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.