Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of cytoplasmic localization from UniProt; the correct primary compartment, redundant with experimental IDA/EXP evidence. Reason: Correct primary localization; LRSAM1 is a cytoplasmic E3 ligase. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269\|PubMed:15256501
GO:0061630 ubiquitin protein ligase activity	IEA GO_REF:0000003	ACCEPT	Summary: EC-mapping (EC 2.3.2.27) electronic assignment of ubiquitin protein ligase activity. LRSAM1 is a genuine RING-type E3 ligase, so this is correct and core. Reason: Core molecular function; LRSAM1 has intrinsic RING E3 ligase activity (EC 2.3.2.27), redundant with the experimental EXP/IDA evidence. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	KEEP AS NON CORE	Summary: High-throughput proteome-scale interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
GO:0005515 protein binding	IPI PMID:16713569 A protein-protein interaction network for human inherited at...	KEEP AS NON CORE	Summary: Interaction from an inherited-ataxia/Purkinje-degeneration interaction network. Bare protein binding is uninformative. Reason: High-throughput/network interactome; bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:19549727 Analysis of the human E2 ubiquitin conjugating enzyme protei...	KEEP AS NON CORE	Summary: Interaction from an E2 ubiquitin-conjugating enzyme interaction network; relevant to LRSAM1's role as a RING E3 that pairs with E2 enzymes. Bare protein binding is uninformative. Reason: Records E2-E3 interaction(s) consistent with LRSAM1's ligase function, but the bare term is uninformative.
GO:0005515 protein binding	IPI PMID:19690564 A comprehensive framework of E2-RING E3 interactions of the ...	KEEP AS NON CORE	Summary: Interaction from a comprehensive E2-RING E3 interaction framework; relevant to LRSAM1 as a RING E3. Bare protein binding is uninformative. Reason: Records E2-RING interactions consistent with LRSAM1's ligase function, but the bare term is uninformative.
GO:0005515 protein binding	IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi...	KEEP AS NON CORE	Summary: Interaction from a genome-wide YFP fluorescence complementation telomere-signaling screen. Bare protein binding is uninformative. Reason: High-throughput screen interaction; bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:25260751 The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in respon...	KEEP AS NON CORE	Summary: Interaction reported in a study of MEKK1 PHD/TAB1 ubiquitination. Bare protein binding is uninformative. Reason: Interactome-type interaction; bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:27615052 A novel missense mutation of CMT2P alters transcription mach...	KEEP AS NON CORE	Summary: Interaction reported in a CMT2P (Charcot-Marie-Tooth) LRSAM1 mutation study. Bare protein binding is uninformative. Reason: Disease-study interaction; bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Binary interactome reference map interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Neurodegeneration interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Cell-specific proteome-scale interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative.
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway-derived generic protein ubiquitination process; correct for an E3 ligase but generic. Reason: Correct but generic; the specific autoubiquitination/polyubiquitination and xenophagy annotations better capture LRSAM1's role. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0005737 cytoplasm	EXP PMID:27615052 A novel missense mutation of CMT2P alters transcription mach...	ACCEPT	Summary: Experimental evidence for cytoplasmic localization of LRSAM1. Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:15256501, ECO:0000269\|PubMed:27615052}
GO:0061630 ubiquitin protein ligase activity	EXP PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	ACCEPT	Summary: Experimental evidence that LRSAM1/Tal is a TSG101-specific E3 ubiquitin ligase. Core molecular function. Reason: Core molecular function directly supported; LRSAM1 has intrinsic RING E3 ligase activity (monoubiquitinates TSG101). Supporting Evidence: PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding
GO:0005515 protein binding	IPI PMID:23245322 The LRR and RING domain protein LRSAM1 is an E3 ligase cruci...	KEEP AS NON CORE	Summary: Interaction(s) reported in the foundational xenophagy study. Bare protein binding is uninformative. Reason: From the key antibacterial-autophagy paper, but the bare term is uninformative; the xenophagy/ligase annotations capture the function. Supporting Evidence: PMID:23245322 LRSAM1 localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal
GO:0005515 protein binding	IPI PMID:25484098 PHF23 (plant homeodomain finger protein 23) negatively regul...	KEEP AS NON CORE	Summary: Interaction with PHF23, the PHD finger protein that ubiquitinates and degrades LRSAM1 to negatively regulate autophagy. Bare protein binding is uninformative. Reason: Records a real regulatory interaction (PHF23-LRSAM1) but the bare term is uninformative. Supporting Evidence: PMID:25484098 PHF23 ... negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1
GO:0051865 protein autoubiquitination	IDA PMID:23245322 The LRR and RING domain protein LRSAM1 is an E3 ligase cruci...	ACCEPT	Summary: Direct evidence of LRSAM1 RING-dependent (auto)ubiquitination activity in the xenophagy study. Reflects intrinsic E3 activity. Reason: Directly demonstrated; autoubiquitination is a hallmark of an active RING E3 ligase and supports LRSAM1's core catalytic function. Supporting Evidence: PMID:23245322 these functions require LRSAM1's leucine-rich repeat and RING domains, respectively
GO:0061630 ubiquitin protein ligase activity	IDA PMID:23245322 The LRR and RING domain protein LRSAM1 is an E3 ligase cruci...	ACCEPT	Summary: Direct evidence that LRSAM1 acts as the E3 ligase generating the ubiquitin signal around intracellular bacteria. Core molecular function. Reason: Core molecular function directly demonstrated; the RING domain is required to generate the bacteria-associated ubiquitin signal. Supporting Evidence: PMID:23245322 We identify LRSAM1 as the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination
GO:1904417 positive regulation of xenophagy	IMP PMID:23245322 The LRR and RING domain protein LRSAM1 is an E3 ligase cruci...	ACCEPT	Summary: Mutant-phenotype evidence (LRSAM1-deficient cells) that LRSAM1 is required for the ubiquitin signal driving xenophagy of intracellular Salmonella. Core biological process. Reason: Core biological process; LRSAM1 generates the bacteria-associated ubiquitin signal that triggers antibacterial autophagy (xenophagy). Supporting Evidence: PMID:23245322 LRSAM1 is required for ubiquitination associated with intracellular bacteria but dispensable for ubiquitination of aggregated proteins
