id: O95361
gene_symbol: TRIM16
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TRIM16 (estrogen-responsive B box protein, EBBP) is a cytoplasmic member of the
  TRIM/RBCC family that is atypical in lacking a canonical N-terminal RING domain:
  its architecture comprises B-box zinc finger(s), a coiled-coil that mediates
  homodimerization (and heterodimerization with other TRIMs such as MID1, TRIM24
  and PML), and a C-terminal B30.2/SPRY domain. Despite lacking a RING, TRIM16 has
  been reported to act as an atypical E3 ubiquitin ligase that autoubiquitinates
  via its B-boxes. Its principal modern function is in selective autophagy of
  damaged endomembranes: TRIM16 serves as a scaffold/receptor that, in a
  ULK1-dependent manner, interacts with galectin-3 (LGALS3) to sense and direct
  autophagy of damaged lysosomes and phagosomes (lysophagy), and it assembles core
  autophagy machinery (BECN1, ATG16L1, SQSTM1/p62 and LC3B/MAP1LC3B) to drive
  autophagic clearance of protein aggregates. Through these activities it regulates
  the p62-KEAP1-NRF2 axis (modulating NRF2 ubiquitination and stability) and
  protects cells against oxidative-stress-induced death following endomembrane
  damage; it is itself phosphorylated by ULK1. TRIM16 localizes mainly to the
  cytoplasm/cytosol (and has been observed in nuclear PML bodies). It was
  originally characterized as the estrogen-responsive B box protein with reported
  roles in keratinocyte differentiation, retinoid (retinoic acid receptor)
  signaling, interleukin-1beta production (binding IL-1 and the NALP1 NACHT domain),
  and tumor suppression (inhibiting cytoplasmic vimentin and nuclear E2F1 in
  neuroblastoma).
alternative_products:
- name: 1 (Alpha)
  id: O95361-1
- name: 2 (Beta)
  id: O95361-2
  sequence_note: VSP_009098
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined-IEA assignment of cytoplasmic localization; the core compartment for TRIM16.
    action: ACCEPT
    reason: Correct core localization; redundant with multiple experimental IDA/EXP cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.'
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of zinc ion binding by the B-box zinc finger.
    action: KEEP_AS_NON_CORE
    reason: Correct (the B-box coordinates Zn2+) but generic; the informative MF relates to autophagy scaffolding/ubiquitination.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: Auto-ubiquitinates via its B-Boxes.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: EC 2.3.2.27-based electronic assignment of ubiquitin protein ligase activity; note EC mapping presumes a RING that TRIM16 lacks.
    action: KEEP_AS_NON_CORE
    reason: TRIM16 lacks a canonical RING; the EC-based IEA is weak and redundant with the experimentally supported (EXP) ligase-activity annotation, which derives from atypical B-box-dependent autoubiquitination.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: Auto-ubiquitinates via its B-Boxes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20729920
  qualifier: enables
  review:
    summary: Interactions with vimentin (VIM) and E2F1 from the neuroblastoma tumor-suppressor study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions (VIM, E2F1) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'O95361; P08670: VIM; NbExp=3; IntAct=EBI-727384, EBI-353844;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  qualifier: enables
  review:
    summary: Interaction (TINF2) from a telomere-signaling YFP complementation screen. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'O95361; Q9BSI4: TINF2; NbExp=2; IntAct=EBI-727384, EBI-717399;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interaction with TRIM16L (Q309B1) from an interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'O95361; Q309B1: TRIM16L; NbExp=4; IntAct=EBI-727384, EBI-21372540;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Interaction with TRIM16L (Q309B1) from a cell-specific interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'O95361; Q309B1: TRIM16L; NbExp=4; IntAct=EBI-727384, EBI-21372540;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Interaction with TRIM16L (Q309B1) from a multimodal cell-map study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'O95361; Q309B1: TRIM16L; NbExp=4; IntAct=EBI-727384, EBI-21372540;'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based (HPA) cytosolic localization, consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the cytoplasmic autophagy-scaffold role.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:27693506
  qualifier: located_in
  review:
    summary: Experimental evidence of cytoplasmic localization in the galectin-3/lysophagy study. Core localization.
