Retromer (VPS35/VPS26A/VPS29) and SORL1 endosome-to-TGN retrograde sorting — clathrin/AP-2/DNM2 internalization, V-ATPase acidification, retromer cargo selection, and RAB9A/AP-1 TGN delivery vs. ESCRT/RAB7A/CTSD lysosomal proteolysis

Transmembrane sorting receptors — including the neuronal sortilin-related receptor SORL1 (SorLA/LR11, which binds amyloid precursor protein APP), cation-independent mannose 6-phosphate receptors (IGF2R/CI-MPR), and Wntless (WLS) — continuously cycle between the trans-Golgi network (TGN), plasma membrane, and endosomes. Cell-surface SORL1-cargo complexes are internalized via clathrin-coated pits (AP2M1, CLTC) and dynamin-2 (DNM2) vesicle scission into early sorting endosomes acidified by V-ATPase (ATP6V1A). On early and maturing sorting endosome membranes, the heterotrimeric retromer cargo-selective complex (CSC), composed of VPS35, VPS26A, and VPS29, recognizes the cytoplasmic FANSHY sorting motif of SORL1 (and aromatic/hydrophobic motifs on CI-MPR and WLS) to partition receptor-cargo complexes into tubular retrograde carriers, actively protecting them from ESCRT-I (TSG101) multivesicular body incorporation and RAB7A-driven lysosomal degradation. Downstream delivery and receptor sorting at the trans-Golgi network are mediated by the TGN/endosomal clathrin adaptor complex AP-1 (AP1B1, AP1G1; PMID:23415225) together with the complementary late-endosome-to-TGN small GTPase RAB9A (which recruits the dynein effector NDE1 to transport late-endosomal receptors to the TGN; PMID:8164745, PMID:34793709, PMID:15078902). When retromer function (VPS35/VPS26A/VPS29) or SORL1 sorting is impaired — a hallmark pathogenic mechanism in Alzheimer disease and Parkinson disease — sorting receptors and their cargo fail to return to the TGN, remain in maturing endosomes, and are routed via TSG101 and RAB7A into lysosomes for proteolytic cleavage (CTSD).

MODULE:retromer_endosome_to_tgn_retrievalDRAFTTransport Stepmodules/retromer_endosome_to_tgn_retrieval.yaml

retrograde transport, endosome to GolgiGO:0042147 cargo adaptor activityGO:0140312 receptor-mediated endocytosisGO:0006898 endosome to lysosome transportGO:0008333

GO:0038024

cargo receptor activity

Recognition and sorting of transmembrane and luminal cargo (including APP) by SORL1.

GO:0042147

retrograde transport, endosome to Golgi

Retromer (VPS35/VPS26A/VPS29)- and RAB9A-dependent retrieval of sorting receptors from endosomes to the trans-Golgi network.

GO:0006898

receptor-mediated endocytosis

Clathrin-, AP-2-, and DNM2-dependent internalization of cell-surface sorting receptors into early endosomes.

GO:0048388

endosomal lumen acidification

V-ATPase-driven proton pumping acidifies early and maturing endosomal compartments.

GO:0008333

endosome to lysosome transport

ESCRT-I (TSG101) and RAB7A route un-retrieved endosomal receptors and cargo to lysosomes for CTSD proteolysis.

PMID:16174740

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.

SORL1 (sorLA/LR11) acts as an intracellular sorting receptor that shuttles cargo between endosomes and the Golgi/TGN to prevent amyloidogenic endosomal processing.

sorLA acts as a sorting receptor that protects APP from processing into Abeta and thereby reduces the burden of amyloidogenic peptide formation

PMID:18193037

Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex.

The conserved VPS35-containing retromer complex retrieves internalized sorting receptors from endosomes back to the Golgi apparatus, preventing their lysosomal degradation.

Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner.

PMID:18193032

Wingless secretion promotes and requires retromer-dependent cycling of Wntless.

Loss of the retromer core subunits Vps35 or Vps26 abolishes endosome-to-Golgi retrieval and diverts internalized cargo receptors to lysosomal degradation.

In the absence of the retromer components Dvps35 or Dvps26, but in presence of Wg, Wls is degraded and Wg secretion impaired.

PMID:32286230

Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain.

Retromer subunit VPS29 opposes Rab7-dependent endolysosomal progression, and VPS29 loss-of-function phenotypes are suppressed by reducing Rab7.

Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5

PMID:15078902

Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer.

Mammalian retromer (VPS26/VPS35/VPS29) localizes to early and maturing multivesicular endosomes to mediate endosome-to-Golgi retrieval of CI-MPR and sortilin, acting alongside or upstream of AP-1 and Rab9-dependent endosome-to-TGN retrieval pathways.

In summary, loss of mVPS26 results in a severe defect in endosome-to-TGN retrieval of the CI-MPR. mVPS26 could mediate retrieval of the CI-MPR from both early and late endosomes.

