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]. 


[-:-]	Unknown node in line: Attribute
[-:-]	Unknown node in line: Attribute
[DataNode:-]	Empty GraphId found. Replacing with: gen_dn_0
[ARROW:id74bb08d8]	Curved connections are not supported.
[LINE:id7ca4460d]	Curved connections are not supported.
[TRANSCRIPTION_TRANSLATION:idcbd96fe9]	Invalid interaction type.
[STIMULATION:idc7e2ae4]	Invalid interaction type.
[LINE:idda829af2]	Invalid interaction type.
[TRANSCRIPTION_TRANSLATION:id315b7e46]	Invalid interaction type.
[Unfolded
protein:b00dc]	 Shape can not be part of reaction. Tranforming to Unknown
[Unfolded
protein:c7ab8]	OVAL cannot be part of a complex. Skipping.
[Legend:f69de]	RECTANGLE cannot be part of a complex. Skipping.
[Unfolded
protein:ad34c]	OVAL cannot be part of a complex. Skipping.
[Complex:ddb54]	Empty element is invalid
[Complex:d8eef]	Empty element is invalid
[Complex:a2d12]	Empty element is invalid
[Complex:fad77]	Empty element is invalid