Endoplasmic reticulum stress response in coronavirus infection (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Endoplasmic reticulum stress response in coronavirus infection" Version="20200325" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">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]. </Comment> <BiopaxRef>be0</BiopaxRef> <BiopaxRef>e5b</BiopaxRef> <Graphics BoardWidth="1855.0" BoardHeight="1000.5" /> <DataNode TextLabel="dsRNA" GraphId="a90b0" Type="Rna"> <Graphics CenterX="376.4915966386533" CenterY="569.3277310924371" Width="66.0084033613445" Height="25.0" ZOrder="28672" FontSize="12" Valign="Middle" ShapeType="RoundedRectangle" /> <Xref Database="Wikidata" ID="Q2819370" /> </DataNode> <DataNode TextLabel="S" GraphId="bd05e" Type="Protein" GroupRef="fbe6f"> <Graphics CenterX="892.333333333332" CenterY="180.3333333333336" Width="70.66666666666401" Height="22.666666666667197" ZOrder="28672" FillColor="ffcccc" FontWeight="Bold" FontSize="12" Valign="Middle" ShapeType="RoundedRectangle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DTC2" /> </DataNode> <DataNode TextLabel="ER protein chaperones&#xA;Lipid biosynthesis&#xA;ER-associated degradation" GraphId="c085b" Type="Pathway"> <Graphics CenterX="1150.5" CenterY="841.25" Width="159.0" Height="55.5" ZOrder="28672" FontSize="12" Valign="Middle" ShapeType="None" /> <Xref Database="" ID="" /> </DataNode> <DataNode TextLabel="Amino acid synthesis&#xA;Antioxidant response&#xA;Apoptosis" GraphId="c90ec" Type="Pathway"> <Graphics CenterX="557.5" CenterY="834.75" Width="133.0" Height="48.5" ZOrder="28672" FontSize="12" Valign="Middle" ShapeType="None" /> <Xref Database="" ID="" /> </DataNode> <DataNode TextLabel="CRE&#xA;cAMP response element" GraphId="d0da6" Type="GeneProduct"> <Graphics CenterX="557.5" CenterY="740.75" Width="143.0" Height="34.5" ZOrder="28672" FontSize="12" Valign="Middle" /> <Xref Database="" ID="" /> </DataNode> <DataNode TextLabel="MERS 4a" GraphId="d43bc" Type="Protein"> <Graphics CenterX="495.7983193277302" CenterY="569.3277310924374" Width="71.4285714285701" Height="25.0" ZOrder="28672" FillColor="ffcccc" FontSize="12" Valign="Middle" ShapeType="RoundedRectangle" /> <Xref 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CenterX="129.0" CenterY="858.0" Width="75.0" Height="25.0" ZOrder="32857" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96A00" /> </DataNode> <DataNode TextLabel="PPP1R3C" GraphId="db1be" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="55.0" CenterY="808.0" Width="75.00000000000001" Height="25.0" ZOrder="32858" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UQK1" /> </DataNode> <DataNode TextLabel="PPP1R3G" GraphId="afccf" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="55.0" CenterY="908.0" Width="75.00000000000001" Height="25.0" ZOrder="32859" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="B7ZBB8" /> </DataNode> <DataNode TextLabel="PPP1R15B" GraphId="eeb86" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="205.0" CenterY="708.25" Width="75.0" Height="25.0" ZOrder="32860" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q5SWA1" /> </DataNode> <DataNode TextLabel="PPP1R12A" 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Database="Uniprot-TrEMBL" ID="Q86XI6" /> </DataNode> <DataNode TextLabel="PPP1R3D" GraphId="dd050" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="55.0" CenterY="833.0" Width="75.00000000000001" Height="25.0" ZOrder="32865" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95685" /> </DataNode> <DataNode TextLabel="PPP1R10" GraphId="dece4" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="129.0" CenterY="708.0" Width="75.0" Height="25.0" ZOrder="32866" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96QC0" /> </DataNode> <DataNode TextLabel="PPP1CB" GraphId="c2427" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="129.0" CenterY="633.0" Width="75.0" Height="25.0" ZOrder="32867" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62140" /> </DataNode> <DataNode TextLabel="PPP1CC" GraphId="ac9fc" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="205.0" CenterY="633.25" Width="75.0" Height="25.0" ZOrder="32868" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P36873" /> </DataNode> <DataNode TextLabel="PPP1CA" GraphId="a4047" Type="Protein" GroupRef="af1d3"> <Graphics CenterX="55.0" CenterY="633.0" Width="75.00000000000001" Height="25.0" ZOrder="32869" FontSize="12" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62136" /> </DataNode> <DataNode TextLabel="CHOP" GraphId="ee767" Type="GeneProduct" GroupRef="b56cd"> <Graphics CenterX="1412.011057054401" CenterY="824.3931888544886" Width="68.0000000000001" Height="24.99999999999995" ZOrder="32883" FontSize="12" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000175197" /> </DataNode> <DataNode TextLabel="XBP1" GraphId="c4311" Type="GeneProduct" GroupRef="b56cd"> <Graphics CenterX="1412.0110570544011" CenterY="799.3931888544887" Width="68.0" Height="25.0" ZOrder="32884" FontSize="12" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000100219" /> </DataNode> <State GraphRef="e0e36" TextLabel="P" GraphId="c5e53"> <Comment>Ser242, Thr255, Thr258, Ser83, Thr88, Thr89, Thr90, Thr446, and Thr451</Comment> <Graphics RelX="0.9823008849557522" RelY="-1.0" Width="15.0" Height="15.0" ShapeType="Oval" /> <Xref Database="" ID="" /> </State> <State GraphRef="b6968" TextLabel="P" GraphId="cd612"> <Comment>parentid=P05198; parentsymbol=EIF2S1; site=IEGMILLsELsRRRI; position=ser49; sitegrpid=450210; ptm=p; direction=u</Comment> <Graphics RelX="1.0" RelY="1.0" Width="15.0" Height="15.0" ShapeType="Oval" /> <Xref Database="" ID="" /> </State> <State GraphRef="b6968" TextLabel="P" GraphId="db803"> <Comment>parentid=P05198; parentsymbol=EIF2S1; site=MILLsELsRRRIRsI; position=ser52; sitegrpid=447635; ptm=p; direction=u</Comment> <Graphics RelX="1.0" RelY="-1.0" Width="15.0" Height="15.0" ShapeType="Oval" /> <Xref Database="" ID="" /> </State> <State GraphRef="a273e" TextLabel="P" GraphId="ef875"> <Comment>parentid=O75460; parentsymbol=ERN1; site=KLAVGRHsFsRRsGV; position=ser724; sitegrpid=7161100; 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</bp:PublicationXref> <bp:openControlledVocabulary xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#"> <bp:TERM xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">stress response pathway</bp:TERM> <bp:ID xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PW:0000237</bp:ID> <bp:Ontology xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pathway Ontology</bp:Ontology> </bp:openControlledVocabulary> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="f7b"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">21543844</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The structure of the PERK kinase domain 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<bp:Ontology xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Disease</bp:Ontology> </bp:openControlledVocabulary> </Biopax> </Pathway>

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