Endoplasmic reticulum stress response in coronavirus infection (WP4861)

Homo sapiens

This pathway model describes how the three branches of the Unfolded Protein Response (UPR) signaling pathway are activated and regulated during human coronavirus infection [DOI: 10.1146/annurev-micro-020518-115759]. During coronavirus infection, viral proteins are produced in large amounts in the ER, exceeding the ER’s protein folding capacity and leading to large amounts of unfolded proteins. This results in ER stress and activation of the UPR through transmembrane sensors PERK, IRE1 and ATF6. Pathways activation occurs when the protein chaperone GRP78 (HSPA5) dissociates from the PERK/IRE1/ATF6 to bind unfolded proteins, which leads to oligomerization, autophosphorylation and activation [DOI: 10.1107/S0907444911006445]. Activated PERK inactivates eIF2α by phosphorylation, leading to a decrease in overall protein synthesis. eIF2α can also be phosphorylated by several other kinases (HRI, GCN2, PKR). PKR activation is shown to be suppressed by coronavirus nsp15 and dsRNA-binding activity of MERS-CoV protein 4a. Activated IRE1 (ERN1) has multiple downstream effects. The IRE1 RNase domain is involved in unconventional splicing of XBP1, creating XBP1S which induces expression of protein folding genes. The RNase domain can also break down mRNAs (IRE1-dependent mRNA decay, RIDD), helping to establish ER homeostasis. Finally, the kinase activity of IRE1 also activates a signaling cascade that leads to the JNK pathway, triggering apoptosis. It is thought that the SARS-CoV E protein suppresses activation of the IRE1 pathway and SARS-CoV-induced apoptosis [10.1371/journal.ppat.1002315]. Activated ATF6 is translocated to Golgi and cleaved [DOI: 10.1016/s1097-2765(00)00133-7] to release ATF6-p50, a transcription factor that induces the expression of protein chaperone genes as well as CHOP and XBP1. There is evidence that SARS-CoV infection inhibits ATF6 cleavage [10.1016/j.virol.2009.02.021].


Kristina Hanspers , Alex Pico , Egon Willighagen , Friederike Ehrhart , Andra Waagmeester , Laurent Winckers , Finterly Hu , Eric Weitz , and Nhung Pham


last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens




Disease Ontology

severe acute respiratory syndrome viral infectious disease

Pathway Ontology

disease pathway stress response pathway


Label Type Compact URI Comment
BCL2 GeneProduct ensembl:ENSG00000171791
PP1 GeneProduct wikidata:Q7251492
SARS E GeneProduct uniprot:P0DTC4
PPP1R16A GeneProduct uniprot:Q96I34
PPP1R1B GeneProduct uniprot:Q9UD71
CHOP GeneProduct ensembl:ENSG00000175197
XBP1 GeneProduct ensembl:ENSG00000100219
S Protein uniprot:P0DTC2
GCN2 Protein uniprot:Q9H492
HRI Protein uniprot:Q9BQI3
MAPK8 Protein uniprot:P45983
ERN1 Protein uniprot:O75460
XBP1 Protein uniprot:P17861
S2P Protein uniprot:O43462
ATF6 Protein uniprot:P18850
BCL2 Protein uniprot:P10415
ATF4 Protein uniprot:P18848
PKR Protein uniprot:P19525
S1P Protein uniprot:Q14703
nsp15 Protein wikidata:Q87917579
EIF2A Protein uniprot:Q53XC0
GADD34 Protein uniprot:O75807
CHOP Protein uniprot:P35638
PERK Protein uniprot:Q9NZJ5
ERN1 Protein uniprot:O75460
ERN1 Protein uniprot:O75460
XBP1u Protein uniprot:P17861
HSPA5 Protein uniprot:P11021
ATF6 Protein uniprot:P18850
ATF6 Protein uniprot:P18850
ATF6-p50 Protein uniprot:P18850
HSPA5 Protein uniprot:P11021
HSPA5 Protein uniprot:P11021
HSPA5 Protein uniprot:P11021
HSPA5 Protein uniprot:P11021
HSPA5 Protein uniprot:P11021
PERK Protein uniprot:Q9NZJ5
PERK Protein uniprot:Q9NZJ5
EIF2A Protein uniprot:Q53XC0
PKR Protein uniprot:P19525
CHOP Protein uniprot:P35638
XBP1 Protein uniprot:P17861
PKR Protein uniprot:P19525
PPP1R14D Protein uniprot:Q9NXH3
PPP1R3E Protein uniprot:Q9H7J1
PPP1R1C Protein uniprot:Q8WVI7
PPP1R3A Protein uniprot:Q16821
PPP1R2 Protein uniprot:P41236
PPP1R8 Protein uniprot:Q12972
PPP1R16B Protein uniprot:Q96T49
PPP1R12C Protein uniprot:Q9BZL4
PPP1R14C Protein uniprot:Q8TAE6
PPP1R11 Protein uniprot:Q5SRK2
PPP1R14B Protein uniprot:Q96C90
PPP1R15A Protein uniprot:O75807
PPP1R9A Protein uniprot:Q9ULJ8
PPP1R9B Protein uniprot:D3DTX6
PPP1R12B Protein uniprot:Q6GQY8
PPP1R1A Protein uniprot:Q13522
PPP1R7 Protein uniprot:Q15435
PPP1R14A Protein uniprot:Q96A00
PPP1R3C Protein uniprot:Q9UQK1
PPP1R3G Protein uniprot:B7ZBB8
PPP1R15B Protein uniprot:Q5SWA1
PPP1R12A Protein uniprot:O14974
PPP1R3F Protein uniprot:Q6ZSY5
PPP1R13B Protein uniprot:Q96KQ4
PPP1R3B Protein uniprot:Q86XI6
PPP1R3D Protein uniprot:O95685
PPP1R10 Protein uniprot:Q96QC0
PPP1CB Protein uniprot:P62140
PPP1CC Protein uniprot:P36873
PPP1CA Protein uniprot:P62136


  1. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Ye J, Rawson RB, Komuro R, Chen X, Davé UP, Prywes R, et al. Mol Cell. 2000 Dec;6(6):1355–64. PubMed Europe PMC Scholia
  2. The structure of the PERK kinase domain suggests the mechanism for its activation. Cui W, Li J, Ron D, Sha B. Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):423–8. PubMed Europe PMC Scholia
  3. Human Coronavirus: Host-Pathogen Interaction. Fung TS, Liu DX. Annu Rev Microbiol. 2019 Sep 8;73:529–57. PubMed Europe PMC Scholia
  4. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. Nature. 2020 Jul;583(7816):459–68. PubMed Europe PMC Scholia