obsolete redundant terms in autophagy branch

[ValWood]

1. mitochondrion disassembly is a strange term? It has a single child mitochondrion autophagy (should these be merged?)

2. What is the difference between "autophagy of mitochondrion" and the child mitophagy?

3. Types of mitophagy in GO are: -mitophagy

   • macromitophagy
   • mitophagy by induced vacuole formation

However the paper I am reading describes 2 types of mitophagy

How do these relate to the GO terms?

4. Finally GO:0061734 parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization

seems a strange term. Is this a step in ubiquitin-mediated microphagy? There is only a regulation term and it's also a child of response to mitochondrial depolarization, but membranes need to be ruptured as part of mitophagy (mitochondria are fragmented to make them a suitable size for engulfment).

Should this term be repurposed as "ubiquitin-dependent mitophagy" ? (and the regulation terms)?

Here is a nice 2018 review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255410/

CC @marcfeuermann @pgaudet

[ValWood]

@marcfeuermann also one for your list Atg44 mitofissin an autophagy specific membrane destabilizer https://www.pombase.org/reference/PMID:37192628 (will be annotated in PomBase tomorrow, beautifully community curated by the author https://curation.pombase.org/pombe/curs/42005ff3ae0fa290/ro)

Family is PTHR28075 | PANTHER | CHROMOSOME 16, WHOLE GENOME SHOTGUN SEQUENCE | IPR013726 | Protein of unknown function DUF1748, fungi

I will see if I can identify the human orthologs shortly but jackhmmr is currently broken

[marcfeuermann]

Hello,

• [x] Just a few thoughts about this. I would merge "mitophagy" and "autophagy of mitochondrion" for sure (these are exact synonyms). Maybe also mitochondrion disassembly as a related synonym. We can keep parents "selective autophagy" (and "organelle dissasembly" ?). Not sure that organization is relevant here, We are talking about degradation.

About point 4: I've never heard about this process before, but yes this could be a child term for mitophagy and I would also change it to "ubiquitin-dependent mitophagy". If the regulatory term is relevant, let's also change the name. About atg44, thanks for the information. I will update the entries in UniProt and annotate the family in PAN-GO. I hope this helps to progress in the cleaning. Regards, Marc.

[ValWood]

Thanks Marc, hopefully, I will get to this soon. We had our first autophagy session at the recent fission yeast meeting (and a lovely keynote from Yoshinori Ohsumi!). So we are now all over autphagy!

https://twitter.com/pombe2023/status/1668058034269208576?ref_src=twsrc%5Etfw%7Ctwcamp%5Eembeddedtimeline%7Ctwterm%5Escreen-name%3APomBase%7Ctwcon%5Es1

[marcfeuermann]

Good choice of topic :-) It is a well studied and well conserved process with many interesting specificities. Enjoy :-)

[pgaudet]

Chatting with Marc - we propose to reorganize the branch to clarify

. autophagy

. . macroautophagy (add synonym: selective autophagy) . . . mitophagy (add synonym: autophagy of mitochondrion) . . . . mitophagy by induced vacuole formation . . . nucleophagy . . . . late nucleophagy (this may be the same as nucleophagy? ) . . . pexophagy (add synonym: autophagy of peroxisome) . . . aggrephagy . . . glycophagy . . . lipophagy . . . lysophagy . . . proteaphagy . . . reticulophagy . . . ribophagy . . . xenophagy

. . microautophagy (New term; PMID:22080117, PMID:32907930) + add synonym: non-selective autophagy . . . microlipophagy . . . micromitophagy . . . micropexophagy . . . lysosomal microautophagy . . . piecemeal microautophagy of the nucleus

. . chaperone-mediated autophagy . . late endosomal microautophagy

autophagy of mitochondrion -> obsolete, unnecessary grouping class autophagy of peroxisome -> obsolete, unnecessary grouping class selective autophagy -> obsolete, unnecessary grouping class

[ValWood]

sounds good!

