TRIM16

UniProt ID: O95361
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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).

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined-IEA assignment of cytoplasmic localization; the core compartment for TRIM16.
Reason: Correct core localization; redundant with multiple experimental IDA/EXP cytoplasm annotations.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.
GO:0008270 zinc ion binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro-based electronic assignment of zinc ion binding by the B-box zinc finger.
Reason: Correct (the B-box coordinates Zn2+) but generic; the informative MF relates to autophagy scaffolding/ubiquitination.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
Auto-ubiquitinates via its B-Boxes.
GO:0061630 ubiquitin protein ligase activity
IEA
GO_REF:0000003 		KEEP AS NON CORE
Summary: EC 2.3.2.27-based electronic assignment of ubiquitin protein ligase activity; note EC mapping presumes a RING that TRIM16 lacks.
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.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
Auto-ubiquitinates via its B-Boxes.
GO:0005515 protein binding
IPI
PMID:20729920
TRIM16 acts as a tumour suppressor by inhibitory effects on ... 		KEEP AS NON CORE
Summary: Interactions with vimentin (VIM) and E2F1 from the neuroblastoma tumor-suppressor study. Bare protein binding is uninformative.
Reason: Records real interactions (VIM, E2F1) but bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
O95361; P08670: VIM; NbExp=3; IntAct=EBI-727384, EBI-353844;
GO:0005515 protein binding
IPI
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifi... 		KEEP AS NON CORE
Summary: Interaction (TINF2) from a telomere-signaling YFP complementation screen. Bare protein binding is uninformative.
Reason: High-throughput interaction; bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
O95361; Q9BSI4: TINF2; NbExp=2; IntAct=EBI-727384, EBI-717399;
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: Interaction with TRIM16L (Q309B1) from an interactome study. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
O95361; Q309B1: TRIM16L; NbExp=4; IntAct=EBI-727384, EBI-21372540;
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: Interaction with TRIM16L (Q309B1) from a cell-specific interactome study. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
O95361; Q309B1: TRIM16L; NbExp=4; IntAct=EBI-727384, EBI-21372540;
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Interaction with TRIM16L (Q309B1) from a multimodal cell-map study. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
O95361; Q309B1: TRIM16L; NbExp=4; IntAct=EBI-727384, EBI-21372540;
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Immunofluorescence-based (HPA) cytosolic localization, consistent with the core cytoplasmic site of action.
Reason: Correct cytosolic localization, consistent with the cytoplasmic autophagy-scaffold role.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.
GO:0005737 cytoplasm
EXP
PMID:27693506
TRIMs and Galectins Globally Cooperate and TRIM16 and Galect... 		ACCEPT
Summary: Experimental evidence of cytoplasmic localization in the galectin-3/lysophagy study. Core localization.
Reason: Core cellular component, experimentally demonstrated where TRIM16 directs autophagy of damaged endomembranes.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.
GO:0061630 ubiquitin protein ligase activity
EXP
PMID:22629402
TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize... 		ACCEPT
Summary: Experimental evidence that TRIM16 acts as an E3 ubiquitin ligase (autoubiquitination via its B-boxes), despite lacking a canonical RING.
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.
Supporting Evidence:
PMID:22629402
TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize with other TRIM family members.
GO:0005515 protein binding
IPI
PMID:25127057
TRIM proteins regulate autophagy and can target autophagic s... 		KEEP AS NON CORE
Summary: Interaction with LC3B/MAP1LC3B (O95166) from the TRIM-autophagy study. Bare protein binding is uninformative.
Reason: Records a real, functionally relevant autophagy interaction (LC3B) but bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
Interacts with p62/SQSTM and LC3B/MAP1LC3B.
GO:0003677 DNA binding
IDA
PMID:16636064
The estrogen-responsive B box protein is a novel regulator o... 		KEEP AS NON CORE
Summary: Direct evidence of DNA binding from the EBBP/retinoid-signaling study.
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.
Supporting Evidence:
PMID:16636064
The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
GO:0005515 protein binding
IPI
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of i... 		KEEP AS NON CORE
Summary: Interactions (IL-1, NALP1) from the IL-1beta-secretion study. Bare protein binding is uninformative.
Reason: Records real interactions but bare protein binding is uninformative; captured more specifically by the IL-1 binding and NACHT domain binding annotations.
Supporting Evidence:
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.
GO:0005737 cytoplasm
IDA
PMID:11919186
The estrogen-responsive B box protein: a novel regulator of ... 		ACCEPT
Summary: Direct evidence of cytoplasmic localization in the keratinocyte-differentiation study. Core localization.
Reason: Correct core localization, experimentally demonstrated.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.
GO:0005737 cytoplasm
IDA
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of i... 		ACCEPT
Summary: Direct evidence of cytoplasmic localization in the IL-1beta study. Core localization.
Reason: Correct core localization, experimentally demonstrated.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.
