SARS-CoV-2 and COVID-19 pathway (WP4846)

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 wikipathways.slack.com #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.
last edited

Authors

Egonw, L Dupuis, Evelo, AlexanderPico, MaintBot, Fehrhart, Mkutmon, and Eweitz

Cited In

Organism

Homo sapiens

Communities

COVID-19

Annotations

Pathway Ontology: disease pathway

Disease Ontology: COVID-19 disease by infectious agent

Participants

Label Type Compact Identifier
surfaceglycoprotein S Protein uniprot:P0DTC2
Protein expression Pathway None
SCARB1 GeneProduct ensembl:ENSG00000073060
Integrative stressresponse Pathway wikipathways:WP4861
40S Complex complexportal:CPX-5223
SLC6A19 GeneProduct ensembl:ENSG00000174358
nsp1 Protein wikidata:Q90038952
Pathogenesis Pathway wikipathways:WP4884
trimer Complex complexportal:CPX-5682
CTSL Protein uniprot:P07711
25HC Metabolite chebi:42977
Viral RNA synthesis Pathway None
TLR7 Protein uniprot:Q9NYK1
TMPRSS4 Protein uniprot:Q9NRS4
NSP3-NSP4-NSP6complex Complex complexportal:CPX-5691
HDL Metabolite chebi:39025
Type I interferoninduction andsignaling Pathway wikipathways:WP4868
complex Complex complexportal:CPX-5688
FURIN Protein uniprot:P09958
Hijack ofubiquitination Pathway wikipathways:WP4860
ACAT GeneProduct ensembl:ENSG00000075239
polymerasecomplex Complex complexportal:CPX-5742
heparan sulfate Metabolite chebi:28815
Activation of NLRP3inflammasome Pathway wikipathways:WP4876
sphingosine Metabolite chebi:16393
S2 subunit Protein wikidata:Q106020384
SARS-CoV-2proteins Protein wikidata:Q82069695
orf1a Protein uniprot:P0DTC1
TMPRSS2 Protein uniprot:O15393
orf1ab Protein uniprot:P0DTD1
ACE2 Protein uniprot:Q9BYF1
dimer Complex complexportal:CPX-5687
ORF3a Protein uniprot:P0DTC3
ORF6 Protein wikidata:Q89226299
ORF7a Protein wikidata:Q88658500
ORF8 Protein wikidata:Q89225654
nucleocapsidprotein Protein uniprot:P0DTC9
membraneglycoprotein Protein uniprot:P0DTC5
envelopeprotein Protein uniprot:P0DTC4
surfaceglycoprotein Protein uniprot:P0DTC2
SARS-CoV-2RNA RNA wikidata:Q82069695
orf1 GeneProduct ncbigene:43740578
ORF3a GeneProduct ncbigene:43740569
ORF6 GeneProduct ncbigene:43740572
ORF7a GeneProduct ncbigene:43740573
ORF8 GeneProduct ncbigene:43740577
ORF10 GeneProduct ncbigene:43740576
nucleocapsidphosphoprotein GeneProduct ncbigene:43740575
membraneglycoprotein GeneProduct ncbigene:43740571