Reactome:R-HSA-8871506

SORL1 transports APP(18-770) from endosome lumen to Golgi lumen

Human SORL1 forms a complex with the retromer cargo-selective complex on early endosomes to retrieve cargo to the trans-Golgi network.

file:human/SORL1/SORL1-ai-review.yaml

SORL1 gene review (human)

Sortilin-related receptor mediating endosome-to-TGN retrograde cargo retrieval in partnership with the retromer complex (UniProtKB:Q92673, GO:0038024, GO:0042147).

file:human/VPS35/VPS35-ai-review.yaml

VPS35 gene review (human)

Central alpha-solenoid scaffold subunit of the human retromer cargo-selective complex (UniProtKB:Q96QK1, GO:0140312, GO:0042147).

file:DROME/Vps35/Vps35-ai-review.yaml

Vps35 gene review (Drosophila)

Central scaffold subunit of the conserved VPS35-VPS26-VPS29 retromer cargo-selective complex (UniProtKB:Q9W277, GO:0140312, GO:0042147).

file:human/VPS26A/VPS26A-ai-review.yaml

VPS26A gene review (human)

Arrestin-fold cargo-recognition subunit of the human retromer complex that binds FANSHY/NPxY sorting motifs (UniProtKB:O75436, GO:0140312, GO:0042147).

file:DROME/Vps26/Vps26-ai-review.yaml

Vps26 gene review (Drosophila)

Arrestin-fold cargo adaptor subunit of the conserved retromer complex (UniProtKB:Q9W552, GO:0042147).

file:human/VPS29/VPS29-ai-review.yaml

VPS29 gene review (human)

Metallophosphoesterase-fold scaffold subunit of the human retromer complex that binds TBC1D5 to regulate RAB7A dynamics (UniProtKB:Q9UBQ0, GO:0140312, GO:0042147).

file:DROME/Vps29/Vps29-ai-review.yaml

Vps29 gene review (Drosophila)

Metallophosphoesterase-fold scaffold subunit of the retromer complex regulating Rab7/TBC1D5 dynamics and endosome-to-Golgi retrieval (UniProtKB:Q9VPX5, GO:0140312, GO:0042147).

file:human/RAB9A/RAB9A-ai-review.yaml

RAB9A gene review (human)

Small GTPase mediating retrograde transport of sorting receptors from endosomes to the trans-Golgi network (UniProtKB:P51151, GO:0003924, GO:0042147).

file:human/AP1B1/AP1B1-ai-review.yaml

AP1B1 gene review (human)

AP-1 clathrin adaptor complex beta-1 subunit sorting cargo between endosomes and the trans-Golgi network (UniProtKB:Q10567, GO:0030276, GO:0016192).

file:SCHPO/apl2/apl2-ai-review.yaml

apl2 gene review (S. pombe)

Conserved fungal AP-1 beta subunit mediating Golgi/endosome clathrin-coated vesicle sorting (UniProtKB:O43079, GO:0005802).

file:worm/apb-1/apb-1-ai-review.yaml

apb-1 gene review (C. elegans)

Conserved invertebrate beta1/2-adaptin subunit shared by AP-1 at the trans-Golgi network and AP-2 at the plasma membrane (UniProtKB:Q9N4F3, GO:0030276, GO:0006886).

file:human/AP1G1/AP1G1-ai-review.yaml

AP1G1 gene review (human)

AP-1 clathrin adaptor complex gamma-1 subunit at the trans-Golgi network and endosomes (UniProtKB:O43747, GO:0035615, GO:0006886).

file:human/AP2M1/AP2M1-ai-review.yaml

AP2M1 gene review (human)

AP-2 mu2 subunit mediating clathrin-dependent internalization of cell-surface SORL1 (UniProtKB:Q96CW1, GO:0005048, GO:0072583).

file:worm/dpy-23/dpy-23-ai-review.yaml

dpy-23 gene review (C. elegans)

Conserved metazoan AP-2 mu2 subunit recognizing YxxPhi sorting motifs for clathrin-dependent internalization of sorting receptors including MIG-14/Wntless (UniProtKB:P35603, GO:0035615, GO:0072583).

file:human/CLTC/CLTC-ai-review.yaml

CLTC gene review (human)

Clathrin heavy chain 1 coat lattice subunit (UniProtKB:Q00610, GO:0005198, GO:0006898).

file:human/DNM2/DNM2-ai-review.yaml

DNM2 gene review (human)

Dynamin-2 GTPase motor driving coated-vesicle neck scission (UniProtKB:P50570, GO:0061791, GO:0099050).

file:human/ATP6V1A/ATP6V1A-ai-review.yaml

ATP6V1A gene review (human)

V-ATPase catalytic subunit A driving endosomal lumen acidification (UniProtKB:P38606, GO:0046961, GO:0048388).

file:human/TSG101/TSG101-ai-review.yaml

TSG101 gene review (human)

ESCRT-I MVB sorting subunit (UniProtKB:Q99816, GO:0043130, GO:0036258).

file:human/RAB7A/RAB7A-ai-review.yaml

RAB7A gene review (human)

Late endosome maturation and lysosome fusion GTPase (UniProtKB:P51149, GO:0003924, GO:0045022, GO:0008333).

file:human/CTSD/CTSD-ai-review.yaml

CTSD gene review (human)

Lysosomal aspartic protease degrading un-retrieved cargo (UniProtKB:P07339, GO:0004190, GO:0006508).