[ValWood]

I will go ahead with the obsoletion notices for autophagy of mitochondrion -> obsolete, unnecessary grouping class autophagy of peroxisome -> obsolete, unnecessary grouping class selective autophagy -> obsolete, unnecessary grouping class

do I also obsolete "mitochondrion disassembly" as an unnecessary grouping term?

[ValWood]

I'm not sure abut the autophagy part.

But this is a bit crazy:

micropexophagy and pexophagy are siblings rather than parent child. This is because:

Comment: (on micropexophagy) Note that this term is not a child of pexophagy because the community usually uses the latter to refer to the macroautophagy process.

SO I think we need to leave this branch alone, or revise the solution. Note that pexophagy and micropexophagy have different parents.

[ValWood]

Really, autophagy of the peroxisome should be renamed => pexophagy and pexophagy renamed => macropexophagy

do you agree? otherwise it's too confusing. The community might call "macropexophagy" "pexophagy" but this is ambiguous and we are supposed to be disambiguating!

[ValWood]

selective autophagy https://github.com/geneontology/go-ontology/issues/26115

autophagy of mitochondrion https://github.com/geneontology/go-ontology/issues/26111

awaiting decision on pexophagy

[ValWood]

Actually Comments

micromitophagy has the same comment. Note that this term is not a child of mitophagy because the community genrally uses that latter to refer to the macroautophagy of mitochondria.

This is too confusing!

Awating decision

[ValWood]

Add https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915032/ to terms

add comments explaining.

[ValWood]

Actions

Summary, we are removing the grouping terms for "autophagy of the specific organalle because they are distinct processes with different components and so it is confusing to group them. Macroautophagy is 'proper' autophagy and uses the autophagy machinery. Microautophagy is direct engulfment by the lysosome/vacuole. We don't want to group these 2 distinct processes. The axis of classification will be macroautophagy and microautophagy.

~autophagy of mitochondrion -> obsolete, unnecessary grouping class Annotation tracker ticket https://github.com/geneontology/go-annotation/issues/4752 Obsoletion notice https://github.com/geneontology/go-announcements/issues/599~ kept as do not annotate

~ autophagy of peroxisome -> obsolete, unnecessary grouping class Annotation tracker ticket https://github.com/geneontology/go-annotation/issues/4753 Oboletion notice https://github.com/geneontology/go-announcements/issues/600~ Kept as do not annotate

• [x] selective autophagy -> obsolete, unnecessary grouping class Ontology ticket https://github.com/geneontology/go-ontology/issues/26115 Announcement https://github.com/geneontology/go-announcements/issues/593 (I have moved all of the children to be directly underneath macroautophagy, and added 'selective. autophagy" as a narrow synonym. because the definition of macroautophagy says: Some types of macroautophagy, e.g. pexophagy, mitophagy, involve selective targeting of the targets to be degraded.

• [x] mitochondrion disassembly -> obsolete, unnecessary grouping class https://github.com/geneontology/go-annotation/issues/4755

• [ ] Add https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915032/ to terms add comments explaining macrophagy/mitophagy

• [x] GO:0030398 peroxisomal membrane disassembly Announcement https://github.com/geneontology/go-announcements/issues/601

• [x] check organelle disassembly parent

[ValWood]

Q GO:0030398 peroxisomal membrane disassembly no annotations. Is this required? It sounds odd? Also defined The controlled breakdown of the membranes of cargo-carrying vesicles formed during peroxisome degradation. PMID:11382760 ? Why cargo carrying?

Update, discussed with @pgaudet will obsolete. Added to actions above.

[ValWood]

One more question @marcfeuermann & @pgaudet

The parentage of all of the "microautophagy" terms is "lysosomal microautophagy" So I suspect yeast curators will no look under here (this is why it took me a while to find the microautophagy terms). Is there any objection to relabeeling this term

lysosome microautophagy -> microautophagy with lysosomal microautophagy as a narrow synonym

[ValWood]

Oh not so fast. Then we would be left with late endosomal microautophagy The autophagy process by which cytosolic proteins targeted for degradation are tagged with a chaperone and are directly transferred into and degraded in a late endosomal compartment.