GO:0005737 cytoplasm
IDA
PMID:9817599
The novel estrogen-responsive B-box protein (EBBP) gene is t... 		ACCEPT
Summary: Direct evidence of cytoplasmic localization in the EBBP-discovery study. Core localization.
Reason: Correct core localization, experimentally demonstrated.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27693506}.
GO:0016605 PML body
IDA
PMID:16636064
The estrogen-responsive B box protein is a novel regulator o... 		KEEP AS NON CORE
Summary: Direct evidence of localization to nuclear PML bodies (EBBP heterodimerizes with PML).
Reason: Experimentally supported but a secondary nuclear-body localization (older EBBP work); the dominant pool is cytoplasmic. Defer to curator.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
Heterodimerizes with
GO:0019966 interleukin-1 binding
IPI
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of i... 		KEEP AS NON CORE
Summary: Direct interaction evidence that TRIM16/EBBP binds interleukin-1 (IL-1).
Reason: Experimentally supported specific MF from EBBP-era work; a secondary activity relative to the core autophagy-scaffold function.
Supporting Evidence:
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.
GO:0032089 NACHT domain binding
IPI
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of i... 		KEEP AS NON CORE
Summary: Direct interaction evidence that TRIM16/EBBP binds the NACHT domain of NALP1.
Reason: Experimentally supported specific MF from EBBP-era work; secondary to the core autophagy-scaffold function.
Supporting Evidence:
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.
GO:0032526 response to retinoic acid
IEP
PMID:16636064
The estrogen-responsive B box protein is a novel regulator o... 		KEEP AS NON CORE
Summary: Expression-pattern evidence that TRIM16/EBBP responds to retinoic acid.
Reason: Supported response/context term from EBBP-era retinoid work; not the core autophagy function.
Supporting Evidence:
PMID:16636064
The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
GO:0032731 positive regulation of interleukin-1 beta production
IMP
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of i... 		KEEP AS NON CORE
Summary: Mutant-phenotype evidence that TRIM16/EBBP enhances IL-1beta secretion/production.
Reason: Experimentally supported (EBBP-era) but a secondary process relative to the core autophagy-scaffold function.
Supporting Evidence:
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.
GO:0045618 positive regulation of keratinocyte differentiation
IDA
PMID:11919186
The estrogen-responsive B box protein: a novel regulator of ... 		KEEP AS NON CORE
Summary: Direct evidence that TRIM16/EBBP positively regulates keratinocyte differentiation.
Reason: Experimentally supported (original EBBP characterization) but a tissue-specific role secondary to the core autophagy function.
Supporting Evidence:
PMID:11919186
The estrogen-responsive B box protein: a novel regulator of keratinocyte differentiation.
GO:0045893 positive regulation of DNA-templated transcription
IDA
PMID:16636064
The estrogen-responsive B box protein is a novel regulator o... 		KEEP AS NON CORE
Summary: Direct evidence that TRIM16/EBBP positively regulates transcription in the retinoid-signaling context.
Reason: Experimentally reported (EBBP-era) but secondary; TRIM16 acts largely as a cytoplasmic autophagy scaffold rather than a core transcriptional regulator. Defer to curator.
Supporting Evidence:
PMID:16636064
The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
GO:0045893 positive regulation of DNA-templated transcription
IDA
PMID:19147277
The estrogen-responsive B box protein (EBBP) restores retino... 		KEEP AS NON CORE
Summary: Direct evidence (via histone acetylation effects restoring retinoid sensitivity) that TRIM16/EBBP positively regulates transcription.
Reason: Experimentally reported (EBBP-era retinoid work) but secondary to the core autophagy function. Defer to curator.
Supporting Evidence:
PMID:19147277
restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation
GO:0048386 positive regulation of retinoic acid receptor signaling pathway
IDA
PMID:16636064
The estrogen-responsive B box protein is a novel regulator o... 		KEEP AS NON CORE
Summary: Direct evidence that TRIM16/EBBP positively regulates retinoic acid receptor signaling.
Reason: Experimentally supported (EBBP-era) but a secondary process relative to the core autophagy function.
Supporting Evidence:
PMID:16636064
The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
GO:0060416 response to growth hormone
IDA
PMID:11919186
The estrogen-responsive B box protein: a novel regulator of ... 		KEEP AS NON CORE
Summary: Direct evidence that TRIM16/EBBP responds to growth hormone.
Reason: Supported response/context term from EBBP-era work; not the core autophagy function.
Supporting Evidence:
PMID:11919186
The estrogen-responsive B box protein: a novel regulator of keratinocyte differentiation.
GO:0006914 autophagy
IDA
PMID:27693506
TRIMs and Galectins Globally Cooperate and TRIM16 and Galect... 		NEW
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.
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.
Supporting Evidence:
PMID:27693506
TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis.
GO:0030674 protein-macromolecule adaptor activity
IPI
PMID:27693506
TRIMs and Galectins Globally Cooperate and TRIM16 and Galect... 		NEW
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).
Reason: Captures TRIM16's core autophagy-receptor/scaffold molecular function (adaptor linking damaged endomembranes to the autophagy apparatus); currently missing from the GOA.
Supporting Evidence:
file:human/TRIM16/TRIM16-uniprot.txt
Acts as a scaffold protein and facilitates

