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Source ontology files for the Gene Ontology
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Integrated Stress Response #19153

Closed sylvainpoux closed 4 years ago

sylvainpoux commented 4 years ago

Hello Pascale (@pgaudet )

following our discussion please find a draft definitions for 2 new terms

Thanks

Sylvain

1) Create: Category: Process Name: Integrated stress response signaling Definition: 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. Synonym: ISR Cross-ref: PMID:27629041 https://en.wikipedia.org/wiki/Integrated_stress_response

Child of GO:0033554 cellular response to stress

parent of? GO:0036499 PERK-mediated unfolded protein response GO:0039585 PKR signal transduction

and we should maybe create terms for the 2 other downstream kinases EIF2AK1/HRI and EIF2AK4/GCN2 (there are Reactome terms for them)

Should be link the following terms to HRI? Not sure as there might be other stress responses not linked to Integrated stress response

GO:0035967 cellular response to topologically incorrect protein GO:0034198 cellular response to amino acid starvation GO:0042149 cellular response to glucose starvation GO:1903916 regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation GO:1903917 positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation GO:1903912 negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation GO:1903898 negative regulation of PERK-mediated unfolded protein response GO:1903899 positive regulation of PERK-mediated unfolded protein response

Delete these terms? We already have Function terms for eiF2alpha phosphorylation/dephosphorylation GO:0036497 eIF2alpha dephosphorylation in response to endoplasmic reticulum stress GO:0036492 eiF2alpha phosphorylation in response to endoplasmic reticulum stress GO:0060733 regulation of eIF2 alpha phosphorylation by amino acid starvation

2) Create: Category: Process Name: Response to mitochondrial stress Definition: Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of mitochondrial stress. Cross-ref: PMID:32132706, PMID:32132707

Child of GO:0033554 cellular response to stress parent of GO:0034514 mitochondrial unfolded protein response

ValWood commented 4 years ago

This will be complicated.

As far as I know (I am not certain about this) there are (at least) 2 things mixed here.

I suspect the "integrated stress response" is what fission yeast researchers call "core environmental stress response" (signals through MAP kinase pathway). There are separate pathways for (nitrogen) starvation and oxidative stress signalling through different MAPK modules. The starvation one is the one which has the eiF2 alpha effector.

There are also different responses for oxygen starvation (hypoxia), signalling in conjunction with ergosterol levels and through SPEBP signalling. This does not go through MAPK and is a different response.

Although some responses are common to many stresses, they are, as far as I know, often differently activated.

So I am not sure how well this suggestion would work across species. I think we might need to keep this more modular.

That said, I do agree that we should remove the "eiF1alpha de/phosphorylation terms", these just make thing more complicated than it already is (MF in BP ontology). Maybe that would be a good first task here?

ValWood commented 4 years ago

OK, "Integrated stress response" is also used by yeast (I have never seen it used by pombe, but it is clearly adopted by yeast)

A useful recent review https://www.ncbi.nlm.nih.gov/pubmed/29167799 This conserved stress response in yeast was termed the General Amino Acid Control (GAAC) because it was initially identified as a response to amino acid depletion that upregulates the genes required for amino acid synthesis 7. However, we now know that this same yeast stress response pathway is also activated by starvation for purines 8, glucose limitation/depletion 9, ER stress 10, growth on non-fermentable carbon sources like ethanol 9, high salt 11, treatment with alkylating agents 12, and TOR inhibition 13,14. As such, here we refer to this yeast stress response pathway by the name used in multicelluar eukaryotes, the Integrated Stress Response (ISR) 15.

So it this essentially a term to encompass ALL stress signalling? That would be useful.... We proba bly need to keep the signalling pathways and the actual responses separate.

ValWood commented 4 years ago

Also see: https://github.com/geneontology/go-ontology/issues/13717 I tried to rationalize some of the terms in this area because it seems very confusing. Perhaps the first step would be to identify all of the terms in this area and then see which ones mean the same, or related things?

I was/am very keen to have a grouping term for PQC (protein quality control system) as many papers seem to use this as the broader grouping. This is becoming increasingly important. The paper I am reading right now:

"Because the hallmarks of many neurodegenerative disorders are aggregates of misfolded proteins (such as huntingtin in Huntington disease or beta-amyloid in Alzheimer disease), the presence of protein aggregates in cells has often been linked to toxicity, so that preventing aggregate formation and accumulation is still proposed to be a priority goal of the PQC system. However, recent evidence demonstrating active and regulated deposition of misfolded polypeptides into specialized cellular locations challenges the view that links aggregation and toxicity." Chaperone-Facilitated Aggregation of Thermo-Sensitive Proteins Shields Them from Degradation during Heat Stress. Cabrera M, Boronat S, Marte L, Vega M, Pérez P, Ayté J, Hidalgo E. Cell Rep. 2020 Feb 18;30(7):2430-2443.e4. doi: 10.1016/j.celrep.2020.01.077. PMID: 32075773

Perhaps a good approach would be to try to revise and group the PQC first, and then address the changes in response to starvation. I know that they overlap but they are also distinct.

pgaudet commented 4 years ago

-- GO:0036499 PERK-mediated unfolded protein response -- GO:0039585 PKR signal transduction

pgaudet commented 4 years ago

+ +[Term] +id: GO:0140468 +name: HRI-mediated signaling +namespace: biological_process +def: "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." [PMID:27629041] +synonym: "EIF2AK1-mediated signaling" EXACT [] +is_a: GO:0140467 ! integrated stress response signaling +property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/19153 xsd:anyURI +created_by: pg +creation_date: 2020-05-26T08:46:15Z + +[Term] +id: GO:0140469 +name: GCN2-mediated signaling +namespace: biological_process +def: "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." [PMID:27629041] +synonym: "EIF2AK4-mediated signaling" EXACT [] +is_a: GO:0140467 ! integrated stress response signaling +property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/19153 xsd:anyURI +created_by: pg +creation_date: 2020-05-26T08:47:25Z

pgaudet commented 4 years ago

@sylvainpoux Please give me any feedback on those terms.

sylvainpoux commented 4 years ago

Hi Pascale,

I slightly changed definitions for these 2 terms (I only added something about the type of stress that trigger these kinases, as each kinase is activated by a different stress)

Apart from that, your definitions are fine for me.

Many thanks

Sylvain

GO:0140468 HRI-mediated signaling biological_process 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." [PMID:27629041]

GO:0140469 GCN2-mediated signaling biological_process "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." [PMID:27629041]

pgaudet commented 4 years ago

Also:

pgaudet commented 4 years ago

This is all we'll do for now.