8Nodes

7Parts

0Variant Sets

0Variants

14Annotons

7Connections

Executable models all models

Agent-based derived from this module

Agent-based model of retromer (VPS35/VPS26A/VPS29) and SORL1 endosome-to-TGN retrograde retrieval vs. RAB7A/CTSD lysosomal degradation

✓ Wild-type retromer retrograde sorting (80% TGN retrieval vs. 20% lysosomal proteolysis)
✓ Retromer loss-of-function (VPS35 / VPS26A / VPS29 deficiency; 100% misrouting to lysosomal degradation)
✓ RAB9A / AP-1 TGN docking block (retrograde carriers arrested prior to trans-Golgi network delivery)
✓ RAB7A late-endosomal maturation block (suppresses lysosomal degradation and routes 100% of cargo to TGN retrieval)
✓ V-ATPase acidification block (ATP6V1A loss; arrest in nascent endocytic vesicles)
✓ Clathrin / AP-2 / DNM2 internalization block (SORL1-cargo complexes trapped at the cell surface)

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Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:retromer_endosome_to_tgn_retrieval deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

13 gene-function check(s) reflected in core functions · 0 conflict(s) · 15 evidence or coverage gap(s) (37 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
sorl1_receptor_binding	SORL1 (human) UniProtKB:Q92673 Family Representative	cargo receptor activity GO:0038024	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap2m1_cargo_selection	AP2M1 (human) UniProtKB:Q96CW1 Family Representative	signal sequence receptor activity GO:0005048	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap2m1_cargo_selection	dpy-23 (C. elegans) UniProtKB:P35603 Family Representative	signal sequence receptor activity GO:0005048	Function Unreviewed No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
cltc_coat_lattice	CLTC (human) UniProtKB:Q00610 Family Representative	structural molecule activity GO:0005198	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dnm2_vesicle_scission	DNM2 (human) UniProtKB:P50570 Family Representative	GTPase motor activity GO:0061791	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atp6v1a_proton_pump	ATP6V1A (human) UniProtKB:P38606 Family Representative	proton-transporting ATPase activity, rotational mechanism GO:0046961	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
vps35_retromer_spine	VPS35 (human) UniProtKB:Q96QK1 Family Representative	cargo adaptor activity GO:0140312	Contributes Only The review records contribution to this activity, not independent enabling. Check whether the module participant should be a complex.
vps35_retromer_spine	Vps35 (Drosophila) UniProtKB:Q9W277 Family Representative	cargo adaptor activity GO:0140312	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
vps26a_arrestin_adaptor	VPS26A (human) UniProtKB:O75436 Family Representative	cargo adaptor activity GO:0140312	Contributes Only The review records contribution to this activity, not independent enabling. Check whether the module participant should be a complex.
vps26a_arrestin_adaptor	Vps26 (Drosophila) UniProtKB:Q9W552 Family Representative	cargo adaptor activity GO:0140312	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
vps29_retromer_subunit	VPS29 (human) UniProtKB:Q9UBQ0 Family Representative	cargo adaptor activity GO:0140312	Contributes Only The review records contribution to this activity, not independent enabling. Check whether the module participant should be a complex.
vps29_retromer_subunit	Vps29 (Drosophila) UniProtKB:Q9VPX5 Family Representative	cargo adaptor activity GO:0140312	Contributes Only The review records contribution to this activity, not independent enabling. Check whether the module participant should be a complex.
rab9a_tgn_tethering	RAB9A (human) UniProtKB:P51151 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap1b1_tgn_adaptor	AP1B1 (human) UniProtKB:Q10567 Family Representative	clathrin binding GO:0030276	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap1b1_tgn_adaptor	apl2 (S. pombe) UniProtKB:O43079 Family Representative	clathrin binding GO:0030276	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap1b1_tgn_adaptor	apb-1 (C. elegans) UniProtKB:Q9N4F3 Family Representative	clathrin binding GO:0030276	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap1g1_tgn_adaptor	AP1G1 (human) UniProtKB:O43747 Family Representative	clathrin-cargo adaptor activity GO:0035615	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
tsg101_escrt_sorting	TSG101 (human) UniProtKB:Q99816 Family Representative	ubiquitin binding GO:0043130	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rab7a_late_maturation	RAB7A (human) UniProtKB:P51149 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rab7a_late_maturation	Rab7 (mouse) UniProtKB:P51150 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ctsd_proteolysis	CTSD (human) UniProtKB:P07339 Family Representative	aspartic-type endopeptidase activity GO:0004190	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sorl1_receptor_binding	Sortilin-related receptor PANTHER:PTHR12106:SF27 Family	cargo receptor activity GO:0038024	Family Supported Family review supports GO:0038024 FAMILY_WIDE. All subfamilies of PTHR12106 (fungal Vps10, metazoan SORT1, SORL1, and SorCS1-3) act as transmembrane cargo-sorting receptors that bind luminal or extracellular cargos via their VPS10 domain and couple them to cytosolic coat/retromer adaptors for vesicular transport.
