heme import across plasma membrane

[Antonialock]

just want advice on what to annotate to PMID:28193844

so to my understanding in fungi, exogenous heme -> endocytosis (likely, observed in other fungi) -> vacuole -> cytosol

these two terms exist:

1. heme import across plasma membrane: The directed movement of heme from outside of a cell, across the plasma membrane and into the cytosol. &
2. endocytic iron import into cell

1 doesn't feel quite right since import is via the vacuole. 2 doesn't specify heme (is it restricted to any iron?)

Should I request a new term? "heme import across plasma membrane into vacuole" or
"endocytic heme import into cell"?

[ValWood]

Good questions. heme transport looks a bit inconsistent anyway. There are grouping terms for 'heme export' but not heme 'import'. Presumably heme is always imported into the vacuole for storage whichever way it enters the cell (guessing?)

"endocytic heme import" would seem to be enough (and the def could say that the heme is imported into the vacuole if this is always true.

@pgaudet any thoughts. We'll open a ticket once we know what to ask for.

[pgaudet]

x import across plasma membrane

means transmembrane transport. It would be nice to make that clearer - suggestions are welcome. Of we agree on this, then TM transport from the extracellular to the vacuole is an addition step - what is the mechanism here ? (seems like we are defining functions :(

(endocytic) import into cell The problem with just 'import' is this is used for 'import into cell', 'import into mitochondria', etc, and as such is a weird grouping term. You can imagine import into the cell being either from the cytoplasm or from an organelle.

Pascale

[Antonialock]

heme transport seems to differ slightly between fungi, but the overall chain of events seem to be:

heme endocytosis to vacuole -> vacuole acts as a store of iron (probably heme in pombe, other organisms may use eg ferritin) -> when iron is needed it is mobilized from the vacuole (in some form) -> cytoplasm (and then I guess it would generally be taken to the mitochondria?)

I don't know if endocytosis is just a fungal thing but bacteria seem to do it differently

human (the purpose of this is a bit different I guess since I suppose it falls under detoxification rather than scavenging for heme...though it could be both in human, dietary heme is taken up?)

[Antonialock]

maybe we need a new term to mean an uptake pathway?

"heme uptake via endocytosis" ?

[ValWood]

x import across plasma membrane means transmembrane transport. It would be nice to make that clearer - suggestions are welcome.

import could mean via endocytosis or transmembrane transport, so probably these should be explicit (i.e heme transmembrane import across the plasma membrane)

Antonia I don't think you need to encode the final destination into the import . that will be described by other steps

[Antonialock]

ok so this isn't transmembrane transport as such?

endocytic heme import across plasma membrane ?

[Antonialock]

or is heme import across plasma membrane sufficient?

[pgaudet]

'across the plasma membrane' was supposed to mean transmembrane.... I am just concerned that MF and BP are identical in this case.

I dont know how to avoid that ?

[ValWood]

Which MF and BP are identical?

[pgaudet]

We have in MF: ATPase-coupled heme transmembrane transporter activity and if we knew of a heme cargo receptor, we should probably create this activity under 'cargo receptor activity'; right ?

[ValWood]

Antonia I don't think "endocytic heme import across plasma membrane ?" works because heme isn't imported across the plasma membrane - the vesicle buds off the membrane, the membrane isn't traversed. It is import into cell, but not import across the plasma membrane.

Which gene product were you trying to annotate here?

[ValWood]

I see shu1

In GO we have

GO:0097037    heme export	is_a
GO:0020028    endocytic hemoglobin import	is_a

so probably we could have

heme import, or endocytic heme import? @pgaudet

[pgaudet]

I will check. This is definitely on the unfinished list of transport/transporters.

Pascale

[Antonialock]

Which gene product were you trying to annotate here?

str3 and shu1

[Antonialock]

We have in MF: ATPase-coupled heme transmembrane transporter activity and if we knew of a heme cargo receptor, we should probably create this activity under 'cargo receptor activity'; right ?

maybe it would be better as a MF...

what would be a better description of the process, heme assimilation? it's a bit unsatisfactory to only have MF, and not describe what the function is used for....

Taken together, these results indicate that Str3 is a second cell-surface membrane protein for > > acquisition of exogenous heme in S. pombe. http://www.jbc.org/content/early/2018/03/16/jbc.RA118.002132.full.pdf

we also have "heme export from vacuole to cytoplasm" is that heme mobilisation?

[ValWood]

It still feels to me that it should be part of some import process

"endocytic heme import/uptake"

what is the MF. Is it some sort of GO:0038024 cargo receptor activity?

[ValWood]

str3 has heme transporter activity  | part of heme import across plasma membrane

shu1 has heme import across plasma membrane

this one needs fixing (heme endocytosis, it isn't tm transport IIRC?)

[ValWood]

Asked the author. Quicker...

[ValWood]

From Simon Labbe

As far as we know, Shu1 is attached to the membrane via a GPI anchor.

A current model suggests that Shu1 binds exogenous hemin at the cell surface (like a heme receptor), and then undergoes internalization from the cell surface to the vacuole. This mechanism requires Nbr1 and proteins of the ESCRT complex. We found that several proteins are ubiquitinated when cells are taking up exogenous hemin as a sole source of heme. We have shown that a subgroup of Ubi4-dependent ubiquitinated proteins interacts with Shu1.

We know that the presence of Nbr1 (most probably ubiquitinated) is required to trigger Shu1 internalization to the vacuolar membrane.

Furthermore, hemin-mediated Shu1 vacuolar targeting also requires the ubiquitin-binding proteins Hse1 (ESCRT-0) and Sst6 (ESCRT-I).

In fact, co-IP experiments have shown that Shu1 associates with both Nbr1 and Hse1 in hemin-treated cells.

Heme import across plasma membrane : is correct for Shu1, though it is not a transmembrane transporter. Shu1 is a cell surface-anchored heme-binding protein.

The exact mechanism whereby Shu1 is internalized when bound to hemin is still an open question…

[ValWood]

https://github.com/geneontology/go-ontology/issues/18671#issuecomment-579279461 will fix