
  5. ''Crystal Structure of the SARS-CoV-2 Non-structural Protein 9, Nsp9.''; iScience, 2020 PubMed Europe PMC Scholia
  6. ''Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2.''; Science, 2020 PubMed Europe PMC Scholia
  7. ''Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant.''; J Transl Med, 2020 PubMed Europe PMC Scholia
  8. ''Presence of Genetic Variants Among Young Men With Severe COVID-19.''; JAMA, 2020 PubMed Europe PMC Scholia
  9. ''Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load.''; PeerJ, 2020 PubMed Europe PMC Scholia
  10. ''The crystal structure of Nsp9 replicase protein of COVID-19'';, 2020
  11. ''Preprint: TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-1 CoV-2 in human airway epithelial cells and provide promising drug targets''; 10.1101/2020.04.15.042085v1, 2020
  12. ''Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system'';, 2020
  13. ''Identification of novel mutations in themethyltransferase complex (Nsp10-Nsp16) of SARS-CoV-2.''; Biochem Biophys Rep, 2020 PubMed Europe PMC Scholia
  14. ''Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites.''; Antiviral Res, 2020 PubMed Europe PMC Scholia
  15. ''Genetic evolution analysis of 2019 novel coronavirus and coronavirus from other species.''; Infect Genet Evol, 2020 PubMed Europe PMC Scholia
  16. ''HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry.''; Nat Metab, 2020 PubMed Europe PMC Scholia
  17. ''The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2.''; J Virol, 2020 PubMed Europe PMC Scholia
  18. ''A potential role for integrins in host cell entry by SARS-CoV-2.''; Antiviral Res, 2020 PubMed Europe PMC Scholia
  19. ''Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions.''; Antiviral Res, 2020 PubMed Europe PMC Scholia
  20. ''Chemistry and Biology of SARS-CoV-2.''; Chem, 2020 PubMed Europe PMC Scholia
  21. ''Presence of Genetic Variants Among Young Men With Severe COVID-19.''; JAMA, 2020 PubMed Europe PMC Scholia
  22. ''From SARS and MERS CoVs to SARS-CoV-2: moving toward more biased codon usage in viral structural and non-structural genes.''; J Med Virol, 2020 PubMed Europe PMC Scholia
  23. ''Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.''; Cell, 2020 PubMed Europe PMC Scholia
  24. ''Simultaneous Treatment of COVID-19 With Serine Protease Inhibitor Camostat and/or Cathepsin L Inhibitor?''; J Clin Med Res, 2020 PubMed Europe PMC Scholia
  25. ''Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?''; Elife, 2020 PubMed Europe PMC Scholia
  26. ''SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2.''; Cell, 2020 PubMed Europe PMC Scholia
  27. ''Cell entry mechanisms of SARS-CoV-2.''; Proc Natl Acad Sci U S A, 2020 PubMed Europe PMC Scholia
  28. ''Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2.''; Science, 2020 PubMed Europe PMC Scholia
  29. ''Structure of replicating SARS-CoV-2 polymerase.''; Nature, 2020 PubMed Europe PMC Scholia
  30. '''';,
  31. ''SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.''; Cell, 2020 PubMed Europe PMC Scholia
  32. ''Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles.''; mBio, 2013 PubMed Europe PMC Scholia
  33. ''The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with S-adenosylmethionine.''; bioRxiv, 2020 PubMed Europe PMC Scholia
  34. ''Sphingosine prevents binding of SARS-CoV-2 spike to its cellular receptor ACE2.''; J Biol Chem, 2020 PubMed Europe PMC Scholia