ap2m1_cargo_selection	AP-2 complex subunit mu PANTHER:PTHR10529:SF236 Family	signal sequence receptor activity GO:0005048	Family Supported Family review supports GO:0005048 FAMILY_WIDE. Mu subunits across AP-1, AP-2, AP-3, and AP-4 directly bind peptide sorting signals (such as YxxPhi motifs) in the cytosolic tails of transmembrane cargos via a conserved hydrophobic pocket on the C-terminal MHD beta-sandwich.
cltc_coat_lattice	Clathrin heavy chain 1 PANTHER:PTHR10292:SF7 Family	structural molecule activity GO:0005198	Family Review Missing No supported structured family review is available for PANTHER:PTHR10292:SF7.
dnm2_vesicle_scission	Dynamin-2 PANTHER:PTHR11566:SF23 Family	GTPase motor activity GO:0061791	Family Review Missing No supported structured family review is available for PANTHER:PTHR11566:SF23.
atp6v1a_proton_pump	V-type proton ATPase catalytic subunit A PANTHER:PTHR43607:SF9 Family	proton-transporting ATPase activity, rotational mechanism GO:0046961	Family Review Missing No supported structured family review is available for PANTHER:PTHR43607:SF9.
vps35_retromer_spine	Vacuolar protein sorting-associated protein 35 PANTHER:PTHR11099:SF0 Family	cargo adaptor activity GO:0140312	Family Supported Family review supports GO:0140312 FAMILY_WIDE. Vps35 is the conserved central platform of the retromer cargo-selective complex across Eukaryota (PTN000120819), directly associating with cytoplasmic tails of transmembrane cargos and with Vps26 and Vps29 to prevent lysosomal missorting.
vps26a_arrestin_adaptor	Vacuolar protein sorting-associated protein 26 PANTHER:PTHR12233:SF4 Family	cargo adaptor activity GO:0140312	Family Supported Family review supports GO:0140312 FAMILY_WIDE. Both canonical retromer Vps26/VPS26A/VPS26B subunits and the retriever subunit VPS26C act as arrestin-fold cargo adaptors that bridge sorting nexins and transmembrane cargo tails to their respective alpha-solenoid scaffolds on endosomal membranes.
vps26a_arrestin_adaptor	Vacuolar protein sorting-associated protein 26 PANTHER:PTHR12233:SF1 Family	cargo adaptor activity GO:0140312	Family Supported Family review supports GO:0140312 FAMILY_WIDE. Both canonical retromer Vps26/VPS26A/VPS26B subunits and the retriever subunit VPS26C act as arrestin-fold cargo adaptors that bridge sorting nexins and transmembrane cargo tails to their respective alpha-solenoid scaffolds on endosomal membranes.
vps29_retromer_subunit	Vacuolar protein sorting-associated protein 29 PANTHER:PTHR11124:SF12 Family	cargo adaptor activity GO:0140312	Family Supported Family review supports GO:0140312 for PANTHER:PTHR11124:SF12. PAINT node PTN000122547 (taxon:2759, Eukaryota) places GO:0140312 (cargo adaptor activity) across eukaryotic Vps29 orthologs (PANTHER:PTHR11124:SF12), which scaffold the C-terminal arch of VPS35 in retromer and VPS35L in retriever; bacterial/archaeal members (PANTHER:PTHR11124:SF26) are soluble phosphodiesterases and do not form membrane-trafficking complexes.
rab9a_tgn_tethering	Ras-related protein Rab-9A PANTHER:PTHR47981:SF9 Family	GTPase activity GO:0003924	Family Review Missing No supported structured family review is available for PANTHER:PTHR47981:SF9.
ap1b1_tgn_adaptor	AP-1/2 complex subunit beta PANTHER:PTHR11134:SF31 Family	clathrin binding GO:0030276	Family Supported Family review supports GO:0030276 for PANTHER:PTHR11134:SF31. Refines the earlier UNRESOLVED assessment now that PTHR11134-paint.tsv and subfamily-specific human AP1B1/AP4B1 UniProt records are cached: AP-1 beta (SF31, including N. crassa NCU09721), shared invertebrate AP-1/2 beta (SF3), AP-2 beta (SF9), and AP-3 beta (SF10, SF11) bind clathrin via canonical clathrin-box motifs in their hinge/appendage domains, whereas AP-4 beta (SF4, UniProtKB:Q9Y6B7) assembles into the non-clathrin AP-4 coat (binding TEPSIN via its appendage domain, PMID:26542808) and does not bind clathrin.
ap1b1_tgn_adaptor	AP-1/2 complex subunit beta PANTHER:PTHR11134:SF3 Family	clathrin binding GO:0030276	Family Supported Family review supports GO:0030276 for PANTHER:PTHR11134:SF3. Refines the earlier UNRESOLVED assessment now that PTHR11134-paint.tsv and subfamily-specific human AP1B1/AP4B1 UniProt records are cached: AP-1 beta (SF31, including N. crassa NCU09721), shared invertebrate AP-1/2 beta (SF3), AP-2 beta (SF9), and AP-3 beta (SF10, SF11) bind clathrin via canonical clathrin-box motifs in their hinge/appendage domains, whereas AP-4 beta (SF4, UniProtKB:Q9Y6B7) assembles into the non-clathrin AP-4 coat (binding TEPSIN via its appendage domain, PMID:26542808) and does not bind clathrin.
ap1g1_tgn_adaptor	AP-1 complex subunit gamma-1 PANTHER:PTHR22780:SF26 Family	clathrin-cargo adaptor activity GO:0035615	Family Supported Family review supports GO:0035615 for PANTHER:PTHR22780:SF26. AP-1 gamma (SF26, SF28; PTN000512793) and AP-2 alpha (SF33, SF30; PTN000512892) are large subunits of clathrin-associated cargo-adaptor complexes, whereas AP-4 epsilon (SF13, UniProtKB:Q9UPM8; PTN000512984) is a subunit of the non-clathrin AP-4 coat complex.
tsg101_escrt_sorting	Tumor susceptibility gene 101 protein PANTHER:PTHR23306:SF17 Family	ubiquitin binding GO:0043130	Family Review Missing No supported structured family review is available for PANTHER:PTHR23306:SF17.
rab7a_late_maturation	Ras-related protein Rab-7a PANTHER:PTHR47981:SF13 Family	GTPase activity GO:0003924	Family Review Missing No supported structured family review is available for PANTHER:PTHR47981:SF13.
ctsd_proteolysis	Cathepsin D PANTHER:PTHR47966:SF42 Family	aspartic-type endopeptidase activity GO:0004190	Family Review Missing No supported structured family review is available for PANTHER:PTHR47966:SF42.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