GO:0098792 xenophagy	IMP PMID:23245322 The LRR and RING domain protein LRSAM1 is an E3 ligase cruci...	NEW	Summary: LRSAM1 is required for ubiquitin-dependent antibacterial autophagy of cytosolic intracellular bacteria, the base xenophagy process. Reason: PN correctly flagged that GOA already supports positive regulation of xenophagy but lacks the base xenophagy process term. The regulation annotation and primary paper support adding GO:0098792 as the more direct process context. Supporting Evidence: PMID:23245322 LRSAM1 is therefore a bacterial recognition protein and ubiquitin ligase that defends the cytoplasm from invasive pathogens
GO:2000786 positive regulation of autophagosome assembly	IMP PMID:25484098 PHF23 (plant homeodomain finger protein 23) negatively regul...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence that LRSAM1 promotes autophagy (its degradation by PHF23 suppresses autophagy). Downstream consequence of LRSAM1's ubiquitin-signaling function. Reason: Real and consistent with LRSAM1 promoting autophagy, but a downstream/secondary process relative to its core E3-ligase ubiquitin-signaling activity that initiates xenophagy. Supporting Evidence: PMID:25484098 PHF23 ... negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1
GO:0016020 membrane	IDA PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	KEEP AS NON CORE	Summary: Direct evidence of membrane-associated (submembranal ring) localization. Consistent with LRSAM1's ESCRT/TSG101-related role at membranes. Reason: Real membrane association (submembranal ring), but a generic compartment term secondary to the primary cytoplasmic/bacterial localization. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt Displays a punctuate distribution and localizes to a submembranal ring
GO:0000209 protein polyubiquitination	IDA PMID:18077552 Regulation of Tsg101 expression by the steadiness box: a rol...	ACCEPT	Summary: Direct evidence of LRSAM1-mediated polyubiquitination (TSG101 regulation context). Reflects core E3 ligase activity. Reason: Directly demonstrated ubiquitination activity consistent with LRSAM1's core RING E3 ligase function. Supporting Evidence: PMID:18077552 Regulation of Tsg101 expression by the steadiness box: a role of Tsg101-associated ligase
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	ACCEPT	Summary: Direct evidence of LRSAM1/Tal ubiquitin-transferase activity toward TSG101. Core molecular function (LRSAM1 is a catalytic RING E3, unlike adaptor-only F-box proteins). Reason: Core molecular function; LRSAM1's RING domain catalyzes ubiquitin transfer to substrates (TSG101). This is genuine catalytic activity, appropriately annotated. Supporting Evidence: PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:18077552 Regulation of Tsg101 expression by the steadiness box: a rol...	ACCEPT	Summary: Direct evidence of LRSAM1 ubiquitin-transferase activity in TSG101 regulation. Core molecular function. Reason: Core molecular function; directly demonstrated ubiquitin transfer activity of the RING E3 ligase. Supporting Evidence: PMID:18077552 a role of Tsg101-associated ligase
GO:0005515 protein binding	IPI PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	KEEP AS NON CORE	Summary: Interaction with TSG101 (the substrate of LRSAM1/Tal). Bare protein binding is uninformative. Reason: Records the functionally central LRSAM1-TSG101 substrate interaction, but the bare term is uninformative; the ubiquitination/endocytosis annotations capture the function. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt Interacts with TSG101 (PubMed:17556548)
GO:0005515 protein binding	IPI PMID:18077552 Regulation of Tsg101 expression by the steadiness box: a rol...	KEEP AS NON CORE	Summary: Interaction with TSG101 in the steadiness-box regulation study. Bare protein binding is uninformative. Reason: Records the LRSAM1-TSG101 interaction but the bare term is uninformative. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt Interacts with TSG101 (PubMed:17556548)
GO:0005737 cytoplasm	IDA PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	ACCEPT	Summary: Direct evidence of cytoplasmic localization (punctate distribution / submembranal ring). Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt Displays a punctuate distribution and localizes to a submembranal ring
GO:0005737 cytoplasm	IDA PMID:18077552 Regulation of Tsg101 expression by the steadiness box: a rol...	ACCEPT	Summary: Direct evidence of cytoplasmic localization in the TSG101-regulation study. Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0030163 protein catabolic process	IMP PMID:18077552 Regulation of Tsg101 expression by the steadiness box: a rol...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence linking LRSAM1 to regulation of TSG101 protein levels (steadiness box). Reflects LRSAM1's ubiquitination-driven control of substrate abundance. Reason: Generic catabolic-process term; consequence of LRSAM1's ubiquitination activity on TSG101 rather than a distinct core process. Supporting Evidence: PMID:18077552 Regulation of Tsg101 expression by the steadiness box
GO:0045806 negative regulation of endocytosis	IMP PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence that LRSAM1/Tal regulates receptor endocytosis by monoubiquitinating TSG101 and inactivating its endocytic-sorting function. Reason: Real ESCRT/TSG101-related role (regulation of EGFR endocytic sorting), but a secondary function distinct from the core antibacterial-xenophagy ubiquitin-ligase role. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors)
GO:0046755 viral budding	IMP PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence that LRSAM1/Tal regulates retrovirus (HIV-1) budding by ubiquitinating TSG101 and inactivating its exocytic-sorting function. Reason: Real ESCRT/TSG101-related role in retroviral budding, but a secondary function distinct from the core antibacterial-xenophagy ligase role. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt exocytic (HIV-1 viral proteins) cargos
GO:0051865 protein autoubiquitination	IDA PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	ACCEPT	Summary: Direct evidence of LRSAM1/Tal autoubiquitination, a hallmark of an active RING E3 ligase. Reason: Directly demonstrated; autoubiquitination supports LRSAM1's core catalytic RING E3 ligase activity. Supporting Evidence: PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase
GO:0070086 ubiquitin-dependent endocytosis	IDA PMID:15256501 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates recept...	KEEP AS NON CORE	Summary: Direct evidence linking LRSAM1/Tal to ubiquitin-dependent endocytic regulation via TSG101 monoubiquitination. Reason: Real ESCRT/TSG101-related endocytic role, but secondary to LRSAM1's core antibacterial-xenophagy ubiquitin-ligase function. Supporting Evidence: file:human/LRSAM1/LRSAM1-uniprot.txt regulates receptor endocytosis and retrovirus budding

