Define starts and ends for integrated stress response signaling (ISR)

[cmungall]

currently there are 36 genes in human annotated to this which seems high

The definitions are inconsistent in how they are phrased, and whether they talk about starts or ends:

• [] GO:0140467 ! integrated stress response signaling "The series of molecular signals generated in response to diverse stress stimuli required to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eIF2 alpha by one of four members of the eIF2a kinase family (EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK and EIF2AK4/GCN2), which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery."
  • [i] GO:0140469 ! GCN2-mediated signaling "A series of reactions in which a signal is passed on to downstream proteins within the cell via GCN2 (also known as EIF2AK4), an intracellular protein kinase that is activated by stress signals, such as amino acid starvation."
  • [i] GO:0140468 ! HRI-mediated signaling "A series of reactions in which a signal is passed on to downstream proteins within the cell via HRI (also known as EIF2AK1), an intracellular protein kinase that is activated by stress signals, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock."
  • [i] GO:0039585 ! PKR/eIFalpha signaling "An intracellular signaling cassette that starts with activation and autophosphorylation of PKR (also known as EIF2AK2), which phosphorylates proteins including the translation initiation factor eIF2 to inhibit translation. PKR is activated by stress signals and during the antiviral response, activated by binding to viral double-stranded RNA (dsRNA) leading to inhibition of protein synthesis during viral infection."
  • [i] GO:0036499 ! PERK-mediated unfolded protein response "The series of molecular signals mediated by the endoplasmic reticulum membrane stress sensor PERK (PKR-like ER kinase). Begins with activation of PERK** in response to endoplasmic reticulum (ER) stress and ends with regulation of a downstream cellular process, e.g. transcription. The main substrate of PERK is the translation initiation factor eIF2alpha. Serine-phosphorylation of eIF2alpha by PERK inactivates eIF2alpha and inhibits general protein translation. In addition, eIF2alpha phosphorylation preferentially increases the translation of selective mRNAs such as ATF4 (activating transcription factor 4), which up regulates a subset of UPR genes required to restore folding capacity."

I propose we model ISR as starting with the activity of the member of the eIF2a kinase family.

Note this would rule out annotations to e.g DELE1
https://amigo.geneontology.org/amigo/reference/PMID:32132706

However, an argument could be made for including this (the def for the PKR form starts "starts with the activation of..."). But we should be clear and consistent!

The end point is trickier. The PERK form is the only one to talk about the end and it says a generic ends with regulation of a downstream cellular process, e.g. transcription. In this case, this could be anything. It could be argued that the endpoint is the transcription regulated by ATF-4 but some might consider it to be extended to include GADD34.

Tangentially related:
geneontology/noctua-alliance-pathway-preview#16

[ValWood]

@PCarme we can put integrated stress response on our target pathway list since fission yeast is used as a complementary
model our PI works on this ! https://pubmed.ncbi.nlm.nih.gov/33313903/

Also tagging @sylvainpoux who has done a lot of work on the human annotation for this area.

So we have 2 experts.