retromer_csc_cargo_selection ⊣ escrt_rab7_degradative_routing [closed]
retromer_csc_cargo_selection is regulated by early_endosome_acidification: feedback loop closed

Gene-review completeness (21/21 grounded genes reviewed)

13 complete review(s) · 11 with deep research · 0 missing review · 10 reviewed but lacking deep research

Gene	Review	Complete	Deep research
AP1B1 Q10567	✓	55/57	✓
AP1G1 O43747	✓	70/82	✗
AP2M1 Q96CW1	✓	129/184	✗
apb-1 Q9N4F3	✓	✓	✓
apl2 O43079	✓	✓	✗
ATP6V1A P38606	✓	✓	✓
CLTC Q00610	✓	✓	✓
CTSD P07339	✓	84/91	✗
DNM2 P50570	✓	170/171	✗
dpy-23 P35603	✓	22/23	✓
Rab7 P51150	✓	✓	✓
RAB7A P51149	✓	✓	✓
RAB9A P51151	✓	50/56	✓
SORL1 Q92673	✓	165/168	✗
TSG101 Q99816	✓	✓	✗
Vps26 Q9W552	✓	✓	✓
VPS26A O75436	✓	✓	✗
VPS29 Q9UBQ0	✓	✓	✗
Vps29 Q9VPX5	✓	✓	✓
VPS35 Q96QK1	✓	✓	✗
Vps35 Q9W277	✓	✓	✓

Tree

Retromer (VPS35/VPS26A/VPS29) and SORL1 endosome-to-TGN retrograde retrieval vs. RAB7A/CTSD lysosomal degradationTransport Stepretromer_endosome_to_tgn_retrieval

Parts
1. 1. SORL1 (SorLA) transmembrane sorting receptor recognition of cargo (such as APP)
2. SORL1 (SorLA) sorting receptor cargo capture at cell surface / early endocytic entryMolecular Functionsorl1_cargo_recognition
  
  Annotons
  - SORL1 (SorLA/LR11): VPS10p-domain transmembrane sorting receptor Family: Sortilin-related receptor
3. 2. clathrin/AP-2 coated-pit capture and DNM2 vesicle scission of cell-surface sorting receptors
4. Clathrin/AP-2 coated pit assembly and DNM2 vesicle scissionTransport Stepclathrin_ap2_internalization
  
  Annotons
  - AP2M1 (AP-2 mu2): tyrosine/acidic-cluster cargo adaptor Family: AP-2 complex subunit mu
  - CLTC (CHC17): clathrin heavy chain coat lattice Family: Clathrin heavy chain 1
  - DNM2 (dynamin-2): coated-vesicle neck scission GTPase Family: Dynamin-2
5. 3. V-ATPase early sorting endosome acidification
6. V-ATPase early sorting endosome acidification (pH ~6.0 sorting compartment)Transport Stepearly_endosome_acidification
  
  Annotons
  - ATP6V1A: V-ATPase catalytic subunit A Family: V-type proton ATPase catalytic subunit A
7. 4. retromer cargo-selective complex (VPS35/VPS26A/VPS29) recognition of SORL1 and tubular retrograde sorting
8. Retromer cargo-selective complex (VPS35/VPS26A/VPS29) recruitment and retrograde tubule sortingTransport Stepretromer_csc_cargo_selection
  
  Annotons
  - VPS35: central alpha-solenoid scaffold of the retromer cargo-selective complex Family: Vacuolar protein sorting-associated protein 35
  - VPS26A: arrestin-fold cargo-recognition subunit of the retromer complex Family: Vacuolar protein sorting-associated protein 26
  - VPS29: metallophosphoesterase-fold retromer assembly and TBC1D5/Rab7 regulatory subunit Family: Vacuolar protein sorting-associated protein 29
9. 5. AP-1 (AP1B1/AP1G1) and complementary RAB9A retrograde carrier delivery and sorting at the trans-Golgi network (TGN)
10. RAB9A & AP-1 (AP1B1/AP1G1) retrograde docking and delivery to the trans-Golgi networkTransport Steprab9a_ap1_tgn_delivery
  
