Endoplasmic reticulum stress response in Coronavirus infection (Homo sapiens)

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1, 342UnfoldedproteinLegendGolgiNucleusMVH infectionER-associatedmRNAGlobal proteintranslationProsurvival genesSplicingSER protein chaperonesdsRNACREcAMP response elementAmino acid synthesisAntioxidant responseApoptosisER protein chaperonesLipid biosynthesisER-associated degradationMERS 4aER lumenATF4RIDDSARS 8abMAPK8PKRS1PApoptosisHRIATF6XBP1BCL2S2PERN1nsp15PP1BCL2GCN2PEIF2APPGADD34CHOPPERKSARS, IBV infectionSARS, OC43,MHV, IBV infectionERN1PUnfoldedproteinERN1PXBP1uHSPA5ATF6UnfoldedproteinATF6ATF6-p50SARS EHSPA5HSPA5HSPA5CytosolHSPA5HSPA5PERKPERKPPEIF2APKRCHOPXBP1dsRNAOC43 infectionPKRPC/EBPCCAAT enhancer binding proteinUPREunfolded proteinresponse elementERSEER stress response elementPP1PPP1R14DPPP1R3EPPP1R16APPP1R1CPPP1R3APPP1R2PPP1R1BPPP1R8PPP1R16BPPP1R12CPPP1R14CPPP1R11PPP1R14BPPP1R15APPP1R9APPP1R9BPPP1R12BPPP1R1APPP1R7PPP1R14APPP1R3CPPP1R3GPPP1R15BPPP1R12APPP1R3FPPP1R13BPPP1R3BPPP1R3DPPP1R10PPP1CBPPP1CCPPP1CAERSEER stress response elementERSE-IIER stress response elementVirus type/speciesPhosphorylationvirus proteinMERSPSARSSARSSARS, 229EMHVMERSCHOPXBP1


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 to 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].

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  1. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Huettenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, Garcia-Sastre A, Shokat KM, Shoichet BK, Krogan NJ; ''A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.''; Nature, 2020 PubMed Europe PMC Scholia
  2. Ye J, Rawson RB, Komuro R, Chen X, Davé UP, Prywes R, Brown MS, Goldstein JL; ''ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.''; Mol Cell, 2000 PubMed Europe PMC Scholia
  3. Fung TS, Liu DX; ''Human Coronavirus: Host-Pathogen Interaction.''; Annu Rev Microbiol, 2019 PubMed Europe PMC Scholia
  4. Cui W, Li J, Ron D, Sha B; ''The structure of the PERK kinase domain suggests the mechanism for its activation.''; Acta Crystallogr D Biol Crystallogr, 2011 PubMed Europe PMC Scholia


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115877view10:13, 19 March 2021FinterlyFixed some weird symbol characters.
115863view16:03, 18 March 2021LaurentUpdated some annotations for DataNodes
114110view08:04, 23 December 2020EgonwConverted two Labels to a DataNode
114083view08:03, 21 December 2020EgonwConverted a few more interacting labels into DataNodes.
112228view07:40, 4 October 2020EgonwModified title
112166view18:34, 29 September 2020Khanspersfixed ptm state comments
111617view20:42, 29 August 2020EgonwModified title
111114view09:24, 13 July 2020EgonwMade a pathway clickable
110816view23:31, 9 June 2020KhanspersModified description
110815view22:49, 9 June 2020KhanspersModified title
110810view10:07, 9 June 2020AndraModified title
110793view00:13, 6 June 2020KhanspersModified description
110792view22:17, 5 June 2020Khanspersupdated lit ref for Gordon et al
110767view12:36, 3 June 2020Fehrhartfixed unconnected line fixed stimulation of transcription/translation
110763view21:36, 2 June 2020Khanspersremoved duplicated label
110762view21:35, 2 June 2020Khanspersminor placement change
110761view21:31, 2 June 2020Khanspersadded legend
110760view21:22, 2 June 2020Khanspersnucleus details
110759view21:11, 2 June 2020Khanspersadded PP1 subunits
110677view23:52, 27 May 2020KhanspersModified title
110676view23:51, 27 May 2020KhanspersModified description
110675view23:51, 27 May 2020Khanspersadded S1P, S2P and missing xrefs
110674view23:27, 27 May 2020KhanspersAdded phospho sites
110673view22:22, 27 May 2020Khanspersfixed typo
110672view22:16, 27 May 2020Khanspersadded details and viral proteins
110670view18:45, 27 May 2020KhanspersModified title
110669view18:40, 27 May 2020Khanspersupdated to protein ids, fixed ER
110665view00:29, 27 May 2020KhanspersModified title
110664view00:28, 27 May 2020Khanspersadded third arm, location etc
110630view23:33, 22 May 2020Khanspersspecified interactions
110629view23:19, 22 May 2020Khanspersadded content
110451view22:43, 12 May 2020Khansperscleared up names, added interactions
110198view20:38, 23 April 2020EgonwTyped proteins as Type="Protein"
109971view18:17, 8 April 2020AlexanderPicoupdated sars nodes per #covidpathways guidelines
109855view13:41, 2 April 2020MaintBotThe label just black.
109854view13:40, 2 April 2020MaintBotStyled the virus node.
109726view21:10, 29 March 2020EgonwAdded a Wikidata identifier for nsp15
109643view19:23, 27 March 2020AlexanderPicoOntology Term : 'viral infectious disease' added !
109632view18:27, 27 March 2020AlexanderPicoOntology Term : 'stress response pathway' added !
109631view18:27, 27 March 2020AlexanderPicoOntology Term : 'severe acute respiratory syndrome' added !
109630view18:26, 27 March 2020AlexanderPicoOntology Term : 'disease pathway' added !
109618view17:18, 27 March 2020Khanspersadded lit ref
109615view16:56, 27 March 2020KhanspersNew pathway