Core Functions

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:
protein-macromolecule adaptor activity
Directly Involved In:
autophagy
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:27693506
    TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis.
  • file:human/TRIM16/TRIM16-uniprot.txt
    Acts as a scaffold protein and facilitates

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:
ubiquitin protein ligase activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:22629402
    TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize with other TRIM family members.
  • file:human/TRIM16/TRIM16-uniprot.txt
    Auto-ubiquitinates via its B-Boxes.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000003
Gene Ontology annotation based on Enzyme Commission mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:9817599
The novel estrogen-responsive B-box protein (EBBP) gene is tamoxifen-regulated in cells expressing an estrogen receptor DNA-binding domain mutant.
  • Identification of EBBP/TRIM16 as an estrogen/tamoxifen-regulated gene; cytoplasmic localization.
PMID:11919186
The estrogen-responsive B box protein: a novel regulator of keratinocyte differentiation.
  • TRIM16/EBBP positively regulates keratinocyte differentiation and responds to growth hormone; cytoplasmic localization.
PMID:16575408
The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion.
  • TRIM16/EBBP binds IL-1 and the NALP1 NACHT domain and enhances IL-1beta secretion/production.
PMID:16636064
The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
  • TRIM16/EBBP regulates retinoid (RA receptor) signaling, binds DNA, positively regulates transcription, and localizes to PML bodies.
PMID:19147277
The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation.
  • TRIM16/EBBP restores retinoid sensitivity in resistant cancer cells via effects on histone acetylation, positively regulating transcription.
PMID:20729920
TRIM16 acts as a tumour suppressor by inhibitory effects on cytoplasmic vimentin and nuclear E2F1 in neuroblastoma cells.
  • TRIM16 acts as a tumor suppressor in neuroblastoma, inhibiting cytoplasmic vimentin and nuclear E2F1.
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
PMID:22629402
TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize with other TRIM family members.
  • 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.
PMID:25127057
TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition.
  • TRIM16 is among TRIMs that regulate autophagy and interacts with autophagy machinery (LC3B).
PMID:27693506
TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis.
  • 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.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.

Suggested Questions for Experts

Q: 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?

Q: 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

Experiment: 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.

Experiment: 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.

📚 Additional Documentation

Notes

(TRIM16-notes.md)

TRIM16 (EBBP, estrogen-responsive B box protein) review notes

UniProt: O95361 (TRIM16_HUMAN). TRIM/RBCC family. EC=2.3.2.27 (with ECO:0000269|PubMed:22629402 - experimental).