    action: ACCEPT
    reason: Core cellular component, experimentally demonstrated where TRIM16 directs autophagy of damaged endomembranes.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:22629402
  qualifier: enables
  review:
    summary: Experimental evidence that TRIM16 acts as an E3 ubiquitin ligase (autoubiquitination via its B-boxes), despite lacking a canonical RING.
    action: ACCEPT
    reason: Experimentally supported by UniProt (EC ECO:0000269|PubMed:22629402); TRIM16 is an atypical B-box-dependent E3 ligase. Retained per guideline not to overrule experimental annotations, though the activity is unusual and the EC/IEA derivation is weaker.
    supported_by:
    - reference_id: PMID:22629402
      supporting_text: TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize with other TRIM family members.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25127057
  qualifier: enables
  review:
    summary: Interaction with LC3B/MAP1LC3B (O95166) from the TRIM-autophagy study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally relevant autophagy interaction (LC3B) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: Interacts with p62/SQSTM and LC3B/MAP1LC3B.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IDA
  original_reference_id: PMID:16636064
  qualifier: enables
  review:
    summary: Direct evidence of DNA binding from the EBBP/retinoid-signaling study.
    action: KEEP_AS_NON_CORE
    reason: Experimentally reported (older EBBP-era work) but TRIM16 lacks a classical DNA-binding domain and the modern core function is cytoplasmic autophagy scaffolding; defer to curator who read the full text.
    supported_by:
    - reference_id: PMID:16636064
      supporting_text: The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16575408
  qualifier: enables
  review:
    summary: Interactions (IL-1, NALP1) from the IL-1beta-secretion study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions but bare protein binding is uninformative; captured more specifically by the IL-1 binding and NACHT domain binding annotations.
    supported_by:
    - reference_id: PMID:16575408
      supporting_text: 'The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11919186
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization in the keratinocyte-differentiation study. Core localization.
    action: ACCEPT
    reason: Correct core localization, experimentally demonstrated.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16575408
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization in the IL-1beta study. Core localization.
    action: ACCEPT
    reason: Correct core localization, experimentally demonstrated.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9817599
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization in the EBBP-discovery study. Core localization.
    action: ACCEPT
    reason: Correct core localization, experimentally demonstrated.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.'
- term:
    id: GO:0016605
    label: PML body
  evidence_type: IDA
  original_reference_id: PMID:16636064
  qualifier: located_in
  review:
    summary: Direct evidence of localization to nuclear PML bodies (EBBP heterodimerizes with PML).
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but a secondary nuclear-body localization (older EBBP work); the dominant pool is cytoplasmic. Defer to curator.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: Heterodimerizes with
- term:
    id: GO:0019966
    label: interleukin-1 binding
  evidence_type: IPI
  original_reference_id: PMID:16575408
  qualifier: enables
  review:
    summary: Direct interaction evidence that TRIM16/EBBP binds interleukin-1 (IL-1).
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported specific MF from EBBP-era work; a secondary activity relative to the core autophagy-scaffold function.
    supported_by:
    - reference_id: PMID:16575408
      supporting_text: 'The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.'
- term:
    id: GO:0032089
    label: NACHT domain binding
  evidence_type: IPI
  original_reference_id: PMID:16575408
  qualifier: enables
  review:
    summary: Direct interaction evidence that TRIM16/EBBP binds the NACHT domain of NALP1.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported specific MF from EBBP-era work; secondary to the core autophagy-scaffold function.
    supported_by:
    - reference_id: PMID:16575408
      supporting_text: 'The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.'
- term:
    id: GO:0032526
    label: response to retinoic acid
  evidence_type: IEP
  original_reference_id: PMID:16636064
  qualifier: involved_in
  review:
    summary: Expression-pattern evidence that TRIM16/EBBP responds to retinoic acid.
    action: KEEP_AS_NON_CORE
    reason: Supported response/context term from EBBP-era retinoid work; not the core autophagy function.
    supported_by:
    - reference_id: PMID:16636064
      supporting_text: The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
- term:
    id: GO:0032731
    label: positive regulation of interleukin-1 beta production
  evidence_type: IMP
  original_reference_id: PMID:16575408
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that TRIM16/EBBP enhances IL-1beta secretion/production.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported (EBBP-era) but a secondary process relative to the core autophagy-scaffold function.
    supported_by:
    - reference_id: PMID:16575408
      supporting_text: 'The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.'