Core Functions

Functions as a RING-type E3 ubiquitin-protein ligase that recognizes cytosolic intracellular bacteria (e.g. Salmonella) via its leucine-rich repeats and generates the bacteria-associated polyubiquitin signal via its RING domain, marking the bacteria for antibacterial autophagy (xenophagy) and lysosomal degradation.

Molecular Function:

ubiquitin protein ligase activity

Directly Involved In:

xenophagy positive regulation of xenophagy protein autoubiquitination

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:23245322
We identify LRSAM1 as the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination

Acts as a TSG101-specific E3 ligase (Tal) that monoubiquitinates the ESCRT-I component TSG101, inactivating its ability to sort endocytic (EGFR) and exocytic (HIV-1) cargo, thereby regulating receptor endocytosis and retroviral budding.

Molecular Function:

ubiquitin-protein transferase activity

Directly Involved In:

ubiquitin-dependent endocytosis

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:15256501
Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding

References

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:15256501

Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding.

LRSAM1 (Tal) is a TSG101-specific E3 ubiquitin ligase that monoubiquitinates TSG101, regulating receptor (EGFR) endocytosis and retrovirus (HIV-1) budding; it autoubiquitinates and localizes to a submembranal ring.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16713569

A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.

PMID:18077552

Regulation of Tsg101 expression by the steadiness box: a role of Tsg101-associated ligase.

PMID:19549727

Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.

PMID:19690564

A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome system.

PMID:21044950

Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.

PMID:23245322

The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium.

LRSAM1 is the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination; it localizes to intracellular bacteria via its LRRs and generates the bacteria-associated ubiquitin signal via its RING, required for bacterial (but not aggregate) ubiquitination.

PMID:25260751

The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25484098

PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1.

PHF23 promotes ubiquitination and degradation of LRSAM1, thereby negatively regulating autophagy; LRSAM1 abundance positively regulates autophagy.

PMID:27615052

A novel missense mutation of CMT2P alters transcription machinery.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

Suggested Experiments

Experiment: Reconstitute LRSAM1 RING-dependent ubiquitination in vitro with defined E1/E2 enzymes and candidate substrates, and test LRR- versus RING-domain mutants for bacterial localization versus ubiquitin-signal generation.

Experiment: Use LRSAM1-knockout and CMT2P patient-derived neurons to assay xenophagy of intracellular bacteria, TSG101-dependent endosomal sorting, and axonal integrity to dissect which LRSAM1 activity underlies the neuropathy.

📚 Additional Documentation

Notes

(LRSAM1-notes.md)

LRSAM1 — review notes

UniProt: Q6UWE0. Gene: LRSAM1 (also Tal, "Tsg101-associated ligase"). Human.

Domain architecture

N-terminal leucine-rich repeats (LRR; multiple REPEAT 30-172) — substrate/target recognition (required for localizing to intracellular bacteria).
Coiled-coil regions (254-380, 510-562) — oligomerization/interaction.
SAM (sterile alpha motif) domain (~569-632; UniProt DOMAIN) — protein interaction.
C-terminal RING-type zinc finger (ZN_FING 675-710) — catalytic E3 ligase domain (required for generating the bacteria-associated ubiquitin signal).
[file:human/LRSAM1/LRSAM1-uniprot.txt FT records]

Core function (synthesized)

LRSAM1 is a RING-type E3 ubiquitin ligase with two well-supported roles:
1. Xenophagy / antibacterial autophagy: LRSAM1 is the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination. It localizes to cytosolic intracellular bacterial pathogens (via its LRRs) and generates the polyubiquitin signal around the bacteria (via its RING), recruiting autophagy adaptors and machinery for lysosomal degradation (xenophagy). Required for bacteria-associated ubiquitination but dispensable for ubiquitination of protein aggregates.
PMID:23245322
[file:human/LRSAM1/LRSAM1-uniprot.txt "Bacterial recognition protein that defends the cytoplasm from invasive pathogens ... generates the bacteria-associated ubiquitin signal leading to autophagy-mediated intracellular bacteria degradation (xenophagy)"]
2. ESCRT/TSG101 regulation (as "Tal"): LRSAM1 monoubiquitinates TSG101 at multiple sites, inactivating TSG101's ability to sort endocytic (EGFR) and exocytic (HIV-1 Gag) cargos; this regulates receptor endocytosis and retroviral budding.
PMID:15256501
PMID:18077552
[file:human/LRSAM1/LRSAM1-uniprot.txt "mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos"]

