possible issues with "unfolded protein response"

[ValWood]

I am annotating a paper on UPR in pombe.

However, I can't use the existing term

GO:0030968 endoplasmic reticulum unfolded protein response

because it is defined

The series of molecular signals generated as a consequence of the presence of unfolded proteins in the endoplasmic reticulum (ER) or other ER-related stress; results in changes in the regulation of transcription and translation. PMID:12042763

and positioned

Ie as a signalling pathway.

AS the process results in the attenuation of translation (and this is invoked in pombe by using the NMD system to degrade mRNA), it seems to be much broader than signalling (although there is obviously a signalling component...

The pathway I am annotating is RIDD:

Additionally, as first demonstrated in D. melanogaster, Ire1 initiates a reaction termed regulated Ire1-dependent mRNA decay, or RIDD, the selective decay of ER-bound mRNAs, 66 thereby reducing the load of protein entering the ER (Hollien and Weissman, 2006).

RIDD occurs in mammalian cells and plants, but not in S.  cerevisiae, where the HAC1 mRNA splicing reaction is the sole output of UPR signaling (Niwa  et al., 2005). In striking contrast, in S. pombe RIDD is the sole output of Ire1.

I don't think we necessarily need a specific term for RIDD (it seems to be mRNA decay part_of GO:0030968 endoplasmic reticulum unfolded protein response

but it doesn't fit the GO:0030968 def.

Any suggestions?

[ValWood]

I'm annotating PMID: 28945192

[ValWood]

https://en.wikipedia.org/wiki/Unfolded_protein_response says that translation attenuation is part or UPR.

so the signalling parentage seems too restrictive?

[ValWood]

"Here, we discovered that in S. pombe the NGD machinery Dom34/Hbs1 and the exosome-associated Ski-complex are critical players in the UPR, acting downstream of Ire1- catalyzed mRNA cleavage"

[ValWood]

So once this is resolved, I think it might be clearer to have a term for RIDD.

If this is appropriate it would be along the lines:

degradation of ER-bound mRNAs synonym RIDD==? synonym Ire1-dependent mRNA decay, def: part of the Unfolded protein response resulting in selective degradation of ER bound mRNAs to attenuate translation in response to ER stress. Mediated by the endonuclease activity of Ire1 and the nonsense mediated decay pathway.

Note that we currently have a term GO:0036498 JSON IRE1-mediated unfolded protein response

but this is defined: A series of molecular signals mediated by the endoplasmic reticulum stress sensor IRE1 (Inositol-requiring transmembrane kinase/endonuclease). Begins with activation of IRE1 in response to endoplasmic reticulum (ER) stress, and ends with regulation of a downstream cellular process, e.g. transcription. One target of activated IRE1 is the transcription factor HAC1 in yeast, or XBP1 in mammals; IRE1 cleaves an intron of a mRNA coding for HAC1/XBP1 to generate an activated HAC1/XBP1 transcription factor, which controls the up regulation of UPR-related genes. At least in mammals, IRE1 can also signal through additional intracellular pathways including JNK and NF-kappaB. PMID:22013210

This is describing only one activity of Ire1 (intron cleavage to activate a TF), the def does not fir RIDD

[ValWood]

I mailed the author about this one. Despite this pathway being referred to as a signalling pathway in the literature, there are clearly components of the UPR response which are not "signalling".

Any input from anyone who knows anything about this area appreciated....

[ValWood]

I have also asked the author.

[krchristie]

I can see a case for making a term for RIDD or "mRNA decay in response to unfolded proteins", or whatever name seems best.

However, I'm understand what you think the problem with the definition of "endoplasmic reticulum unfolded protein response, GO:0030968".

[ValWood]

Hi Karen,

The problem is that I think RIDD causes a true path violation.

"unfolded protein response" is described as a signalling pathway , and has "signalling " parentage.

The part of the UPR described in RIDD involves the process of mRNA cleavage and involves components of the noGO decay pathway (dom34 peloto and the Ski complex). To me it seems really strange to have these annotated to "signalling" but hey do appear to be part of the RIDD-UPR which leads to translation attenuation.

People do refer to the UPR as a signalling pathway though. So I'm a bit stuck ....it seems that logically the UPR must be more than just signalling.

I mailed the author for input but I didn't hear back yet.....

[ValWood]

From the author:

• The UPR is a signaling pathway. We are studying the RIDD branch of the pathway, which by some definitions, might not be considered signaling (as you suggested), because the output is mRNA decay. From reading the definition of signaling, this seems to be a bit of a grey area but I tend to agree with your assessment.
• I wonder whether GO:0036498 is the most reasonable term to put these 4 genes under (without signaling parentage) since it is specific as to which part of the UPR that is involved. (Or the new GO term for ER-bound mRNA catabolic process you propose).

[ValWood]

Note that: i) The author agrees this isn't signalling ii) we can't use GO:0036498 because it Does have a signalling parent

Therefore I think an new term for the RIDD pathway without a signalling parent is required.

[pgaudet]

Assigned @vanaukenk because I think she has been looking at this pathway recently.