Domain architecture - KEY: TRIM16 LACKS a canonical RING domain

  • B-box zinc finger(s): ZN_FING 72-122 [UniProt FT]
  • Coiled-coil (homodimerization)
  • C-terminal B30.2/SPRY domain: DOMAIN 355-553 [UniProt FT]
  • InterPro: B30.2/SPRY, B-box; PANTHER "B-BOX DOMAIN CONTAINING". No RING-HC.
  • UniProt: "Auto-ubiquitinates via its B-Boxes" {ECO:0000269|PubMed:22629402} -> unusual; ligase activity attributed to B-boxes, not a RING.

E3 ligase activity - experimentally claimed but atypical

  • UniProt FUNCTION: "E3 ubiquitin ligase that plays an essential role in the organization of autophagic response and ubiquitination upon lysosomal and phagosomal damages." {ECO:0000269|PubMed:22629402, 27693506, 30143514}
  • EC=2.3.2.27 with experimental evidence {ECO:0000269|PubMed:22629402}.
  • PMID:22629402 "TRIM16 acts as an E3 ubiquitin ligase and can heterodimerize with other TRIM family members" - in vitro autoubiquitination via B-boxes.
  • DECISION: The GO:0061630 ubiquitin protein ligase activity with EXP evidence (PMID:22629402) is experimentally supported per UniProt -> ACCEPT (do not REMOVE; the curator/UniProt assert experimental ligase activity even though it lacks a RING). However, the EC-based IEA assignment (GO_REF:0000003) assumes RING-type and is weaker -> KEEP_AS_NON_CORE / note. The task warns to be careful with catalytic claims for TRIM16 because it lacks a canonical RING; but UniProt explicitly cites experimental evidence, so ACCEPT the EXP one and frame core function as autophagy receptor/scaffold + atypical B-box ligase.

Core functions (modern view)

  1. Autophagy receptor/scaffold for damaged endomembranes (lysophagy) and protein aggregates. Interacts with Galectin-3/LGALS3 (ULK1-dependent) to direct autophagy of damaged endomembranes; scaffolds p62/SQSTM1, ATG16L1, LC3B/MAP1LC3B, BECN1; regulates p62-KEAP1-NRF2 signaling (modulates NRF2 ubiquitination/stability); protects against oxidative-stress-induced cell death from endomembrane damage. [PMID:27693506 "TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis"; UniProt FUNCTION]
  2. NOTE: The TRIM16 GOA stub does NOT currently contain an autophagy BP term (e.g. GO:0006914). The autophagy/lysophagy role is the modern core function but is captured in UniProt FUNCTION, not in the existing GOA annotations to be reviewed. -> propose new term / cover in core_functions.
  3. Phosphorylated by ULK1 (PMID:27693506).
  4. Older "EBBP" literature functions (mostly tumor-suppressor/differentiation/RA, in neuroblastoma and keratinocytes):
  5. Tumor suppressor: inhibits cytoplasmic vimentin and nuclear E2F1 in neuroblastoma (PMID:20729920).
  6. Positive regulator of keratinocyte differentiation (PMID:11919186).
  7. Enhances IL-1beta secretion / positive regulation of IL-1beta production; binds IL-1 and NACHT domain (NALP1) (PMID:16575408).
  8. Regulates retinoid signaling: positive regulation of RA receptor signaling, restores retinoid sensitivity via histone acetylation (PMID:16636064, PMID:19147277).
  9. Response to retinoic acid (IEP, PMID:16636064), response to growth hormone (PMID:11919186).
  10. DNA binding (IDA, PMID:16636064) and positive regulation of DNA-templated transcription (IDA, PMID:16636064/19147277): TRIM16 reported to act in nucleus on transcription; this is from EBBP-era work. These are real IDA annotations -> ACCEPT/KEEP_AS_NON_CORE; do not REMOVE experimental annotations.
  11. PML body localization (IDA, PMID:16636064).

Localization

  • Cytoplasm (IDA, EXP PMID:27693506; multiple older IDA). Core.
  • Cytosol (IDA HPA).
  • PML body (IDA PMID:16636064): nuclear body; older EBBP work.

