Phagocytosis Modules

Goal: a set of taxon-neutral modules that follow a particle from recognition
to the programmes its digestion switches on in the phagocyte. Each step is built
from PANTHER families with exemplar members from several lineages, and the
families and exemplar genes are reviewed as the modules are built.

This project grew out of go-ontology#32748
and #32152, where the
GO phagocytosis branch was found to stop at digestion. The proposal sent to the
GO editors is at https://claude.ai/artifact/8MJjKA2M2SDjcZAs9dL1ET.

Module tree

Order	Module	Status	Scope
—	`phagocytosis` (umbrella)	DRAFT	Composes the steps below with `module_ref`
1	`phagocytic_engulfment`	DRAFT, revised	Recognition, Rho-GTPase activation, actin, cup closure
2	`phagosome_maturation`	DRAFT, revised	Rab5 → Rab7, fusion, acidification, NOX2
3	`phagolysosomal_cargo_degradation`	DRAFT	DNase II, cathepsins, amoebal lysozyme; export of amino acids, nucleosides, heme, cholesterol
4	Post-phagocytic programmes (optional parts)	DRAFT	See below

Post-phagocytic programmes. Each is a separate module because each has its own
trigger, signalling chain and output. The umbrella lists them as optional
alternatives.

Module	Trigger	Genes doing the work	Lineage evidence
`efferocytosis_induced_macrophage_proliferation`	apoptotic-cell DNA digested by DNase II	DNASE2, PRKDC, RICTOR, MYC, BHLHE40; MERTK arm	mouse
`efferocytosis_induced_macrophage_priming`	corpse engulfment	drpr, bsk	Drosophila
`efferocytosis_induced_anti_inflammatory_programme`	cargo sterols, fatty acids, tryptophan, methionine, DNA	NR1H2/3, PPARD, SIRT1/PBX1, IDO1/AHR, TLR9, DNMT3A/PTGS2, SLC12A2	mouse
`heme_induced_iron_recycling_macrophage_differentiation`	heme from engulfed erythrocytes	SLC48A1, BACH1, SPIC, HMOX1	mouse

Design rules

Taxon-neutral where the biology is. Engulfment, maturation and digestion
are eukaryote-wide (amoebae feed this way), so their core annotons use
PANTHER families with exemplars from mammals, nematodes, insects and, where
conserved, Dictyostelium. Lineage-specific parts, such as vertebrate
opsonin receptors or NOX2, are variants or optional parts.
Programmes are lineage-bounded. The post-phagocytic programmes are
context-limited to the clade where they are shown. Their participants are
still families, and whether a programme extends beyond that clade is recorded
as a knowledge gap or tested as an OpenScientist hypothesis.
Genes doing the work, not readouts. Only gene products shown to carry out
a step (loss of function, rescue, epistasis) become annotons. Expression
markers such as CD68 or LGALS3 are not participants.
Families are checked. UniProt PANTHER cross-references are checked
against interpro/panther/panther.obo, and PTNs come only from local PAINT
files.

Family assignments where PANTHER and UniProt disagree

The modules follow PANTHER's own classification files (the member index), and
record the UniProt cross-reference in a note when it differs.

Protein	PANTHER classification	UniProt cross-reference	Used
ced-1 (Q9XWD6), drpr (Q9W0A0)	PTHR24035:SF109 PROTEIN DRAPER	PTHR24043:SF8	PTHR24035:SF109
MEGF10 (Q96KG7)	PTHR24035:SF136	PTHR24052:SF13	PTHR24035
AKT1 (P31749, P31750)	PTHR24356:SF171	PTHR24351	PTHR24356:SF171

The existing phagocytic_engulfment grounding of CED-1/MEGF10 in PTHR24035
therefore agrees with PANTHER.

OpenScientist hypotheses

Each was one phylogenetic-profile question, run with the project defaults. The
reports are in the gene folders and are cited from the modules.

Question	Verdict	Effect on modules
Is the DNA-PKcs route limited by PRKDC distribution? (report)	Partly supported. DNA-PKcs is ancestral to animals (sponges, cnidarians, most insects) and lost in Drosophila and C. elegans.	Proliferation module: taxon note and knowledge gap rewritten.
Do SPIC and heme-sensing BACH1 co-occur? (report)	Partly supported. SPIC is a jawed-vertebrate gene, never without BACH1; the BACH1 C-terminal CP motif is conserved in bony vertebrates.	Heme module: taxon note.
Is HRG1 in phagotrophic protists? (report)	Mostly refuted. Animals and choanoflagellates, one Acanthamoeba ortholog, none in Dictyostelium.	Degradation module: heme export marked animal-specific.
Is DNase II in phagotrophic protists? (report)	Partly supported. Ancient but patchy; in Dictyostelium and Acanthamoeba, absent from choanoflagellates; does not track phagotrophy.	Degradation module: DNase II note.

Reviews completed

Gene reviews: DNASE2, nuc-1, SLC48A1, SPIC, BACH1, BHLHE40, PRKDC, drpr.
PANTHER family reviews: PTHR10858 (DNase II) and PTHR31525 (HRG1). Both
suggest PAINT fixes: move apoptotic DNA fragmentation from the DNase II root
to an animal node, and restrict the HRG1 lysosomal membrane annotation to
SF1.

Plan

Resolve families and PTNs for every participant. (in progress)
Build the four post-phagocytic programme modules. (done, DRAFT)
Build phagolysosomal_cargo_degradation and the phagocytosis umbrella. (done, DRAFT)
Revise phagocytic_engulfment and phagosome_maturation toward family
selectors with cross-lineage exemplars. (done: both now Eukaryota context,
with Dictyostelium exemplars where conserved)
Write family reviews for the key families and gene reviews for exemplars
that lack them. (eight gene reviews and two family reviews done; still to
do: GULP1, ELMO1, DOCK1, MERTK and the CED-1/MEGF10 family)
Run the OpenScientist hypotheses and fold the results into the modules.
(done)