Catalytic activity / E3 ligase

LRSAM1 has genuine intrinsic RING E3 ligase activity (EC 2.3.2.27); demonstrated autoubiquitination and substrate ubiquitination. Unlike adaptor-only F-box proteins, the RING is catalytic, so ubiquitin-protein transferase activity (GO:0004842) and ubiquitin protein ligase activity (GO:0061630) are CORE/correct.
[file:human/LRSAM1/LRSAM1-uniprot.txt "CATALYTIC ACTIVITY ... EC=2.3.2.27"]
[PMID:23245322; PMID:15256501]

Regulation

PHF23 (PHD finger protein 23) promotes ubiquitination and degradation of LRSAM1, negatively regulating autophagy.
PMID:25484098

Localization

Cytoplasm, punctate distribution and a submembranal ring; relocalizes to intracellular bacterial pathogens.
[file:human/LRSAM1/LRSAM1-uniprot.txt SUBCELLULAR LOCATION]

Disease

LRSAM1 mutations cause Charcot-Marie-Tooth disease type 2P (CMT2P), an axonal peripheral neuropathy.
PMID:27615052

Annotation judgments

Core ACCEPT: ubiquitin protein ligase activity (GO:0061630 EXP/IDA), ubiquitin-protein transferase activity (GO:0004842 IDA), protein autoubiquitination (GO:0051865), protein polyubiquitination (GO:0000209), positive regulation of xenophagy (GO:1904417), cytoplasm localization.
KEEP_AS_NON_CORE: TSG101/ESCRT-related: ubiquitin-dependent endocytosis (GO:0070086), negative regulation of endocytosis (GO:0045806), viral budding (GO:0046755), protein catabolic process (GO:0030163), membrane (GO:0016020); positive regulation of autophagosome assembly (GO:2000786, downstream of xenophagy ubiquitination); protein ubiquitination IEA (generic).
ubiquitin protein ligase activity IEA from EC mapping (GO_REF:0000003): ACCEPT (correct, redundant with EXP).
protein binding (GO:0005515) — KEEP_AS_NON_CORE (uninformative bare term; many high-throughput interactome PMIDs).
The EC-based IEA is fine because LRSAM1 genuinely has the EC 2.3.2.27 activity.

Pn Notes

(LRSAM1-pn-notes.md)

LRSAM1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q6UWE0
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-14
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/LRSAM1/LRSAM1-ai-review.yaml
AIGR review HTML: missing - genes/human/LRSAM1/LRSAM1-ai-review.html
Gene notes: present - genes/human/LRSAM1/LRSAM1-notes.md
GOA TSV: present - genes/human/LRSAM1/LRSAM1-goa.tsv
UniProt record: present - genes/human/LRSAM1/LRSAM1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/LRSAM1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/LRSAM1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: LRSAM1 (leucine-rich repeat and sterile alpha motif-containing protein 1; also called Tal, the Tsg101-associated ligase) is a cytoplasmic RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27). Its domain architecture comprises N-terminal leucine-rich repeats (LRRs) that mediate target recognition, central coiled-coil and SAM (sterile alpha motif) domains, and a C-terminal RING-type zinc finger that provides catalytic E3 ligase activity. LRSAM1 has two principal, experimentally established functions. First, it is a bacterial recognition protein and the E3 ligase responsible for antibacterial autophagy (xenophagy): it localizes to cytosolic intracellular bacterial pathogens (such as Salmonella Typhimurium) via its LRRs and generates the polyubiquitin signal around the bacteria via its RING domain, recruiting autophagy adaptors and machinery to target the bacteria for lysosomal degradation; this activity is required for bacteria-associated ubiquitination but is dispensable for ubiquitination of protein aggregates. Second, as Tal it monoubiquitinates the ESCRT-I component TSG101 at multiple sites, inactivating TSG101's ability to sort endocytic (EGF receptor) and exocytic (HIV-1 viral protein) cargos, thereby regulating receptor endocytosis and retroviral budding. LRSAM1 displays a punctate cytoplasmic distribution and a submembranal ring, and relocalizes to intracellular bacteria during infection. Its abundance is controlled by PHF23, which promotes LRSAM1 ubiquitination and degradation to negatively regulate autophagy. Mutations in LRSAM1 cause Charcot-Marie-Tooth disease type 2P (CMT2P), an axonal peripheral neuropathy.
Existing/core annotation action counts: ACCEPT: 13; KEEP_AS_NON_CORE: 22; NEW: 1

PN Consistency Summary

Consistency: Excellent. Deep research, review and PN all agree LRSAM1 is a genuine catalytic RING E3 (EC 2.3.2.27) that (a) recognizes cytosolic bacteria via LRRs and generates the bacteria-associated polyUb signal via its RING to drive xenophagy (PMID:23245322), and (b) as Tal monoubiquitinates TSG101 (ESCRT) controlling endocytosis/retroviral budding. PN row2 ("genuine catalytic RING E3") matches the review's ACCEPT of GO:0061630/GO:0004842 as CORE. No contradictions.
PN story / NEW pressure: Row1 projects GO:0098792 xenophagy (verified real; ABSENT from GOA as the base process). PN flags it goa_status=supported_by_goa_regulation — confirmed: GOA carries GO:1904417 positive regulation of xenophagy (IMP, PMID:23245322) but NOT the parent GO:0098792. The review accepts GO:1904417 as core and never adds the base xenophagy term. So GO:0098792 is a defensible ADD (the regulation term already in GOA strongly supports it). Row2 GO:0061630 is correctly already_in_goa_exact (EXP/IDA/IEA all present) — keep the catalytic ligase MF as core (matches the KEY PATTERN: LRSAM1 generates the autophagy ubiquitin signal).
Evidence alignment: Strong. PN row1 ref (LRR+RING LRSAM1 E3 xenophagy of Salmonella = PMID:23245322) is the review's HIGH/VERIFIED anchor. PN row2 "19489725 / rev" is a family-review pointer not in the review.
Verdict: Fully consistent and mutually reinforcing; catalytic ligase MF is core (already in GOA); base xenophagy BP is a justified ADD the review omits (regulation child already curated).