envelopeprotein GeneProduct ncbigene:43740570
surfaceglycoprotein GeneProduct ncbigene:43740568
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
membraneglycoprotein M Protein uniprot:P0DTC5
orf1ab Protein uniprot:P0DTD1
nsp2 Protein wikidata:Q89006922
PL2-PRO Protein wikidata:Q87917581
3CL-PRO Protein wikidata:Q87917582
nsp4 Protein wikidata:Q90038956
nsp7 Protein wikidata:Q90038963
nsp8 Protein wikidata:Q88659350
nsp9 Protein wikidata:Q89686805
nsp10 Protein wikidata:Q87917572
nsp12 Protein wikidata:Q94647436
nsp13 Protein wikidata:Q94648377
ExoN Protein wikidata:Q94648393
nsp15 Protein wikidata:Q87917579
nsp16 Protein wikidata:Q87917579
nsp6 Protein Wikidata
nsp5 Protein Wikidata
SARS-CoV-2RNA Rna Wikidata
nucleocapsidprotein N Protein Uniprot-TrEMBL
envelopeprotein E Protein Uniprot-TrEMBL
ORF10 Protein Wikidata
nsp9 Protein Wikidata
nsp9 Protein Wikidata
orf1 GeneProduct Entrez Gene
ORF7b Protein Wikidata
ORF7b GeneProduct Entrez Gene
nsp16 Protein Wikidata
nsp10 Protein wikidata:Q87917572
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
ACE2 Protein uniprot:Q9BYF1
recognition complex Complex complexportal:CPX-5683
PL2-PRO Protein wikidata:Q87917581
nsp4 Protein wikidata:Q90038956
nsp6 Protein wikidata:Q88656943
ACE2 Protein uniprot:Q9BYF1
ORF3a Protein uniprot:P0DTC3
nsp9 Protein wikidata:Q89686805
nsp10 Protein wikidata:Q87917572
nsp1-40Scomplex Complex wikidata:Q109653022
nsp1 Protein wikidata:Q90038952
ORF14 Protein uniprot:P0DTD3
S2 subunit Protein wikidata:Q106020384
nsp8 Protein wikidata:Q88659350
NRP1 Protein uniprot:O14786
Endocytosis Pathway None
orf1 GeneProduct ncbigene:43740578
nsp7 Protein wikidata:Q90038963
nsp8 Protein wikidata:Q88659350
nsp12 Protein wikidata:Q94647436
orf1ab Protein uniprot:P0DTD1
orf1ab Protein uniprot:P0DTD1
complex Complex complexportal:CPX-5685
Type I interferoninduction andsignaling Pathway wikipathways:WP4868
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
recognition complex Complex complexportal:CPX-5684
ACE2 Protein uniprot:Q9BYF1
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
HDL Metabolite chebi:39025
ACE2 Protein uniprot:Q9BYF1
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
recognition complex Complex complexportal:CPX-5684
SCARB1 GeneProduct ensembl:ENSG00000073060
HDL Metabolite chebi:39025
Membranefusion Pathway None
cholesterol Metabolite chebi:16113
cholesterol Metabolite chebi:16113

