gpt1 unfolded protein response?

[ValWood]

this gives a violation, and looks odd as "unfolded protein response" is a signalling pathway

assign to original curator when canto back

[Antonialock]

This was from a genetic interactions paper. I removed the annotations to UPR, I don't think it is very good evidence for BPs.

According to PMID:23066505 the UPR in pombe is different from cerevisiae. In cereivisae, Ire1 activates the UPR by direct splicing of an mRNA. This trigger the increased expression of ER genes and boosts ER protein folding capacity. This role is conserved in metazoa.

In PMID:23066505 it is shown that in pombe, activation of ire1 leads to the decay of mRNAs that all encode proteins entering the ER. "in Drosophila cells that Ire1 induction not only results in splicing of XBP1 mRNA but also mediates enhanced mRNA breakdown. This output of Ire1 activation, termed ‘regulated Ire1-dependent decay’ (RIDD), is conserved in mammalian cells, but not in S. cerevisiae,"

RIDD seems fairly well established https://www.ncbi.nlm.nih.gov/pubmed/26108623 But there is not GO term for it? Should I request? there is already a term for the "other" downstream happenings from ire1

IRE1-mediated unfolded protein response 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.

[ValWood]

I don't really know anything about this, I have only ever annotated to these from inference. Let's leave for now. Can come back to this....

[Antonialock]

It's ok, it is not very complicated,

In cerevisiae/metazoa during ER stress, ire1 cleaves a transcript called HAC1/XBP1, this leads to expression of more folding proteins, and increased folding capacity.

In pombe/meatazoa during ER stress, ire1 selectively degrades "difficult to fold" proteins, thereby giving the protein folding machinery an easier time.

Physiologically it looks like a really important pathway (development, drug target..).

Look at this diagram:

"The two Ire1 functions, RIDD and splicing of Xbp1 mRNA, can be uncoupled in vitro, allowing a better understanding of the physiological output of each pathway."

[Antonialock]

(A) S. cerevisiae Ire1 is activated by ER stress. Upon activation, Ire1 undergoes trans-autophosphorylation and oligomerization. HAC1 mRNA is spliced by activated Ire1 through its RNase domain. Upon translation, transcription factor Hac1 up-regulates UPR target genes to restore homoeostasis.

(B) In S. pombe upon ER stress, Ire1 triggers downstream RIDD; the protein BiP1′s poly-A tail is recognized and cleaved by RIDD, but BiP1 protein is stabilized despite the cleavage of its mRNA. BiP1 protein is important for cell survival during stress condition; there are possible unknown candidates also involved in stress response, either in ER lumen or on ER membrane.

[Antonialock]

i also removed the annotation from cnx1 and ire1 from the interactions paper.

ire1 is now replaced with experimental evidence from 24768994 calnexin has ISO

[ValWood]

Hi

Can you list which annotations were deleted here? I need to collate them,

Thanks

Val

[ValWood]

Interesting. I remember spending ages trying to find hac1...

[Antonialock]

hah, typical eh...If this is true then what's pretty cool is that human retained both pathways whereas yeast ditched different ones...seems unusual

[Antonialock]

The only annotation that will disappear is gpt1 GO:0030968 endoplasmic reticulum unfolded protein response IMP

From the same paper ( PMID:22682253) I also removed the same annotation from cnx1 and ire1 (because the evidence wasn't very good in that paper) but I found a different paper supporting an exp annotation for ire1 and cnx1 will have an ISO.

[ValWood]

was this "indirect" or just plain "annotation error"

[Antonialock]

weak evidence, genetic interactions and nothing else. I think the annotation is correct for ire1 but not gpt1

[ValWood]

OK thanks! genetic interactions are not good unless there is a really strong phenotype uniquely associated with the process.