translation factors, various

[ValWood]

I'm trying to build a GO-CAM of mitochondrial translation , and I see many issues with translation factors.

1. translation initiation factor
   is under "translation initiation" but is also under regulation fo translation".
   This seems incorrect, the initiation factors are part_of translation?

2. We don't have a way to describe the individual activities of "translation initiation factors"
   These include:

Inhibit the recruitment of the ribosome large subunit to the small subunit (via mtIF3) (until the initiation complex is properly assembled)
Recruit the small ribosomal subunit to the initiator tRNA (Formation of the Pre-Initiation Complex (PIC)) involving mtIF2 and fMet-tRNAi).
Recruit small ribosomal subunit to the mRNA (no need for cap recognition or extensive mRNA recruitment).
Recruit initiator tRNA to the small ribosomal subunit (via mtIF2).
Start codon recognition (via mtIF2 and GTP hydrolysis).
Recruit the large subunit to form the complete initiation complex.

(for all initiation and a few extra activities for eukaryotic)

3. The description of "translation iniitation" factor is vague
   Defined Functions in the initiation of ribosome-mediated translation of mRNA into a polypeptide.

but there are factors that act upstream of these iniitation steps in 'pre-initiation' (PPR proteins that act generally to recruit mRNAs, and to recruit TIFs to the ribosome are not themselves considered to be TIFs but fit this definition).

[ValWood]

4. mRNA regulatory element binding translation repressor activity
   should be is_a
    translation factor activity, RNA binding

[ValWood]

5. translation initiation factor activity
   is_a translation factor activity RNA binding but this is not always true

[ValWood]

6. translation activator activity is a subclass of “translation regulator activity, nucleic acid binding
   but some translation factors don’t bind mRNA directly

[ValWood]

7. the positioning of inititation, elongation and termination factors under
   GO:0008135 translation factor activity, RNA binding
   is problematic because not all of these factors bind to RNA it seems, for example "mtEFG1: This factor is involved in the translocation of the ribosome along the mRNA after peptide bond formation, similar to EF-G in prokaryotic translation. It interacts with the ribosome but does not bind mRNA directly"
   mtRRF (Mitochondrial Ribosome Recycling Factor): This factor helps disassemble the ribosomal complex after translation. While it is crucial for terminating translation, it does not bind mRNA directly.
   there appear to be a number of translation factors that don't bind to RNA (also this doesn't seem to be an ideal way to classify these activities)

[ValWood]

Step 1, obsolete the terms with "nucleic acid binding"
Step 2 separate "translation factors from translation regulators GO:0008135
translation factor activity, RNA binding
Step 3 make the RNA binding terms children of the more general terms

[ValWood]

The problems here are big.

Translation regulator activity is defined:
Any molecular function involved in the initiation, activation, perpetuation, repression or termination of polypeptide synthesis at the ribosome.

So this includes all translation factors, involved in translation and has the parentage:

This means that ALL translation factors, become annotated to "regulation of translation" even if they are actually part_of translation. This is a perpetual problem with making MF term "translation factor" . I'm not sure how to fix this.

[ValWood]

Here is a radical proposal.
We obsolete all of the translation factor/translation regulator terms.
We should be annotating to the activities,a nd if we don't know tham, just the process.

So for termination factor PomBase has 10 annotations
8 have an activity in addition. to translation termination factor
erf1 GTPase regulator activity
sup35 GTPase activity
hsb1 GTPase activity
dom35 GTPase regulator activity
pth3 aminoacyl-tRNA hydrolase activity
pth4 aminoacyl-tRNA hydrolase activity
mrf1 ?
rrf1 ? this might be ribosome disassembly
tif51 ? possibly a ribosome RNA adaptor?
tif512 ? possibly a ribosome RNA adaptor?

so the question (which has been raised before) is what do we mean by "translation factors" other than "an entity involved in translation". These should really be synonyms of the related process rather than trying to collect a bag of unrelated functions.

Then we would only need to deal with "translation regulator" which could probably be similarly addressed?

[ValWood]

Some of the translation regulators probably make sense but need better labels

GO:1903231 mRNA base-pairing translational repressor activity
A translation repressor activity that acts by base-pairing with an mRNA. The binding can result in targeting the mRNA for degradation or interfering with mRNA translation, hence resulting in posttranscriptional gene silencing. PMID:18197166 PMID:20533884

Comments
This term is intended for microRNAs that act by base-pairing with a target mRNA.

reading this term label, I would not know it was intended for microRNAs

[pgaudet]

Please feel free to suggest a better label for GO:1903231 mRNA base-pairing translational repressor activity
@RLovering @hattrill @gantonazzo and I didn't love it either! but we couldn't think of anything better at the time.

[hattrill]

GO:1903231 mRNA base-pairing translational repressor activity is not just for miRNAs, but other classes of ncRNA - as it describes the activity not the type of ncRNA, I think it is better than mRNA binding.

The only thing I can think of is to change it to: mRNA base-pairing mediated posttranscriptional gene silencing - which divorces it from translational regulator activity but is a bit of a mouthful.

[hattrill]

Bit wary of getting rid of some of the activities under translation factor/translation regulator terms as things like 'GTPase activity' very vague and are really describing the 'switch' rather than mechanism.