- term:
    id: GO:0045618
    label: positive regulation of keratinocyte differentiation
  evidence_type: IDA
  original_reference_id: PMID:11919186
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM16/EBBP positively regulates keratinocyte differentiation.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported (original EBBP characterization) but a tissue-specific role secondary to the core autophagy function.
    supported_by:
    - reference_id: PMID:11919186
      supporting_text: 'The estrogen-responsive B box protein: a novel regulator of keratinocyte differentiation.'
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:16636064
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM16/EBBP positively regulates transcription in the retinoid-signaling context.
    action: KEEP_AS_NON_CORE
    reason: Experimentally reported (EBBP-era) but secondary; TRIM16 acts largely as a cytoplasmic autophagy scaffold rather than a core transcriptional regulator. Defer to curator.
    supported_by:
    - reference_id: PMID:16636064
      supporting_text: The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:19147277
  qualifier: involved_in
  review:
    summary: Direct evidence (via histone acetylation effects restoring retinoid sensitivity) that TRIM16/EBBP positively regulates transcription.
    action: KEEP_AS_NON_CORE
    reason: Experimentally reported (EBBP-era retinoid work) but secondary to the core autophagy function. Defer to curator.
    supported_by:
    - reference_id: PMID:19147277
      supporting_text: restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation
- term:
    id: GO:0048386
    label: positive regulation of retinoic acid receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:16636064
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM16/EBBP positively regulates retinoic acid receptor signaling.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported (EBBP-era) but a secondary process relative to the core autophagy function.
    supported_by:
    - reference_id: PMID:16636064
      supporting_text: The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
- term:
    id: GO:0060416
    label: response to growth hormone
  evidence_type: IDA
  original_reference_id: PMID:11919186
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM16/EBBP responds to growth hormone.
    action: KEEP_AS_NON_CORE
    reason: Supported response/context term from EBBP-era work; not the core autophagy function.
    supported_by:
    - reference_id: PMID:11919186
      supporting_text: 'The estrogen-responsive B box protein: a novel regulator of keratinocyte differentiation.'
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IDA
  original_reference_id: PMID:27693506
  qualifier: involved_in
  review:
    summary: Proposed new annotation. TRIM16 directs selective autophagy of damaged endomembranes (lysophagy) and protein aggregates; this core modern function is documented in UniProt and PMID:27693506 but absent from the current GOA.
    action: NEW
    reason: The galectin-3/ULK1-dependent lysophagy and aggrephagy role is the core modern function of TRIM16 and should be annotated; it is currently missing from the GOA.
    supported_by:
    - reference_id: PMID:27693506
      supporting_text: TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:27693506
  qualifier: enables
  review:
    summary: Proposed new annotation. TRIM16 acts as a scaffold/adaptor bridging galectin-3-decorated damaged membranes and autophagy receptors/machinery (SQSTM1/p62, ATG16L1, LC3B, BECN1).
    action: NEW
    reason: Captures TRIM16's core autophagy-receptor/scaffold molecular function (adaptor linking damaged endomembranes to the autophagy apparatus); currently missing from the GOA.
    supported_by:
    - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
      supporting_text: Acts as a scaffold protein and facilitates
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9817599
  title: The novel estrogen-responsive B-box protein (EBBP) gene is tamoxifen-regulated in cells expressing an estrogen receptor DNA-binding domain mutant.
  findings:
  - statement: Identification of EBBP/TRIM16 as an estrogen/tamoxifen-regulated gene; cytoplasmic localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Original EBBP identification; source of an early cytoplasmic localization annotation.
- id: PMID:11919186
  title: 'The estrogen-responsive B box protein: a novel regulator of keratinocyte differentiation.'
  findings:
  - statement: TRIM16/EBBP positively regulates keratinocyte differentiation and responds to growth hormone; cytoplasmic localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes EBBP-era keratinocyte differentiation and growth-hormone-response roles.
- id: PMID:16575408
  title: 'The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.'
  findings:
  - statement: TRIM16/EBBP binds IL-1 and the NALP1 NACHT domain and enhances IL-1beta secretion/production.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of interleukin-1 binding, NACHT domain binding, and positive regulation of IL-1beta production annotations.