External references


View all...
NameTypeDatabase referenceComment
ATF4ProteinP18848 (Uniprot-TrEMBL)
ATF6-p50ProteinP18850 (Uniprot-TrEMBL)
ATF6ProteinP18850 (Uniprot-TrEMBL)
Amino acid synthesis

Antioxidant response

ApoptosisPathwayWP354 (WikiPathways)
BCL2GeneProductENSG00000171791 (Ensembl)
BCL2ProteinP10415 (Uniprot-TrEMBL)
C/EBP CCAAT enhancer binding proteinProtein
CHOPGeneProductENSG00000175197 (Ensembl)
CHOPProteinP35638 (Uniprot-TrEMBL)
CRE cAMP response elementGeneProduct
EIF2AProteinQ53XC0 (Uniprot-TrEMBL)
ER protein chaperones

Lipid biosynthesis

ER-associated degradation
ER-associated mRNARna
ERN1ProteinO75460 (Uniprot-TrEMBL)
GADD34ProteinO75807 (Uniprot-TrEMBL)
GCN2ProteinQ9H492 (Uniprot-TrEMBL)
Global protein translationPathway
HRIProteinQ9BQI3 (Uniprot-TrEMBL)
HSPA5ProteinP11021 (Uniprot-TrEMBL)
MAPK8ProteinP45983 (Uniprot-TrEMBL)
MERS 4aProtein
PERKProteinQ9NZJ5 (Uniprot-TrEMBL)
PKRProteinP19525 (Uniprot-TrEMBL)
PP1Q7251492 (Wikidata)
PPP1CAProteinP62136 (Uniprot-TrEMBL)
PPP1CBProteinP62140 (Uniprot-TrEMBL)
PPP1CCProteinP36873 (Uniprot-TrEMBL)
PPP1R10ProteinQ96QC0 (Uniprot-TrEMBL)
PPP1R11ProteinQ5SRK2 (Uniprot-TrEMBL)
PPP1R12AProteinO14974 (Uniprot-TrEMBL)
PPP1R12BProteinQ6GQY8 (Uniprot-TrEMBL)
PPP1R12CProteinQ9BZL4 (Uniprot-TrEMBL)
PPP1R13BProteinQ96KQ4 (Uniprot-TrEMBL)
PPP1R14AProteinQ96A00 (Uniprot-TrEMBL)
PPP1R14BProteinQ96C90 (Uniprot-TrEMBL)
PPP1R14CProteinQ8TAE6 (Uniprot-TrEMBL)
PPP1R14DProteinQ9NXH3 (Uniprot-TrEMBL)
PPP1R15AProteinO75807 (Uniprot-TrEMBL)
PPP1R15BProteinQ5SWA1 (Uniprot-TrEMBL)
PPP1R16AGeneProductQ96I34 (Uniprot-TrEMBL)
PPP1R16BProteinQ96T49 (Uniprot-TrEMBL)
PPP1R1AProteinQ13522 (Uniprot-TrEMBL)
PPP1R1BGeneProductQ9UD71 (Uniprot-TrEMBL)
PPP1R1CProteinQ8WVI7 (Uniprot-TrEMBL)
PPP1R2ProteinP41236 (Uniprot-TrEMBL)
PPP1R3AProteinQ16821 (Uniprot-TrEMBL)
PPP1R3BProteinQ86XI6 (Uniprot-TrEMBL)
PPP1R3CProteinQ9UQK1 (Uniprot-TrEMBL)
PPP1R3DProteinO95685 (Uniprot-TrEMBL)
PPP1R3EProteinQ9H7J1 (Uniprot-TrEMBL)
PPP1R3FProteinQ6ZSY5 (Uniprot-TrEMBL)
PPP1R3GProteinB7ZBB8 (Uniprot-TrEMBL)
PPP1R7ProteinQ15435 (Uniprot-TrEMBL)
PPP1R8ProteinQ12972 (Uniprot-TrEMBL)
PPP1R9AProteinQ9ULJ8 (Uniprot-TrEMBL)
PPP1R9BProteinD3DTX6 (Uniprot-TrEMBL)
S1PProteinQ14703 (Uniprot-TrEMBL)
S2PProteinO43462 (Uniprot-TrEMBL)
SARS 8abGeneProduct
SARS EGeneProductP0DTC4 (Uniprot-SwissProt)
SARS, IBV infectionPathway
SARS, OC43, MHV, IBV infectionPathway
SProteinP0DTC2 (Uniprot-SwissProt)
XBP1GeneProductENSG00000100219 (Ensembl)
XBP1ProteinP17861 (Uniprot-TrEMBL)
XBP1uProteinP17861 (Uniprot-TrEMBL)
nsp15ProteinQ87917579 (Wikidata)

Annotated Interactions

No annotated interactions

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