Full Consistency Review

UniProt: Q6UWE0 (Tal) · batch: proteostasis-batch-2026-06-14 · review status: COMPLETE (thorough; catalytic RING E3; xenophagy + TSG101/ESCRT; CMT2P; 2 PN rows)
PN placement: row1 ALP|...|Marking substrates for selective autophagy|Xenophagy|Intracellular pathogen ubiquitination; row2 UPS|E3 ubiquitin and UBL ligases|RING|other|LRR. PN-node mapping: row1 Xenophagy type→mapped GO:0098792 xenophagy (subtype contextual no_mapping); row2 RING group→mapped GO:0061630 ubiquitin protein ligase activity (class context_only/too_broad).
Consistency: Excellent. Deep research, review and PN all agree LRSAM1 is a genuine catalytic RING E3 (EC 2.3.2.27) that (a) recognizes cytosolic bacteria via LRRs and generates the bacteria-associated polyUb signal via its RING to drive xenophagy (PMID:23245322), and (b) as Tal monoubiquitinates TSG101 (ESCRT) controlling endocytosis/retroviral budding. PN row2 ("genuine catalytic RING E3") matches the review's ACCEPT of GO:0061630/GO:0004842 as CORE. No contradictions.
PN story / NEW pressure: Row1 projects GO:0098792 xenophagy (verified real; ABSENT from GOA as the base process). PN flags it goa_status=supported_by_goa_regulation — confirmed: GOA carries GO:1904417 positive regulation of xenophagy (IMP, PMID:23245322) but NOT the parent GO:0098792. The review accepts GO:1904417 as core and never adds the base xenophagy term. So GO:0098792 is a defensible ADD (the regulation term already in GOA strongly supports it). Row2 GO:0061630 is correctly already_in_goa_exact (EXP/IDA/IEA all present) — keep the catalytic ligase MF as core (matches the KEY PATTERN: LRSAM1 generates the autophagy ubiquitin signal).
Mapping strategy: Correct. Catalytic RING→GO:0061630 (exact, in GOA); Xenophagy type→GO:0098792 (narrower-but-inside the process). The contextual "Intracellular pathogen ubiquitination" subtype is appropriately no_mapping. The xenophagy process projection is consistent with — not broader than — the review's accepted GO:1904417; no TOMM20-style over-reach.
Evidence alignment: Strong. PN row1 ref (LRR+RING LRSAM1 E3 xenophagy of Salmonella = PMID:23245322) is the review's HIGH/VERIFIED anchor. PN row2 "19489725 / rev" is a family-review pointer not in the review.
Verdict: Fully consistent and mutually reinforcing; catalytic ligase MF is core (already in GOA); base xenophagy BP is a justified ADD the review omits (regulation child already curated).
Recommended edits: [YAML] add GO:0098792 xenophagy (BP, involved_in) — the base process is absent though GO:1904417 (its positive-regulation child) is already accepted as core; cite PMID:23245322.
2026-06-18 follow-up: Implemented the YAML edit: added GO:0098792 xenophagy as a NEW recommendation and added the base process to the core xenophagy function while retaining GO:1904417 positive regulation of xenophagy.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-14
review_yaml: genes/human/LRSAM1/LRSAM1-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | Xenophagy | Intracellular pathogen ubiquitination

UniProt: Q6UWE0
In branches: ALP, UPS
Notes: E3 ligase involved in ubiquitin-dependent autophagy of intracellular pathogens
PN references (titles):
- The LRR and RING Domain Protein LRSAM1 Is an E3 Ligase Crucial for Ubiquitin-Dependent Autophagy of Intracellular Salmonella Typhimurium - ScienceDirect
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Xenophagy|Intracellular pathogen ubiquitination
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Xenophagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0098792 xenophagy]
  rationale: This PN type groups xenophagy-specific marking steps that label cargo for selective autophagic clearance. That is narrower than, but clearly inside, the xenophagy process.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | other | LRR

UniProt: Q6UWE0
In branches: ALP, UPS
Signature domains: IPR001841
Auxiliary domains: IPR001611
PN references (titles):
- 19489725 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|other|LRR
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|other
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