References

  1. Angelini MM, Akhlaghpour M, Neuman BW, Buchmeier MJ. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. mBio. 2013 Aug 13;4(4):e00524-13. PubMed Europe PMC Scholia
  2. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 Apr;46(4):586–90. PubMed Europe PMC Scholia
  3. Sigrist CJ, Bridge A, Le Mercier P. A potential role for integrins in host cell entry by SARS-CoV-2. Antiviral Res. 2020 May;177:104759. PubMed Europe PMC Scholia
  4. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444–8. PubMed Europe PMC Scholia
  5. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. PubMed Europe PMC Scholia
  6. Walls AC, Park Y-J, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020 Apr 16;181(2):281-292.e6. PubMed Europe PMC Scholia
  7. Kandeel M, Ibrahim A, Fayez M, Al-Nazawi M. From SARS and MERS CoVs to SARS-CoV-2: Moving toward more biased codon usage in viral structural and nonstructural genes. J Med Virol. 2020 Jun;92(6):660–6. PubMed Europe PMC Scholia
  8. Li C, Yang Y, Ren L. Genetic evolution analysis of 2019 novel coronavirus and coronavirus from other species. Infect Genet Evol. 2020 Aug;82:104285. PubMed Europe PMC Scholia
  9. Shannon A, Le NT-T, Selisko B, Eydoux C, Alvarez K, Guillemot J-C, et al. Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites. Antiviral Res. 2020 Jun;178:104793. PubMed Europe PMC Scholia
  10. Pachetti M, Marini B, Benedetti F, Giudici F, Mauro E, Storici P, et al. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med. 2020 Apr 22;18(1):179. PubMed Europe PMC Scholia
  11. Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A. 2020 May 26;117(21):11727–34. PubMed Europe PMC Scholia
  12. Zang R, Gomez Castro MF, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020 May 13;5(47):eabc3582. PubMed Europe PMC Scholia
  13. Hillen HS, Kokic G, Farnung L, Dienemann C, Tegunov D, Cramer P. Structure of replicating SARS-CoV-2 polymerase. Nature. 2020 Aug;584(7819):154–6. PubMed Europe PMC Scholia
  14. Bittmann S, Weissenstein A, Villalon G, Moschuring-Alieva E, Luchter E. Simultaneous Treatment of COVID-19 With Serine Protease Inhibitor Camostat and/or Cathepsin L Inhibitor? J Clin Med Res. 2020 May;12(5):320–2. PubMed Europe PMC Scholia
  15. Rosas-Lemus M, Minasov G, Shuvalova L, Inniss NL, Kiryukhina O, Wiersum G, et al. The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with S-adenosylmethionine. bioRxiv. 2020 Apr 26;2020.04.17.047498. PubMed Europe PMC Scholia
  16. Dömling A, Gao L. Chemistry and Biology of SARS-CoV-2. Chem. 2020 Jun 11;6(6):1283–95. PubMed Europe PMC Scholia
  17. Littler DR, Gully BS, Colson RN, Rossjohn J. Crystal Structure of the SARS-CoV-2 Non-structural Protein 9, Nsp9. iScience. 2020 Jul 24;23(7):101258. PubMed Europe PMC Scholia
  18. Kim SY, Jin W, Sood A, Montgomery DW, Grant OC, Fuster MM, et al. Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions. Antiviral Res. 2020 Sep;181:104873. PubMed Europe PMC Scholia
  19. Pique-Regi R, Romero R, Tarca AL, Luca F, Xu Y, Alazizi A, et al. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? Elife. 2020 Jul 14;9:e58716. PubMed Europe PMC Scholia
  20. Thoms M, Buschauer R, Ameismeier M, Koepke L, Denk T, Hirschenberger M, et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020 Sep 4;369(6508):1249–55. PubMed Europe PMC Scholia
  21. van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA. 2020 Aug 18;324(7):663–73. PubMed Europe PMC Scholia
  22. Edwards MJ, Becker KA, Gripp B, Hoffmann M, Keitsch S, Wilker B, et al. Sphingosine prevents binding of SARS-CoV-2 spike to its cellular receptor ACE2. J Biol Chem. 2020 Nov 6;295(45):15174–82. PubMed Europe PMC Scholia
  23. Ogando NS, Zevenhoven-Dobbe JC, van der Meer Y, Bredenbeek PJ, Posthuma CC, Snijder EJ. The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2. J Virol. 2020 Nov 9;94(23):e01246-20. PubMed Europe PMC Scholia
  24. Wang S, Li W, Hui H, Tiwari SK, Zhang Q, Croker BA, et al. Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by depleting membrane cholesterol. EMBO J. 2020 Nov 2;39(21):e106057. PubMed Europe PMC Scholia
  25. Clausen TM, Sandoval DR, Spliid CB, Pihl J, Perrett HR, Painter CD, et al. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell. 2020 Nov 12;183(4):1043-1057.e15. PubMed Europe PMC Scholia
  26. Azad GK. Identification of novel mutations in the methyltransferase complex (Nsp10-Nsp16) of SARS-CoV-2. Biochem Biophys Rep. 2020 Dec;24:100833. PubMed Europe PMC Scholia
  27. Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020 Nov 13;370(6518):856–60. PubMed Europe PMC Scholia
  28. Eskier D, Suner A, Oktay Y, Karakülah G. Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load. PeerJ. 2020 Oct 12;8:e10181. PubMed Europe PMC Scholia
  29. Wei C, Wan L, Yan Q, Wang X, Zhang J, Yang X, et al. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Nat Metab. 2020 Dec;2(12):1391–400. PubMed Europe PMC Scholia