Notes on specific annotations

  • GO:0061630 ubiquitin protein ligase activity EXP (PMID:22629402): ACCEPT (experimentally supported autoubiquitination via B-boxes, per UniProt EC ECO:0000269).
  • GO:0061630 ubiquitin protein ligase activity IEA EC (GO_REF:0000003): KEEP_AS_NON_CORE (EC mapping assumes RING; redundant with the EXP one).
  • protein binding (GO:0005515) IPI: VIM (P08670), E2F1 (Q01094), TINF2 (Q9BSI4), TRIM16L (Q309B1 x3), MAP1LC3B (O95166, PMID:25127057), IL1B/NALP1 (P29466, PMID:16575408). Bare protein binding -> KEEP_AS_NON_CORE.
  • GO:0019966 interleukin-1 binding (IPI PMID:16575408): specific MF; older EBBP work. KEEP_AS_NON_CORE.
  • GO:0032089 NACHT domain binding (IPI PMID:16575408): binds NALP1 NACHT domain. KEEP_AS_NON_CORE.
  • GO:0003677 DNA binding (IDA PMID:16636064): KEEP_AS_NON_CORE (older work; TRIM16 lacks a classic DBD but reported to bind DNA/act in transcription).
  • GO:0045893 positive regulation of DNA-templated transcription (IDA x2): KEEP_AS_NON_CORE (EBBP-era retinoid/transcription role).
  • GO:0048386 positive regulation of RA receptor signaling (IDA): KEEP_AS_NON_CORE.
  • GO:0032526 response to retinoic acid (IEP), GO:0060416 response to growth hormone (IDA): KEEP_AS_NON_CORE (response/context terms).
  • GO:0032731 positive regulation of IL-1beta production (IMP PMID:16575408): KEEP_AS_NON_CORE.
  • GO:0045618 positive regulation of keratinocyte differentiation (IDA PMID:11919186): KEEP_AS_NON_CORE.
  • GO:0008270 zinc ion binding (IEA): KEEP_AS_NON_CORE (B-box coordinates Zn).
  • GO:0016605 PML body (IDA): KEEP_AS_NON_CORE.

GO IDs verified relevant

  • GO:0061630 ubiquitin protein ligase activity (atypical B-box, experimentally claimed)
  • GO:0006914 autophagy (core modern function - not in current GOA stub; propose)
  • GO:0005737 cytoplasm / GO:0005829 cytosol (core CC)

Pn Notes

(TRIM16-pn-notes.md)

TRIM16 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O95361
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-14
  • Batch change status: added

Source Files Checked

Deep Research Files

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

AIGR Review Snapshot

  • 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).
  • Existing/core annotation action counts: ACCEPT: 7; KEEP_AS_NON_CORE: 20; NEW: 2

PN Consistency Summary

  • Consistency: Consistent, and the RING-less caveat is correctly recognized on BOTH sides. PN explicitly labels TRIM16 TRIM / unclassified | ringless & SPRY, and the review/notes repeatedly flag that TRIM16 LACKS a canonical RING and only autoubiquitinates atypically via its B-boxes (PMID:22629402). PN, review and notes agree the modern core function is galectin-3/ULK1-dependent lysophagy + aggrephagy scaffolding (PMID:27693506). No contradictions on biology.
  • PN story / NEW pressure: Strong, defensible ADD pressure: the autophagy role is genuinely absent from GOA (confirmed — TRIM16 GOA has NO autophagy term). The review already adds it as two NEW annotations (GO:0006914 autophagy + GO:0030674 protein-macromolecule adaptor activity). PN's lysophagy node elevates the cargo-adaptor MF GO:0160247 (verified real) over bare protein binding — exactly the prescribed pattern, and more specific than the review's GO:0030674. Important ontology correction: the PN-node rationale claims "the current GO cache lacks a dedicated lysophagy process term" — this is WRONG: GO:0062093 lysophagy EXISTS (verified, def "selective autophagy in which a damaged lysosome is degraded by macroautophagy"). So a lysophagy process term is available in addition to the cargo-adaptor MF.
  • Evidence alignment: Strong overlap. PN cites the LIR/cargo-receptor review and the TRIM16-galectin-3 paper (= PMID:27693506, review HIGH) and 33791238 (TRIM review). Review refs (PMID:27693506, 22629402, 25127057) cover lysophagy + atypical ligase + LC3B.
  • Verdict: Consistent; lysophagy ADD warranted; RING-less caveat correctly handled. Recommended edits: [MAP] fix the Lysophagy node rationale — GO:0062093 lysophagy exists; add it as the process target alongside GO:0160247. [YAML] upgrade the review's NEW GO:0030674 adaptor MF to the more specific GO:0160247 autophagy cargo adaptor activity, and add GO:0062093 lysophagy (involved_in, PMID:27693506) as the specific process. [YAML] retain GO:0061630 only as the atypical B-box autoubiquitination capture (do not assert RING catalytic ligase function).