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122702view14:57, 3 May 2022NhungPImprove layout
122701view14:54, 3 May 2022NhungPIncrease font and adjust layout to improve readability
120585view19:04, 17 December 2021EweitzFix case
120249view15:50, 20 November 2021EgonwAdded a missing identifier
118977view06:25, 6 June 2021EgonwTyped an interaction
118845view09:23, 2 June 2021EweitzOntology Term : 'COVID-19' added !
118844view09:23, 2 June 2021EweitzOntology Term : 'DOID:2945' removed !
118843view09:22, 2 June 2021EweitzModified title
115843view15:10, 18 March 2021Fehrhartadded S2 identifiers
115453view20:45, 19 February 2021EgonwFixed some references
115447view11:56, 19 February 2021EgonwAnnotated a number of interactions has translocations
115428view09:49, 19 February 2021EgonwAdded more references on interactions
115282view16:49, 9 February 2021FehrhartAdded peer reviewed paper to preprint version of reference
114429view19:16, 10 January 2021EgonwCholesterol depletion results in inhibition of membrane fusion.
114428view18:14, 10 January 2021EgonwAdded an alternative uptake mechanism.
114246view13:22, 29 December 2020EgonwTwo more articles
114234view06:23, 28 December 2020EgonwAdded a reported role of nsp14
113854view20:14, 1 December 2020EgonwAdded a role suggested for sphingosine.
113819view10:11, 28 November 2020EgonwAdded citation for nsp9 crystal structure and added heparan sulfate binding
113702view08:59, 17 November 2020Fehrhartsmall graphical updates
111980view19:27, 13 September 2020EgonwMore literature references linked to interactions.
111364view05:28, 3 August 2020EgonwConverted two interacting Label's to DataNode's.
111358view11:24, 2 August 2020EgonwAnother preprint is published now.
111357view11:18, 2 August 2020EgonwReplaced a DOI by the PubMed ID.
111348view04:56, 30 July 2020EgonwCompleted the TLR7 route, now with PubMed ID.
111317view09:38, 28 July 2020EgonwAdded new recent insight
111242view09:19, 27 July 2020EgonwAdded another reference.
111228view16:08, 26 July 2020EgonwRemoved another bit of info backed by the removed preprint.
111227view16:02, 26 July 2020EgonwRemoved a preprint marked for image duplication:
111226view15:59, 26 July 2020EgonwAdded another complex, and a nice YouTube video.
110895view09:40, 18 June 2020EgonwAdded another article about the role of FURIN
110894view06:59, 18 June 2020EgonwRestructured the map.
110893view06:49, 18 June 2020EgonwAdded NRP1
110890view20:54, 17 June 2020EgonwAdded the polymerase cmoplex.
110889view20:06, 17 June 2020EgonwA bit more literature
110886view17:44, 17 June 2020EgonwAdded another reference
110832view13:05, 11 June 2020Egonw
110811view22:26, 9 June 2020Mkutmonfix unconnected line
110668view18:35, 27 May 2020EgonwMade a few pathway nodes have a shape
110650view05:27, 25 May 2020EgonwAdded the missing protein identifier
110619view16:04, 21 May 2020EgonwOkay, it's getting complex :/
110618view15:42, 21 May 2020EgonwAdded two more recent papers (HT Chem2W)
110617view15:05, 21 May 2020EgonwAdded a new protein reported by UniProt.
110616view10:32, 21 May 2020EgonwAdded the Wikidata identifier for nsp1
110615view10:13, 21 May 2020EgonwLinked the preprint also to the inhibition interaction.
110614view10:12, 21 May 2020EgonwAdded the ECO code
110613view09:41, 21 May 2020EgonwFirst bit of conclusions captured.
110612view08:55, 21 May 2020EgonwAdded a preprint about nsp1 ribosome binding.
110577view08:11, 19 May 2020EveloModified description
110576view07:44, 19 May 2020EveloModified description

External references


View all...
NameTypeDatabase referenceComment
25HCMetaboliteCHEBI:42977 (ChEBI)
3CL-PROProteinQ87917582 (Wikidata)
40SComplexCPX-5223 (Complex Portal)
ACATGeneProductENSG00000075239 (Ensembl)
ACE2ProteinQ9BYF1 (Uniprot-TrEMBL)
Activation of