[deustp01]

Can an endosome degrade things?

A quick look in Wikipedia, stopping short of actual research papers confirms that late endosomes can become lysosomes. The boundary here may be fuzzy.

If a vesicle has degrading enzymes, isn't it, by definition, a vacuole?

Is there a yeast - animal distinction here in the meaning of "vacuole"?

[ValWood]

OK late endosomal microautophagy is described: https://europepmc.org/article/MED/21238931

perhaps we can broaden he definition of "microautophagy" above to include degradation by endosomes.

[ValWood]

Is there a yeast - animal distinction here in the meaning of "vacuole"?

not really. vacuole is a parent of lysosome.

[deustp01]

not really. vacuole is a parent of lysosome.

The animal cells I'm familiar with can have intracellular storage structures but they are not called vacuoles, so that parentage looks odd.

[ValWood]

Correction. There is a term yeast-type vacuole GO:0000324 fungal-type vacuole A vacuole that has both lytic and storage functions.

The lysosome is defined as a lytic vacuole.

[ValWood]

...so the common parent would be "lytic vacuole"

[ValWood]

The animal cells I'm familiar with can have intracellular storage structures but they are not called vacuoles, so that parentage looks odd.

@deustp01 what are these storage compartments called?

[ValWood]

The current definition of vacuole does not state that vacuoles need to function as storage structures, or that all storage structures are vacuoles. It is fairly agnostic, but allows us to group vacuoles functionally further down in the structure, so I think we are OK here (at least for the time being, I'm sure it could be improved)

GO:0005773 vacuole Definition (GO:0005773 GONUTS page) A closed structure, found only in eukaryotic cells, that is completely surrounded by unit membrane and contains liquid material. Cells contain one or several vacuoles, that may have different functions from each other. Vacuoles have a diverse array of functions. They can act as a storage organelle for nutrients or waste products, as a degradative compartment, as a cost-effective way of increasing cell size, and as a homeostatic regulator controlling both turgor pressure and pH of the cytosol.

[deustp01]

lipid droplets, glycogen granules. Secretory and exocytic vesicles which, depending on the physiological state of the organism can persist for a long time before being used. I guess that last one may be a bit of a stretch.

[ValWood]

Microautophagy should probably be defined:

A type of autophagy where cytosolic components are ingested by late endosomes, lysosomes or yeast-type lytic vacuoles by direct invagination of the compartment membrane without prior sequestration into an autophagosome. The engulfing membranes fuse, resulting in the lysosomal delivery of the cargo wrapped in a single membrane derived from the invaginated lysosomal membrane.

The key point being that no autophagosome is involved.

[ValWood]

lipid droplets, glycogen granules. Secretory and exocytic vesicles which, depending on the physiological state of the organism can persist for a long time before being used. I guess that last one may be a bit of a stretch.

OK. I think we are OK with existing vacuole definition for the reason described above, which basically says that vacuoles may or may not be storage compartments.

[pgaudet]

@marcfeuermann also proposes merging (obsoleting/replacing) GO:0044805 late nucleophagy into nucleophagy; the difference is that this somehow happens more slowly, or is delayed compared to 'normal' autophagy, but it's the same mechanism, and all the same proteins are involved.

Thanks, Pascale

[ValWood]

• Used the definition of microautophagy above,
• Made lysosomal autophagy a "narrow synonym"
• Standardized microautophagy subtype definitions to Degradation of a "blah" by microautophagy.
• changed label "mitophagy by induced vacuole formation" to mitophagy by internal vacuole formation" to make it clearer what there difference is. The definition seems to be a bit iffy compared to the paper (single annotation alert!)