  Annotons
  - RAB9A: late-endosome-to-TGN retrograde transport GTPase Family: Ras-related protein Rab-9A
  - AP1B1: AP-1 clathrin adaptor complex beta-1 subunit Family: AP-1/2 complex subunit beta
  - AP1G1: AP-1 clathrin adaptor complex gamma-1 subunit Family: AP-1 complex subunit gamma-1
11. 6. ESCRT-I MVB sorting and RAB7A-mediated late endosome routing of un-retrieved receptors and cargo
12. TSG101/ESCRT-I MVB sorting and RAB7A late endosome routing of un-retrieved cargoTransport Stepescrt_rab7_degradative_routing
  
  Annotons
  - TSG101: ESCRT-I ubiquitin-binding MVB sorting subunit Family: Tumor susceptibility gene 101 protein
  - RAB7A / Rab7: late endosome maturation and lysosome-tethering GTPase Family: Ras-related protein Rab-7a
13. 7. lysosomal fusion and CTSD-mediated proteolytic degradation of un-retrieved receptors and cargo
14. Lysosomal fusion and CTSD luminal proteolysis of mis-sorted receptors & cargoMolecular Functionctsd_lysosomal_proteolysis
  
  Annotons
  - CTSD (cathepsin D): lysosomal aspartic endopeptidase Family: Cathepsin D

Details

Retromer (VPS35/VPS26A/VPS29) and SORL1 endosome-to-TGN retrograde retrieval vs. RAB7A/CTSD lysosomal degradationTransport Stepretromer_endosome_to_tgn_retrieval

retrograde transport, endosome to GolgiGO:0042147 cargo adaptor activityGO:0140312 receptor-mediated endocytosisGO:0006898 endosome to lysosome transportGO:0008333

Constructed for the DELIVEROME and ABM_TRAFFICKING projects to represent retromer (VPS35/VPS26A/VPS29) and SORL1-mediated endosome-to-TGN retrograde retrieval versus lysosomal degradation as an executable agent-based model (ABM) derived directly from the module graph. All protein participants are grounded to completed AIGR gene reviews (human SORL1, VPS35, VPS26A, VPS29, RAB9A, AP1B1, AP1G1, AP2M1, CLTC, DNM2, ATP6V1A, TSG101, RAB7A, CTSD; Drosophila Vps35, Vps26, Vps29; S. pombe apl2; C. elegans apb-1, dpy-23; and mouse Rab7) and verified PANTHER family/subfamily identifiers.

Connections

sorl1_cargo_recognition -> clathrin_ap2_internalization Provides Input For

Cell-surface SORL1-cargo complexes are captured into clathrin/AP-2 coated pits and internalized via DNM2 vesicle scission.

clathrin_ap2_internalization -> early_endosome_acidification Provides Input For

Internalized coated vesicles uncoat and fuse with V-ATPase-acidified early sorting endosomes.

early_endosome_acidification -> retromer_csc_cargo_selection Provides Input For

Internalized SORL1-cargo complexes on acidified sorting endosomes are recognized via the cytoplasmic FANSHY motif by the VPS35/VPS26A/VPS29 retromer core.

early_endosome_acidification -> escrt_rab7_degradative_routing Provides Input For

Sorting-endosome receptors and cargo not captured into retrograde tubules progress into TSG101/RAB7A maturing late endosomes.

retromer_csc_cargo_selection -> escrt_rab7_degradative_routing Negatively Regulates

Active retromer (VPS35/VPS26A/VPS29) extracts sorting receptors into retrograde tubules and recruits TBC1D5 via VPS29 to restrain RAB7A activity, protecting cargo from late-endosomal and lysosomal degradation (PMID:18193032, PMID:32286230).

retromer_csc_cargo_selection -> rab9a_ap1_tgn_delivery Provides Input For

Retromer-sorted cargo receptors on early and maturing endosomes are delivered to the trans-Golgi network via AP-1 (AP1B1/AP1G1) adaptor sorting and complementary/sequential RAB9A-mediated late-endosome-to-TGN retrograde transport (PMID:15078902, PMID:23415225, PMID:34793709).

escrt_rab7_degradative_routing -> ctsd_lysosomal_proteolysis Provides Input For

Mature RAB7A-positive late endosomes fuse with lysosomes where CTSD degrades un-retrieved sorting receptors and cargo.

Part 1: SORL1 (SorLA) transmembrane sorting receptor recognition of cargo (such as APP)

SORL1 (SorLA) sorting receptor cargo capture at cell surface / early endocytic entryMolecular Functionsorl1_cargo_recognition

Annotons

SORL1 (SorLA/LR11): VPS10p-domain transmembrane sorting receptor

sorl1_receptor_binding

Participant: Family: Sortilin-related receptor

Family:

Sortilin-related receptorPANTHER:PTHR12106:SF27

Representative Members: SORL1 (human)UniProtKB:Q92673

Function

cargo receptor activityGO:0038024

Substrates: amyloid precursor protein (APP) and endocytic sorting cargo

Processes

retrograde transport, endosome to GolgiGO:0042147 receptor-mediated endocytosisGO:0006898

Locations

early endosome membraneGO:0031901 trans-Golgi networkGO:0005802

Captures transmembrane cargo (such as APP) and undergoes clathrin/AP-2 endocytosis followed by retromer-mediated retrograde retrieval to the trans-Golgi network.