GO:0098792 xenophagy | scope=ok_for_propagation_to_go | goa_status=supported_by_goa_regulation | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Xenophagy
GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q6UWE0
gene_symbol: LRSAM1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  LRSAM1 (leucine-rich repeat and sterile alpha motif-containing protein 1; also
  called Tal, the Tsg101-associated ligase) is a cytoplasmic RING-type E3
  ubiquitin-protein ligase (EC 2.3.2.27). Its domain architecture comprises
  N-terminal leucine-rich repeats (LRRs) that mediate target recognition,
  central coiled-coil and SAM (sterile alpha motif) domains, and a C-terminal
  RING-type zinc finger that provides catalytic E3 ligase activity. LRSAM1 has
  two principal, experimentally established functions. First, it is a bacterial
  recognition protein and the E3 ligase responsible for antibacterial autophagy
  (xenophagy): it localizes to cytosolic intracellular bacterial pathogens (such
  as Salmonella Typhimurium) via its LRRs and generates the polyubiquitin signal
  around the bacteria via its RING domain, recruiting autophagy adaptors and
  machinery to target the bacteria for lysosomal degradation; this activity is
  required for bacteria-associated ubiquitination but is dispensable for
  ubiquitination of protein aggregates. Second, as Tal it monoubiquitinates the
  ESCRT-I component TSG101 at multiple sites, inactivating TSG101's ability to
  sort endocytic (EGF receptor) and exocytic (HIV-1 viral protein) cargos,
  thereby regulating receptor endocytosis and retroviral budding. LRSAM1
  displays a punctate cytoplasmic distribution and a submembranal ring, and
  relocalizes to intracellular bacteria during infection. Its abundance is
  controlled by PHF23, which promotes LRSAM1 ubiquitination and degradation to
  negatively regulate autophagy. Mutations in LRSAM1 cause Charcot-Marie-Tooth
  disease type 2P (CMT2P), an axonal peripheral neuropathy.
alternative_products:
- name: '1'
  id: Q6UWE0-1
- name: '2'
  id: Q6UWE0-2
  sequence_note: VSP_012661
- name: '3'
  id: Q6UWE0-3
  sequence_note: VSP_012660
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoplasmic localization from UniProt; the correct primary compartment, redundant with experimental IDA/EXP evidence.
    action: ACCEPT
    reason: Correct primary localization; LRSAM1 is a cytoplasmic E3 ligase.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15256501'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: EC-mapping (EC 2.3.2.27) electronic assignment of ubiquitin protein ligase activity. LRSAM1 is a genuine RING-type E3 ligase, so this is correct and core.
    action: ACCEPT
    reason: Core molecular function; LRSAM1 has intrinsic RING E3 ligase activity (EC 2.3.2.27), redundant with the experimental EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput proteome-scale interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  qualifier: enables
  review:
    summary: Interaction from an inherited-ataxia/Purkinje-degeneration interaction network. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput/network interactome; bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19549727
  qualifier: enables
  review:
    summary: Interaction from an E2 ubiquitin-conjugating enzyme interaction network; relevant to LRSAM1's role as a RING E3 that pairs with E2 enzymes. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records E2-E3 interaction(s) consistent with LRSAM1's ligase function, but the bare term is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19690564
  qualifier: enables
  review:
    summary: Interaction from a comprehensive E2-RING E3 interaction framework; relevant to LRSAM1 as a RING E3. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records E2-RING interactions consistent with LRSAM1's ligase function, but the bare term is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  qualifier: enables
  review:
    summary: Interaction from a genome-wide YFP fluorescence complementation telomere-signaling screen. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput screen interaction; bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25260751
  qualifier: enables
  review:
    summary: Interaction reported in a study of MEKK1 PHD/TAB1 ubiquitination. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Interactome-type interaction; bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27615052
  qualifier: enables
  review:
    summary: Interaction reported in a CMT2P (Charcot-Marie-Tooth) LRSAM1 mutation study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Disease-study interaction; bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific proteome-scale interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived generic protein ubiquitination process; correct for an E3 ligase but generic.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific autoubiquitination/polyubiquitination and xenophagy annotations better capture LRSAM1's role.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:27615052
  qualifier: located_in
  review:
    summary: Experimental evidence for cytoplasmic localization of LRSAM1. Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:15256501, ECO:0000269|PubMed:27615052}
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:15256501
  qualifier: enables
  review:
    summary: Experimental evidence that LRSAM1/Tal is a TSG101-specific E3 ubiquitin ligase. Core molecular function.
    action: ACCEPT
    reason: Core molecular function directly supported; LRSAM1 has intrinsic RING E3 ligase activity (monoubiquitinates TSG101).
    supported_by:
    - reference_id: PMID:15256501
      supporting_text: Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23245322
  qualifier: enables
  review:
    summary: Interaction(s) reported in the foundational xenophagy study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: From the key antibacterial-autophagy paper, but the bare term is uninformative; the xenophagy/ligase annotations capture the function.
    supported_by:
    - reference_id: PMID:23245322
      supporting_text: LRSAM1 localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25484098
  qualifier: enables
  review:
    summary: Interaction with PHF23, the PHD finger protein that ubiquitinates and degrades LRSAM1 to negatively regulate autophagy. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real regulatory interaction (PHF23-LRSAM1) but the bare term is uninformative.
    supported_by:
    - reference_id: PMID:25484098
      supporting_text: PHF23 ... negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:23245322
  qualifier: involved_in
  review:
    summary: Direct evidence of LRSAM1 RING-dependent (auto)ubiquitination activity in the xenophagy study. Reflects intrinsic E3 activity.
    action: ACCEPT