- id: PMID:16636064
  title: The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
  findings:
  - statement: TRIM16/EBBP regulates retinoid (RA receptor) signaling, binds DNA, positively regulates transcription, and localizes to PML bodies.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of DNA binding, positive regulation of transcription, RA receptor signaling, response to RA, and PML body annotations (EBBP-era nuclear/retinoid functions).
- id: PMID:19147277
  title: The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation.
  findings:
  - statement: TRIM16/EBBP restores retinoid sensitivity in resistant cancer cells via effects on histone acetylation, positively regulating transcription.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of a second positive regulation of DNA-templated transcription annotation.
- id: PMID:20729920
  title: TRIM16 acts as a tumour suppressor by inhibitory effects on cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells.
  findings:
  - statement: TRIM16 acts as a tumor suppressor in neuroblastoma, inhibiting cytoplasmic vimentin and nuclear E2F1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of VIM and E2F1 protein-binding annotations; establishes a tumor-suppressor role.
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput YFP complementation screen; source of a bare protein binding (TINF2) annotation.
- id: PMID:22629402
  title: TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize with other TRIM family members.
  findings:
  - statement: TRIM16 acts as an E3 ubiquitin ligase (autoubiquitinating via its B-boxes) and heterodimerizes with other TRIM family members, despite lacking a canonical RING domain.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Experimental basis for TRIM16's atypical (RING-less, B-box-dependent) E3 ubiquitin ligase activity.
- id: PMID:25127057
  title: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition.
  findings:
  - statement: TRIM16 is among TRIMs that regulate autophagy and interacts with autophagy machinery (LC3B).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract-only. Supports TRIM16 LC3B interaction and the autophagy-regulatory role.
- id: PMID:27693506
  title: TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis.
  findings:
  - statement: TRIM16 cooperates with galectin-3 (in a ULK1-dependent manner) to direct autophagy of damaged endomembranes (lysosomes/phagosomes), acting as a scaffold assembling autophagy machinery and protecting against oxidative-stress-induced cell death.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Establishes the core modern function of TRIM16 as a galectin-3-interacting receptor/scaffold for autophagy of damaged endomembranes (lysophagy).
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding (TRIM16L) annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding (TRIM16L) annotation.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput multimodal cell map; source of a bare protein binding (TRIM16L) annotation.
core_functions:
- description: Acts as a galectin-3-interacting receptor/scaffold for selective autophagy of damaged endomembranes (lysophagy) and protein aggregates, assembling core autophagy machinery (BECN1, ATG16L1, SQSTM1/p62, LC3B) in a ULK1-dependent manner and thereby protecting cells against oxidative-stress-induced death after endomembrane damage.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:27693506
    supporting_text: TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis.
  - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
    supporting_text: Acts as a scaffold protein and facilitates
  directly_involved_in:
  - id: GO:0006914
    label: autophagy
- description: Functions as an atypical (RING-less, B-box-dependent) E3 ubiquitin ligase that autoubiquitinates and contributes to ubiquitination during the autophagic response to lysosomal/phagosomal damage, including modulation of NRF2 stability in the p62-KEAP1-NRF2 axis.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:22629402
    supporting_text: TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize with other TRIM family members.
  - reference_id: file:human/TRIM16/TRIM16-uniprot.txt
    supporting_text: Auto-ubiquitinates via its B-Boxes.
proposed_new_terms: []
suggested_questions:
- question: Given that TRIM16 lacks a canonical RING domain, what is the structural and mechanistic basis for its reported B-box-dependent E3 ubiquitin ligase activity, and is the activity intrinsic or dependent on heterodimerization with RING-bearing TRIMs?
- question: The current GOA annotations for TRIM16 do not include an autophagy biological-process term despite the well-established galectin-3/lysophagy role - should an autophagy/selective-autophagy-receptor annotation be added based on PMID:27693506?
suggested_experiments:
- description: Reconstitute TRIM16 E3 ligase activity in vitro with purified TRIM16 (wild-type vs B-box mutants) and candidate E2s to determine whether autoubiquitination/substrate ubiquitination is intrinsic to the B-boxes or requires a heterodimeric RING-bearing TRIM partner.
- description: Use galectin-3- and ULK1-phosphosite TRIM16 mutants in lysosomal-damage assays (e.g. LLOMe treatment) to dissect how galectin-3 binding and ULK1 phosphorylation control TRIM16-directed lysophagy and aggregate clearance.