Part 2: clathrin/AP-2 coated-pit capture and DNM2 vesicle scission of cell-surface sorting receptors

Clathrin/AP-2 coated pit assembly and DNM2 vesicle scissionTransport Stepclathrin_ap2_internalization

Annotons

AP2M1 (AP-2 mu2): tyrosine/acidic-cluster cargo adaptor

ap2m1_cargo_selection

Participant: Family: AP-2 complex subunit mu

Family:

AP-2 complex subunit muPANTHER:PTHR10529:SF236

Representative Members: AP2M1 (human)UniProtKB:Q96CW1 dpy-23 (C. elegans)UniProtKB:P35603

Function

signal sequence receptor activityGO:0005048

Processes

clathrin-dependent endocytosisGO:0072583 receptor internalizationGO:0031623

Locations

clathrin-coated pitGO:0005905

Couples cell-surface SORL1 and CI-MPR receptors into plasma-membrane clathrin-coated pits.

CLTC (CHC17): clathrin heavy chain coat lattice

cltc_coat_lattice

Participant: Family: Clathrin heavy chain 1

Family:

Clathrin heavy chain 1PANTHER:PTHR10292:SF7

Representative Members: CLTC (human)UniProtKB:Q00610

Function

structural molecule activityGO:0005198

Processes

receptor-mediated endocytosisGO:0006898 clathrin coat assemblyGO:0048268

Locations

clathrin-coated endocytic vesicleGO:0045334

Forms the polyhedral clathrin cage that invaginates sorting-receptor-containing pits.

DNM2 (dynamin-2): coated-vesicle neck scission GTPase

dnm2_vesicle_scission

Participant: Family: Dynamin-2

Family:

Dynamin-2PANTHER:PTHR11566:SF23

Representative Members: DNM2 (human)UniProtKB:P50570

Function

GTPase motor activityGO:0061791

Processes

vesicle scissionGO:0099050 receptor-mediated endocytosisGO:0006898

Locations

clathrin-coated pitGO:0005905

Catalyzes GTP-dependent scission of clathrin-coated pits to deliver internalized SORL1-cargo complexes to early sorting endosomes.

Part 3: V-ATPase early sorting endosome acidification

V-ATPase early sorting endosome acidification (pH ~6.0 sorting compartment)Transport Stepearly_endosome_acidification

Annotons

ATP6V1A: V-ATPase catalytic subunit A

atp6v1a_proton_pump

Participant: Family: V-type proton ATPase catalytic subunit A

Family:

V-type proton ATPase catalytic subunit APANTHER:PTHR43607:SF9

Representative Members: ATP6V1A (human)UniProtKB:P38606

Function

proton-transporting ATPase activity, rotational mechanismGO:0046961

Processes

endosomal lumen acidificationGO:0048388 proton transmembrane transportGO:1902600

Locations

endosome membraneGO:0010008 lysosomal membraneGO:0005765

Establishes the mildly acidic lumen (pH ~6.0) of the sorting endosome where retromer recruitment and tubular retrograde sorting compete with ESCRT/RAB7A degradative maturation.

Part 4: retromer cargo-selective complex (VPS35/VPS26A/VPS29) recognition of SORL1 and tubular retrograde sorting

Retromer cargo-selective complex (VPS35/VPS26A/VPS29) recruitment and retrograde tubule sortingTransport Stepretromer_csc_cargo_selection

Context

early endosome membraneGO:0031901 late endosome membraneGO:0031902

Annotons

VPS35: central alpha-solenoid scaffold of the retromer cargo-selective complex

vps35_retromer_spine

Participant: Family: Vacuolar protein sorting-associated protein 35

Family:

Vacuolar protein sorting-associated protein 35PANTHER:PTHR11099:SF0

Representative Members: VPS35 (human)UniProtKB:Q96QK1 Vps35 (Drosophila)UniProtKB:Q9W277

Function

cargo adaptor activityGO:0140312

Processes

retrograde transport, endosome to GolgiGO:0042147 endocytic recyclingGO:0032456

Locations

early endosomeGO:0005769 late endosomeGO:0005770

Serves as the central structural beam of the retromer heterotrimer, bridging VPS26A at its N-terminus and VPS29 at its C-terminus to capture SORL1 (via its FANSHY motif) and CI-MPR on sorting endosomes.

VPS26A: arrestin-fold cargo-recognition subunit of the retromer complex

vps26a_arrestin_adaptor

Participant: Family: Vacuolar protein sorting-associated protein 26

Family:

Vacuolar protein sorting-associated protein 26

Representative Members: VPS26A (human)UniProtKB:O75436 Vps26 (Drosophila)UniProtKB:Q9W552

Function

cargo adaptor activityGO:0140312

Processes

retrograde transport, endosome to GolgiGO:0042147

Locations

early endosomeGO:0005769 late endosomeGO:0005770

Binds the cytoplasmic FANSHY tail motif of SORL1 and cooperates with sorting nexins (SNX3/SNX27) to concentrate cargo into nascent retrograde tubules.

VPS29: metallophosphoesterase-fold retromer assembly and TBC1D5/Rab7 regulatory subunit

vps29_retromer_subunit

Participant: Family: Vacuolar protein sorting-associated protein 29

Family:

Vacuolar protein sorting-associated protein 29PANTHER:PTHR11124:SF12

Representative Members: VPS29 (human)UniProtKB:Q9UBQ0 Vps29 (Drosophila)UniProtKB:Q9VPX5

Function

cargo adaptor activityGO:0140312

Processes

retrograde transport, endosome to GolgiGO:0042147

Locations

early endosomeGO:0005769 late endosomeGO:0005770

Caps the C-terminus of VPS35 to drive retromer arch assembly and recruits TBC1D5 to inactivate RAB7A on retrieval domains, preventing premature degradative maturation.