    reason: Directly demonstrated; autoubiquitination is a hallmark of an active RING E3 ligase and supports LRSAM1's core catalytic function.
    supported_by:
    - reference_id: PMID:23245322
      supporting_text: these functions require LRSAM1's leucine-rich repeat and RING domains, respectively
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:23245322
  qualifier: enables
  review:
    summary: Direct evidence that LRSAM1 acts as the E3 ligase generating the ubiquitin signal around intracellular bacteria. Core molecular function.
    action: ACCEPT
    reason: Core molecular function directly demonstrated; the RING domain is required to generate the bacteria-associated ubiquitin signal.
    supported_by:
    - reference_id: PMID:23245322
      supporting_text: We identify LRSAM1 as the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination
- term:
    id: GO:1904417
    label: positive regulation of xenophagy
  evidence_type: IMP
  original_reference_id: PMID:23245322
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence (LRSAM1-deficient cells) that LRSAM1 is required for the ubiquitin signal driving xenophagy of intracellular Salmonella. Core biological process.
    action: ACCEPT
    reason: Core biological process; LRSAM1 generates the bacteria-associated ubiquitin signal that triggers antibacterial autophagy (xenophagy).
    supported_by:
    - reference_id: PMID:23245322
      supporting_text: LRSAM1 is required for ubiquitination associated with intracellular bacteria but dispensable for ubiquitination of aggregated proteins
- term:
    id: GO:0098792
    label: xenophagy
  evidence_type: IMP
  original_reference_id: PMID:23245322
  qualifier: involved_in
  review:
    summary: LRSAM1 is required for ubiquitin-dependent antibacterial autophagy of cytosolic intracellular bacteria, the base xenophagy process.
    action: NEW
    reason: PN correctly flagged that GOA already supports positive regulation of xenophagy but lacks the base xenophagy process term. The regulation annotation and primary paper support adding GO:0098792 as the more direct process context.
    supported_by:
    - reference_id: PMID:23245322
      supporting_text: LRSAM1 is therefore a bacterial recognition protein and ubiquitin ligase that defends the cytoplasm from invasive pathogens
      reference_section_type: ABSTRACT
- term:
    id: GO:2000786
    label: positive regulation of autophagosome assembly
  evidence_type: IMP
  original_reference_id: PMID:25484098
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that LRSAM1 promotes autophagy (its degradation by PHF23 suppresses autophagy). Downstream consequence of LRSAM1's ubiquitin-signaling function.
    action: KEEP_AS_NON_CORE
    reason: Real and consistent with LRSAM1 promoting autophagy, but a downstream/secondary process relative to its core E3-ligase ubiquitin-signaling activity that initiates xenophagy.
    supported_by:
    - reference_id: PMID:25484098
      supporting_text: PHF23 ... negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:15256501
  qualifier: located_in
  review:
    summary: Direct evidence of membrane-associated (submembranal ring) localization. Consistent with LRSAM1's ESCRT/TSG101-related role at membranes.
    action: KEEP_AS_NON_CORE
    reason: Real membrane association (submembranal ring), but a generic compartment term secondary to the primary cytoplasmic/bacterial localization.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: Displays a punctuate distribution and localizes to a submembranal ring
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:18077552
  qualifier: involved_in
  review:
    summary: Direct evidence of LRSAM1-mediated polyubiquitination (TSG101 regulation context). Reflects core E3 ligase activity.
    action: ACCEPT
    reason: Directly demonstrated ubiquitination activity consistent with LRSAM1's core RING E3 ligase function.
    supported_by:
    - reference_id: PMID:18077552
      supporting_text: 'Regulation of Tsg101 expression by the steadiness box: a role of Tsg101-associated ligase'
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:15256501
  qualifier: enables
  review:
    summary: Direct evidence of LRSAM1/Tal ubiquitin-transferase activity toward TSG101. Core molecular function (LRSAM1 is a catalytic RING E3, unlike adaptor-only F-box proteins).
    action: ACCEPT
    reason: Core molecular function; LRSAM1's RING domain catalyzes ubiquitin transfer to substrates (TSG101). This is genuine catalytic activity, appropriately annotated.
    supported_by:
    - reference_id: PMID:15256501
      supporting_text: Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:18077552
  qualifier: enables
  review:
    summary: Direct evidence of LRSAM1 ubiquitin-transferase activity in TSG101 regulation. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; directly demonstrated ubiquitin transfer activity of the RING E3 ligase.
    supported_by:
    - reference_id: PMID:18077552
      supporting_text: a role of Tsg101-associated ligase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15256501
  qualifier: enables
  review:
    summary: Interaction with TSG101 (the substrate of LRSAM1/Tal). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central LRSAM1-TSG101 substrate interaction, but the bare term is uninformative; the ubiquitination/endocytosis annotations capture the function.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: Interacts with TSG101 (PubMed:17556548)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18077552
  qualifier: enables
  review:
    summary: Interaction with TSG101 in the steadiness-box regulation study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the LRSAM1-TSG101 interaction but the bare term is uninformative.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: Interacts with TSG101 (PubMed:17556548)
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15256501
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization (punctate distribution / submembranal ring). Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: Displays a punctuate distribution and localizes to a submembranal ring
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18077552
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization in the TSG101-regulation study. Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:18077552
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking LRSAM1 to regulation of TSG101 protein levels (steadiness box). Reflects LRSAM1's ubiquitination-driven control of substrate abundance.
    action: KEEP_AS_NON_CORE
    reason: Generic catabolic-process term; consequence of LRSAM1's ubiquitination activity on TSG101 rather than a distinct core process.
    supported_by:
    - reference_id: PMID:18077552
      supporting_text: 'Regulation of Tsg101 expression by the steadiness box'
- term:
    id: GO:0045806
    label: negative regulation of endocytosis