[ValWood]

• moved wikepedia ref "macromitophagy" down to macromitophagy
• made mitophagy narrow synonym rather than 'related'

[ValWood]

We need a better definition of "autophagy" which is inclusive of nucleophagy. Current def is The cellular catabolic process in which cells digest parts of their own cytoplasm; allows for both recycling of macromolecular constituents under conditions of cellular stress and remodeling the intracellular structure for cell differentiation.

@pgaudet @marcfeuermann suggestions?

[ValWood]

-moved late endosomal microautophagy under 'microautophagy'

[ValWood]

• added GO check "do not annotate' to autophagy of peroxisome autophagy of mitochondrion

[ValWood]

Still to do. Correct autophagy definition so that it includes nucleophagy.

The cellular catabolic process in which cells digest parts of their own cytoplasm; allows for both recycling of macromolecular constituents under conditions of cellular stress and remodeling the intracellular structure for cell differentiation.

consider The cellular catabolic process in which cells digest parts of their own cell by lytic vacuoles or lysosomes for both recycling of macromolecular constituents under conditions of cellular stress and remodeling the intracellular structure for cell differentiation.

[pgaudet]

We need a better definition of "autophagy" which is inclusive of nucleophagy.

Current: The cellular catabolic process in which cells digest parts of their own cytoplasm; allows for both recycling of macromolecular constituents under conditions of cellular stress and remodeling the intracellular structure for cell differentiation.

• [x] Proposed:

The cellular catabolic process in which cells digest cellular materials, such as organelles and other macromolecular constituents. Autophagy serves to provide essential nutrients under conditions of cellular stress; or can remodel intracellular structures during cell differentiation.

What do you think ?

[ValWood]

I used the suggested def extended by "or non-self materials such as intracellular pathogens" because xenophagy is also under here.

I will now delete some of the unnecessary comments related to anomalies like "rdfs:comment "Targeted macroautophagy sometimes targets regions of cytoplasm containing non-self, such as virus particles or components (e.g. see PMID:20159618). As this is essentially the same process as macroautophagy that encloses and digests only self, the term autophagy is still used despite the enclosure of some non-self (non-auto) entities." because this is easily dealt with by extending the definition to be inclusive. i.e. just don't restrict to self-eating

[ValWood]

Also need a more succinct definition of macroautophagy:

Currently: The major inducible pathway for the general turnover of cytoplasmic constituents in eukaryotic cells, it is also responsible for the degradation of active cytoplasmic enzymes and organelles during nutrient starvation. Macroautophagy involves the formation of double-membrane-bounded autophagosomes which enclose the cytoplasmic constituent targeted for degradation in a membrane-bounded structure. Autophagosomes then fuse with a lysosome (or vacuole) releasing single-membrane-bounded autophagic bodies that are then degraded within the lysosome (or vacuole). Some types of macroautophagy, e.g. pexophagy, mitophagy, involve selective targeting of the targets to be degraded.

Suggest: The autophagic process that involves the bulk degradation of damaged or unnecessary cellular constituents or intracellular pathogens, and proceeds via an autophagosome which subsequently fuses with a lysosome or vacuole.

(we don't need to define the process details here)

[ValWood]

Or could be even more simply "The autophagic process that proceeds via an autophagosome" (the autophagosome is the differential here from the sibling microautophagy terms

[ValWood]

deleted While making xenophagy a subclass of (macro)autophagy may seem to directly contradict the definition of autophagy (literally self eating), it is clear that the same pathway is involved as in macroautophagy that doesn't target foreign material: formation of double-membrane-bounded autophagosomes that enclose a region of cytoplasm for degradation. from xenophagy(fix by correcting definitions)

[ValWood]

I standardized the various definitions of all of the children of macrophagy to The selective degradation of x by macroautophagy.

I can add some gloss or a comment if useful once macrophagy is correctly defined.

[ValWood]

• [x] Added Macroautophagy "The autophagic process that proceeds via an autophagosome"

[ValWood]

Closing, everything remaining is in new tickets