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Source ontology files for the Gene Ontology
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Redundant terms for Gcn2–eIF2α signaling pathway #15399

Open ValWood opened 6 years ago

ValWood commented 6 years ago

summary of the biology from: PMID:29432178

One of the best-studied examples is the response to amino acid starvation. Amino acid starvation causes an accumulation of uncharged tRNAs, which activate a signaling pathway that leads to a reduction of the translation of the majority of cellular mRNAs. Simultaneously, the translation of specific mRNAs, some of them encoding key transcription factors, is induced. These transcription factors, in turn, launch a transcriptional program that promotes cellular survival under stress. This program is called the general amino acid control (GAAC) in yeast (2) and the amino acid response (AAR) in mammals (3).

Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59:407–450. Kilberg MS, Balasubramanian M, Fu L, Shan J (2012) The transcription factor network associated with the amino acid response in mammalian cells. Adv Nutr 3:295–306. the current term "cellular response to amino acid starvation" Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of deprivation of amino acids. PMID:7765311 Definition (GO:0070321 GONUTS page) Any process that modulates the frequency, rate or extent of the frequency, rate or extent of translation as a result of a stimulus indicating deprivation of nitrogen.

we also have GO:0070321 regulation of translation in response to nitrogen starvation

which seems like the translational repression represented by this pathway?

but it has no annotation or reference . If it is it might be better as regulation of translation in response to amino acid starvation?

the term I would like is "signaling in response to amino acid starvation" Any signaling that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of deprivation of amino acids.

This is a nice description of the conserved pathway

This translational response to amino acid depletion is medi- ated by proteins of the Gcn2 protein kinase family, which are conserved throughout eukaryotes (4). Gcn2 is activated by deacylated tRNAs and phosphorylates the translation initiation factor eIF2, which is required to deliver the initiator tRNA to the ribosome, in its α-subunit. eIF2 is a GTP-binding protein whose activation requires the activity of the GTP/GDP-exchange factor eIF2B, which facilitates the exchange of GDP with GTP. Phos- phorylated eIF2 binds to eIF2B with high affinity, behaving as a competitive inhibitor. As eIF2 is more abundant than eIF2B, this binding leads to the rapid sequestration of all cellular eIF2B and thus triggers a global down-regulation of translation (5).

ValWood commented 6 years ago

consider merging GO:0060733 regulation of eIF2 alpha phosphorylation by amino acid starvation

into this term? or renaming?

ValWood commented 6 years ago

I'm not sure what the rules are for signalling pathways...

ValWood commented 6 years ago

I will sort this at some point.

We have positive regulation of G2/M transition of mitotic cell cycle involved in cellular response to nitrogen starvation (GO:1905287)

which is the endosulphine signalling pathway.

I'm not sure how the positive and negative regulation within a pathway should be represented in GO.

It is this: https://user-images.githubusercontent.com/7359272/28414532-f9a20056-6d43-11e7-9b4c-c16d5de508f9.jpg

pgaudet commented 4 years ago

I think this was done here #19153 ?

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."

@ValWood is this right ?

ValWood commented 4 years ago

Yes GCN2-mediated signalling is the term I needed for the amino-acid starvation. I think this term

the annotations are all GCN2 and inhibitors except https://www.pombase.org/gene/SPAC6B12.15

I will come back to the endosulphine one soon. I'm doing the stress pathways in detail at the moment.

ValWood commented 4 years ago

https://www.pombase.org/gene/SPAC6B12.15 (cpc2) is also GCN2-mediated signalling https://www.pombase.org/reference/PMID:23671279

pgaudet commented 4 years ago

GO:0060733 regulation of eIF2 alpha phosphorylation by amino acid starvation could merge with GCN2-mediated signaling?

GO:0060733 has 8 EXP annotations, all part of the GCN2-mediated signaling.

pgaudet commented 4 years ago

There is not only a problem with the 'regulation of phosphorylation' parent class (GO:0010998 regulation of translational initiation by eIF2 alpha phosphorylation), but also with siblings:

merge into GO:0036499 PERK-mediated unfolded protein response (need to check if 'regulation' is appropriate or if annotations are to members of the pathway

Thanks, Pascale

ValWood commented 4 years ago

This kinase is HRI HRI-mediated signaling Exact synonym: EIF2AK1-mediated signaling

usually annotated to eukaryotic translation initiation factor 2alpha kinase activity I don't think we need a heme dependency (how is it dependent? it does not appear to bind to heme?)

ValWood commented 4 years ago

in heme deficiency, HRI is essential

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),

note that the existing synonym EIF2AK1-mediated signaling

should be narrow

I think the pathway can be

hdrabkin commented 4 years ago

The heme-regulated eIF2α kinase: see https://ashpublications.org/blood/article/109/7/2693/125631/Regulation-of-protein-synthesis-by-the-heme

ValWood commented 4 years ago

So it is also a heme sensor? i.e. eukaryotic translation initiation factor 2alpha kinase activity plus heme sensor?

"HRI phosphorylates the α-subunit of eukaryotic translational initiation factor 2 (eIF2α) in heme deficiency, thereby inhibiting protein synthesis globally. In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains."

the kinase is inactivated by heme binding, not heme-dependent is that right? this seems to be just one possible signal that is detected ?

The definitions of HRI signalling is Definition (GO:0140468 GONUTS page) 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

so there does not seem to be a need to instantiate heme-regulated kinase? it would be better to annotate the direction of regulation of signalling when heme is bound?

hdrabkin commented 4 years ago

Depends on which eif2a kinase we are talking about. Heme is probably only relevant for reticulocytes, etc. In other cell types, it is activated by dsRNA. "In addition to HRI, 3 other eIF2kinases are known: the double-strandedRNA-dependent eIF2kinase (PKR), the GCN2 protein kinase,and the ER resident kinase (PERK). The 4 eIF2kinases share: .."

ValWood commented 4 years ago

maybe the existing term needs to mnore tightly defined, and the heme part needs its own activity. It seems like an overkill though because many kinases are going to also act as sensors. I am annotating one right now:

mak2 is a protein histidine kinase activity and a peroxide sensor activity

ValWood commented 4 years ago

Depends on which eif2a kinase we are talking about

Harold, there are 4 pathways for pathways that converge on eIF2 alpha named for the terminal kinases:

GO:0140468    HRI-mediated signaling GO:0036499    PERK-mediated unfolded protein response GO:0039585    PKR-mediated signaling GO:0140469    GCN2-mediated signaling

pgaudet commented 4 years ago

I will do those

merge into GO:0036499 PERK-mediated unfolded protein response (need to check if 'regulation' is appropriate or if annotations are to members of the pathway

Not sure what the action is for GO:0010999 regulation of eIF2 alpha phosphorylation by heme.

Thanks, Pascale