  evidence_type: IMP
  original_reference_id: PMID:15256501
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that LRSAM1/Tal regulates receptor endocytosis by monoubiquitinating TSG101 and inactivating its endocytic-sorting function.
    action: KEEP_AS_NON_CORE
    reason: Real ESCRT/TSG101-related role (regulation of EGFR endocytic sorting), but a secondary function distinct from the core antibacterial-xenophagy ubiquitin-ligase role.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors)
- term:
    id: GO:0046755
    label: viral budding
  evidence_type: IMP
  original_reference_id: PMID:15256501
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that LRSAM1/Tal regulates retrovirus (HIV-1) budding by ubiquitinating TSG101 and inactivating its exocytic-sorting function.
    action: KEEP_AS_NON_CORE
    reason: Real ESCRT/TSG101-related role in retroviral budding, but a secondary function distinct from the core antibacterial-xenophagy ligase role.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: exocytic (HIV-1 viral proteins) cargos
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:15256501
  qualifier: involved_in
  review:
    summary: Direct evidence of LRSAM1/Tal autoubiquitination, a hallmark of an active RING E3 ligase.
    action: ACCEPT
    reason: Directly demonstrated; autoubiquitination supports LRSAM1's core catalytic RING E3 ligase activity.
    supported_by:
    - reference_id: PMID:15256501
      supporting_text: Tal, a Tsg101-specific E3 ubiquitin ligase
- term:
    id: GO:0070086
    label: ubiquitin-dependent endocytosis
  evidence_type: IDA
  original_reference_id: PMID:15256501
  qualifier: involved_in
  review:
    summary: Direct evidence linking LRSAM1/Tal to ubiquitin-dependent endocytic regulation via TSG101 monoubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Real ESCRT/TSG101-related endocytic role, but secondary to LRSAM1's core antibacterial-xenophagy ubiquitin-ligase function.
    supported_by:
    - reference_id: file:human/LRSAM1/LRSAM1-uniprot.txt
      supporting_text: regulates receptor endocytosis and retrovirus budding
references:
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:15256501
  title: Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis
    and retrovirus budding.
  findings:
  - statement: LRSAM1 (Tal) is a TSG101-specific E3 ubiquitin ligase that monoubiquitinates TSG101, regulating receptor (EGFR) endocytosis and retrovirus (HIV-1) budding; it autoubiquitinates and localizes to a submembranal ring.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational paper establishing LRSAM1/Tal as a catalytic RING E3 ligase and its ESCRT/TSG101 role. Abstract-only in cache.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders
    of Purkinje cell degeneration.
  findings: []
- id: PMID:18077552
  title: 'Regulation of Tsg101 expression by the steadiness box: a role of Tsg101-associated
    ligase.'
  findings: []
- id: PMID:19549727
  title: Analysis of the human E2 ubiquitin conjugating enzyme protein interaction
    network.
  findings: []
- id: PMID:19690564
  title: A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome
    system.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators
    for telomere signaling in human cells.
  findings: []
- id: PMID:23245322
  title: The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent
    autophagy of intracellular Salmonella Typhimurium.
  findings:
  - statement: LRSAM1 is the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination; it localizes to intracellular bacteria via its LRRs and generates the bacteria-associated ubiquitin signal via its RING, required for bacterial (but not aggregate) ubiquitination.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Foundational paper establishing LRSAM1's core xenophagy ubiquitin-ligase function; confirmed in LRSAM1-deficient patient cells.
- id: PMID:25260751
  title: The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25484098
  title: PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy
    by promoting ubiquitination and degradation of E3 ligase LRSAM1.
  findings:
  - statement: PHF23 promotes ubiquitination and degradation of LRSAM1, thereby negatively regulating autophagy; LRSAM1 abundance positively regulates autophagy.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes upstream regulation of LRSAM1 stability (by PHF23) controlling autophagy. Abstract-only in cache.
- id: PMID:27615052
  title: A novel missense mutation of CMT2P alters transcription machinery.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
core_functions:
- description: Functions as a RING-type E3 ubiquitin-protein ligase that recognizes cytosolic intracellular bacteria (e.g. Salmonella) via its leucine-rich repeats and generates the bacteria-associated polyubiquitin signal via its RING domain, marking the bacteria for antibacterial autophagy (xenophagy) and lysosomal degradation.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  supported_by:
  - reference_id: PMID:23245322
    supporting_text: We identify LRSAM1 as the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination
  locations:
  - id: GO:0005737
    label: cytoplasm
  directly_involved_in:
  - id: GO:0098792
    label: xenophagy
  - id: GO:1904417
    label: positive regulation of xenophagy
  - id: GO:0051865
    label: protein autoubiquitination
- description: Acts as a TSG101-specific E3 ligase (Tal) that monoubiquitinates the ESCRT-I component TSG101, inactivating its ability to sort endocytic (EGFR) and exocytic (HIV-1) cargo, thereby regulating receptor endocytosis and retroviral budding.
  molecular_function:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  supported_by:
  - reference_id: PMID:15256501
    supporting_text: Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding
  locations:
  - id: GO:0005737
    label: cytoplasm
  directly_involved_in:
  - id: GO:0070086
    label: ubiquitin-dependent endocytosis
suggested_questions:
- question: How does LRSAM1 achieve selectivity for cytosolic bacteria versus other ubiquitination targets, and what feature(s) of the bacterial surface are recognized by its leucine-rich repeats?
- question: How do LRSAM1's two activities (antibacterial xenophagy and ESCRT/TSG101 regulation) relate to the axonal phenotype of Charcot-Marie-Tooth disease type 2P (CMT2P)?
suggested_experiments:
- description: Reconstitute LRSAM1 RING-dependent ubiquitination in vitro with defined E1/E2 enzymes and candidate substrates, and test LRR- versus RING-domain mutants for bacterial localization versus ubiquitin-signal generation.
- description: Use LRSAM1-knockout and CMT2P patient-derived neurons to assay xenophagy of intracellular bacteria, TSG101-dependent endosomal sorting, and axonal integrity to dissect which LRSAM1 activity underlies the neuropathy.

LRSAM1

Gene Description