PathwayWP4876 (WikiPathways)
CTSLProteinP07711 (Uniprot-TrEMBL)
ExoNProteinQ94648393 (Wikidata) nsp14
FURINProteinP09958 (Uniprot-TrEMBL)
HDLMetaboliteCHEBI:39025 (ChEBI)
Hijack of ubiquitinationPathwayWP4860 (WikiPathways)
Integrative stress responsePathwayWP4861 (WikiPathways)
Membrane fusionPathway
NRP1ProteinO14786 (Uniprot-TrEMBL)
NSP3-NSP4-NSP6 complexComplexCPX-5691 (Complex Portal)
ORF10GeneProduct43740576 (Entrez Gene)
ORF10ProteinQ89227548 (Wikidata)
ORF14ProteinP0DTD3 (Uniprot-TrEMBL)
ORF3aGeneProduct43740569 (Entrez Gene)
ORF3aProteinP0DTC3 (Uniprot-TrEMBL)
ORF6GeneProduct43740572 (Entrez Gene)
ORF6ProteinQ89226299 (Wikidata)
ORF7aGeneProduct43740573 (Entrez Gene)
ORF7aProteinQ88658500 (Wikidata)
ORF7bGeneProduct43740574 (Entrez Gene)
ORF7bProteinQ88089438 (Wikidata)
ORF8GeneProduct43740577 (Entrez Gene)
ORF8ProteinQ89225654 (Wikidata)
PL2-PROProteinQ87917581 (Wikidata) nsp3
PathogenesisPathwayWP4884 (WikiPathways)
Protein expressionPathway
S2 subunitProteinQ106020384 (Wikidata)
SARS-CoV-2 RNARnaQ82069695 (Wikidata)
SARS-CoV-2 proteinsProteinQ82069695 (Wikidata)
SCARB1GeneProductENSG00000073060 (Ensembl)
SLC6A19GeneProductENSG00000174358 (Ensembl)
TLR7ProteinQ9NYK1 (Uniprot-TrEMBL)
TMPRSS2ProteinO15393 (Uniprot-TrEMBL)
TMPRSS4ProteinQ9NRS4 (Uniprot-TrEMBL)
Type I interferon

induction and

PathwayWP4868 (WikiPathways)
Viral RNA synthesisPathway
cholesterolMetaboliteCHEBI:16113 (ChEBI)
complexComplexCPX-5685 (Complex Portal)
complexComplexCPX-5688 (Complex Portal)
dimerComplexCPX-5687 (Complex Portal)
envelope protein EProteinP0DTC4 (Uniprot-TrEMBL)
envelope proteinGeneProduct43740570 (Entrez Gene)
envelope proteinProteinP0DTC4 (Uniprot-TrEMBL)
heparan sulfateMetaboliteCHEBI:28815 (ChEBI)
membrane glycoprotein MProteinP0DTC5 (Uniprot-TrEMBL)
membrane glycoproteinGeneProduct43740571 (Entrez Gene)
membrane glycoproteinProteinP0DTC5 (Uniprot-TrEMBL)
nsp1-40S complexComplexQ109653022 (Wikidata)
nsp10ProteinQ87917572 (Wikidata) nsp10
nsp12ProteinQ94647436 (Wikidata) RdRp
nsp13ProteinQ94648377 (Wikidata) Helicase
nsp15ProteinQ87917579 (Wikidata) NendoU
nsp16ProteinQ87917579 (Wikidata) 2'-O-methyltransferase
nsp1ProteinQ90038952 (Wikidata) Host translation inhibitor nsp1
nsp2ProteinQ89006922 (Wikidata)
nsp4ProteinQ90038956 (Wikidata)
nsp5ProteinQ87917582 (Wikidata)
nsp6ProteinQ88656943 (Wikidata)
nsp7ProteinQ90038963 (Wikidata)
nsp8ProteinQ88659350 (Wikidata)
nsp9ProteinQ89686805 (Wikidata)
nucleocapsid phosphoproteinGeneProduct43740575 (Entrez Gene)
nucleocapsid protein NProteinP0DTC9 (Uniprot-TrEMBL)
nucleocapsid proteinProteinP0DTC9 (Uniprot-TrEMBL)
orf1GeneProduct43740578 (Entrez Gene)
orf1aProteinP0DTC1 (Uniprot-TrEMBL)
orf1abProteinP0DTD1 (Uniprot-TrEMBL)
polymerase complexComplexCPX-5742 (Complex Portal)
recognition complexComplexCPX-5683 (Complex Portal)
recognition complexComplexCPX-5684 (Complex Portal)
sphingosineMetaboliteCHEBI:16393 (ChEBI)
surface glycoprotein SProteinP0DTC2 (Uniprot-TrEMBL)
surface glycoproteinGeneProduct43740568 (Entrez Gene)
surface glycoproteinProteinP0DTC2 (Uniprot-TrEMBL)
trimerComplexCPX-5682 (Complex Portal)

Annotated Interactions

No annotated interactions

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