Part 5: AP-1 (AP1B1/AP1G1) and complementary RAB9A retrograde carrier delivery and sorting at the trans-Golgi network (TGN)

RAB9A & AP-1 (AP1B1/AP1G1) retrograde docking and delivery to the trans-Golgi networkTransport Steprab9a_ap1_tgn_delivery

Context

trans-Golgi network membraneGO:0032588

Annotons

RAB9A: late-endosome-to-TGN retrograde transport GTPase

rab9a_tgn_tethering

Participant: Family: Ras-related protein Rab-9A

Family:

Ras-related protein Rab-9APANTHER:PTHR47981:SF9

Representative Members: RAB9A (human)UniProtKB:P51151

Function

GTPase activityGO:0003924

Processes

retrograde transport, endosome to GolgiGO:0042147

Locations

late endosomeGO:0005770 trans-Golgi network membraneGO:0032588

Mediates complementary/sequential late-endosome-to-TGN retrograde receptor transport (PMID:8164745, PMID:15078902) by recruiting the dynein adaptor NDE1/NDEL1 (PMID:34793709).

AP1B1: AP-1 clathrin adaptor complex beta-1 subunit

ap1b1_tgn_adaptor

Participant: Family: AP-1/2 complex subunit beta

Family:

AP-1/2 complex subunit beta

Representative Members: AP1B1 (human)UniProtKB:Q10567 apl2 (S. pombe)UniProtKB:O43079 apb-1 (C. elegans)UniProtKB:Q9N4F3

Function

clathrin bindingGO:0030276

Processes

vesicle-mediated transportGO:0016192

Locations

trans-Golgi network membraneGO:0032588

Links the TGN/endosomal AP-1 adaptor core to clathrin coats during bidirectional TGN-endosome sorting of SORL1 and CI-MPR.

AP1G1: AP-1 clathrin adaptor complex gamma-1 subunit

ap1g1_tgn_adaptor

Participant: Family: AP-1 complex subunit gamma-1

Family:

AP-1 complex subunit gamma-1PANTHER:PTHR22780:SF26

Representative Members: AP1G1 (human)UniProtKB:O43747

Function

clathrin-cargo adaptor activityGO:0035615

Processes

intracellular protein transportGO:0006886

Locations

trans-Golgi network membraneGO:0032588

Anchors the AP-1 clathrin adaptor complex to Arf1-GTP and PI4P-enriched trans-Golgi network membranes to complete retrograde receptor retrieval and TGN retention.

Part 6: ESCRT-I MVB sorting and RAB7A-mediated late endosome routing of un-retrieved receptors and cargo

TSG101/ESCRT-I MVB sorting and RAB7A late endosome routing of un-retrieved cargoTransport Stepescrt_rab7_degradative_routing

Context

late endosome membraneGO:0031902

Annotons

TSG101: ESCRT-I ubiquitin-binding MVB sorting subunit

tsg101_escrt_sorting

Participant: Family: Tumor susceptibility gene 101 protein

Family:

Tumor susceptibility gene 101 proteinPANTHER:PTHR23306:SF17

Representative Members: TSG101 (human)UniProtKB:Q99816

Function

ubiquitin bindingGO:0043130

Processes

multivesicular body assemblyGO:0036258 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathwayGO:0043162

Locations

late endosome membraneGO:0031902 early endosome membraneGO:0031901

Captures un-retrieved sorting receptors and cargo into intraluminal vesicles of maturing multivesicular bodies.

RAB7A / Rab7: late endosome maturation and lysosome-tethering GTPase

rab7a_late_maturation

Participant: Family: Ras-related protein Rab-7a

Family:

Ras-related protein Rab-7aPANTHER:PTHR47981:SF13

Representative Members: RAB7A (human)UniProtKB:P51149 Rab7 (mouse)UniProtKB:P51150

Function

GTPase activityGO:0003924

Processes

early endosome to late endosome transportGO:0045022 endosome to lysosome transportGO:0008333

Locations

late endosomeGO:0005770 late endosome membraneGO:0031902

Drives maturation of endosomes lacking retromer/TBC1D5 protection into late endosomes destined for lysosomal fusion.

Part 7: lysosomal fusion and CTSD-mediated proteolytic degradation of un-retrieved receptors and cargo

Lysosomal fusion and CTSD luminal proteolysis of mis-sorted receptors & cargoMolecular Functionctsd_lysosomal_proteolysis

Annotons

CTSD (cathepsin D): lysosomal aspartic endopeptidase

ctsd_proteolysis

Participant: Family: Cathepsin D

Family:

Cathepsin DPANTHER:PTHR47966:SF42

Representative Members: CTSD (human)UniProtKB:P07339

Function

aspartic-type endopeptidase activityGO:0004190

Processes

proteolysisGO:0006508

Locations

lysosomal lumenGO:0043202 endosome lumenGO:0031904

Executes terminal lysosomal proteolysis of sorting receptors (SORL1, CI-MPR, WLS) and cargo when retromer-mediated endosome-to-TGN retrieval fails.