[ValWood]

Ok, we can keep the "translation factors", but in this case we need a clearer separation between "translation factors" which are part of translation and the other types of "translation regulators" that act upstream of translation.
In this case, maybe the simplest solution is to have:

translation regulator
-- group all regulators under here
translation factor
-- translation initiation factor
-- translation elongation factor
-- translation termination factor

?

[hattrill]

I think that seems like a good idea. I would even suggest that if we can separate the translation factors from this, then 'translation regulator activity' could go as this is vague. But perhaps hive off the translation factors first and see what annotations we are left with.

[ValWood]

I will do this.

I did want to annotate this mitochondrial complex as a pre-initiation "translation activator" as it's a regulator but upsteam of initiation, and it is a specific factor not a general one. That's what began this ticket IIRC.
We'll see..... I'll tackle this next week.

[ValWood]

In this case, how would we define "translation factor activity"?

The specific translation factors are defined
GO:0008079 translation termination factor activity
Functions in the termination of translation.

GO:0008135 translation factor activity, RNA binding
Functions during translation by binding to RNA during polypeptide synthesis at the ribosome.

This would make
translation factor
Functions during translation

but this isn't correct because the gene specific regulators upstream of the initiation factors also function during translation.
Any suggestions? @hattrill @pgaudet

[pgaudet]

Proposal: translation factor def: A molecular function required for translation of a mRNA into a protein. Functions either during part of initiation, elongation or termination of translation.

[ValWood]

I just spotted that @raymond91105 had a comment about regulators. just as the call ended. Could you paste it here? thanks
Val

[ValWood]

We should then tease out the individual activities for the "factors"
https://www.nature.com/articles/s41580-023-00624-9?fromPaywallRec=false
and add child terms with parents to actual activities

[raymond91125]

I just spotted that @raymond91105 had a comment about regulators. just as the call ended. Could you paste it here? thanks Val

Are ALL "translation factors" involved in ALL translations thus any factors that are only involved in SOME translations are regarded as "translation regulators"?

[ValWood]

Good question. I think this is how transcription is modelled (more or less)
All the core machinery is part_of , and the gene specific parts are regulators.
@pgaudet ?

[pgaudet]

I dont know the exact biology - but I dont think ALL "translation factors" need to be involved in ALL translations; we can have processes that are mediated by various versions of a complex in different conditions

@raymond91125 did I understand your question correctly?

[raymond91125]

I think in that sense, the various versions would still be of one MF which participants in ALL translations.
Formally, translation has_part some translation factor activity; and it's not true that translation has_part some translation regulator activity.
Nothing in biology is 100% so ALL should probably be MOST. Then the formal definition (has_part) does not apply.
Just to emphasize that I am no expert in translation terminology.

[sjm41]

Proposal: translation factor def: A molecular function required for translation of a mRNA into a protein. Functions either during part of initiation, elongation or termination of translation.

There are also 'recycling/reinitiation factors' - I'm not sure if these also need to be considered here.
We wrote a short review of the fly cyto & mito translation factors a few years ago that might be helpful in terms of general classification - contains citations to several more comprehensive reviews:
https://www.tandfonline.com/doi/full/10.1080/19336934.2016.1220464#abstract

[ValWood]

Not all initation factors are involved in all iniitations. SOme are only involved in initiation in response to stress.
The distinction we are trying to make for the regulators is that they act pre-initiation.

The current definition of initiation is "
Definition | Parents
The process preceding formation of the peptide bond between the first two amino acids of a protein. This includes the formation of a complex of the ribosome, mRNA or circRNA, and an initiation complex that contains the first aminoacyl-tRNA. 

The important part of this definition is really the second clause, if my understanding is correct, initiation is the formation of the formation of a complex of the ribosome, mRNA or circRNA, and an initiation complex that contains the first aminoacyl-tRNA. 

the steps which support individual RNAs incorporation into the initiation complex are called 'translation regulators' but not called translation factors . I guess this is because they are not part of the translation machinery per se (perhaps this should be in the definitions of the translation and translation factor terms?).

[ValWood]

There are also 'recycling/reinitiation factors' - I'm not sure if these also need to be considered here.

good point. Most of the "recycling factors appear to also be described as initiation and termination factors. For example
translation release factor activity mrf1 is a recycling factor.

We also have the term "translation reinitiation," which is part of "translation initiation" (reinitiation appears to be considered to be part of ribosome recycling). We have a term "GO:0032790 ribosome disassembly" which is not related to translation (but has the narrow synonym ribosome recycling.

"ribosome disassembly" has one child "rescue of stalled ribosome" (which is linked to translational elongation)

I'm not sure that "ribosome disassembly" is a great term, because the ribosome is dissembled by different pathways in different contexts
i) ribosome quality control pathways (to deal with problems during elongation)
ii) ribosome recycling (after termination)

I'm hoping that all of the recycling factors are also initiation or termination factors and this part can be punted.

[ValWood]

I wonder if, because we know all of the translation factors (I can't remember a new cytosolic one being published while working on fission yeast?), I can just list the complexes in the respective definition gloss. This shouldn't really be an annotation issue because everyone knows which gene products/complexes are tifs- it should only be an ontology issue.
Once the rearrangement is done it will be easy to use the matrix to check for annotation outliers.