Full Consistency Review

  • UniProt: O95361 (EBBP) · batch: proteostasis-batch-2026-06-14 · review status: COMPLETE (thorough)
  • PN placement: 2 rows — ALP|Autophagy substrate selection|Selective autophagy receptor|Lysophagy; UPS|E3 ubiquitin and UBL ligases|RING|TRIM / unclassified|ringless & SPRY. PN-node mapping: Lysophagy type → mapped/ok GO:0160247 autophagy cargo adaptor activity (new_to_goa); RING group → mapped/ok GO:0061630 ubiquitin protein ligase activity (already_in_goa_exact); E3-ligase ancestors = context_only/no_mapping.
  • Consistency: Consistent, and the RING-less caveat is correctly recognized on BOTH sides. PN explicitly labels TRIM16 TRIM / unclassified | ringless & SPRY, and the review/notes repeatedly flag that TRIM16 LACKS a canonical RING and only autoubiquitinates atypically via its B-boxes (PMID:22629402). PN, review and notes agree the modern core function is galectin-3/ULK1-dependent lysophagy + aggrephagy scaffolding (PMID:27693506). No contradictions on biology.
  • PN story / NEW pressure: Strong, defensible ADD pressure: the autophagy role is genuinely absent from GOA (confirmed — TRIM16 GOA has NO autophagy term). The review already adds it as two NEW annotations (GO:0006914 autophagy + GO:0030674 protein-macromolecule adaptor activity). PN's lysophagy node elevates the cargo-adaptor MF GO:0160247 (verified real) over bare protein binding — exactly the prescribed pattern, and more specific than the review's GO:0030674. Important ontology correction: the PN-node rationale claims "the current GO cache lacks a dedicated lysophagy process term" — this is WRONG: GO:0062093 lysophagy EXISTS (verified, def "selective autophagy in which a damaged lysosome is degraded by macroautophagy"). So a lysophagy process term is available in addition to the cargo-adaptor MF.
  • Mapping strategy: CRITICAL — do NOT assign catalytic ligase MF on biological grounds, since TRIM16 is RING-less; but here the RING node's GO:0061630 is already_in_goa_exact via the EC/IEA + an EXP autoubiquitination annotation, so it is retained as an atypical-ligase capture rather than a PN-driven new catalytic claim. The PN correctly routes the headline biology through the cargo-adaptor MF (GO:0160247), not through catalytic ligase. Node is sound; only the "lysophagy term absent" rationale needs fixing, and the process term should be added.
  • Evidence alignment: Strong overlap. PN cites the LIR/cargo-receptor review and the TRIM16-galectin-3 paper (= PMID:27693506, review HIGH) and 33791238 (TRIM review). Review refs (PMID:27693506, 22629402, 25127057) cover lysophagy + atypical ligase + LC3B.
  • Verdict: Consistent; lysophagy ADD warranted; RING-less caveat correctly handled. Recommended edits: [MAP] fix the Lysophagy node rationale — GO:0062093 lysophagy exists; add it as the process target alongside GO:0160247. [YAML] upgrade the review's NEW GO:0030674 adaptor MF to the more specific GO:0160247 autophagy cargo adaptor activity, and add GO:0062093 lysophagy (involved_in, PMID:27693506) as the specific process. [YAML] retain GO:0061630 only as the atypical B-box autoubiquitination capture (do not assert RING catalytic ligase function).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-14
  • review_yaml: genes/human/TRIM16/TRIM16-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Lysophagy

  • UniProt: O95361
  • In branches: ALP, UPS
  • Notes: Receptor for selective autophagy. An E3 ubiquitin ligase. TRIM16, interacted with Galectin-3 in a ULK1-dependent manner. TRIM16, through integration of Galectin- and ubiquitin-based processes, coordinated recognition of membrane damage with mobilization of the core autophagy regulators ATG16L1, ULK1, and Beclin 1 in response to damaged endomembranes.
  • PN references (titles):
    • Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors - ScienceDirect
    • TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis - ScienceDirect
  • PN-node mapping records (path + ancestors):
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Lysophagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0160247 autophagy cargo adaptor activity]
      rationale: The PN lysophagy receptor class denotes factors that recognize damaged lysosomal cargo and couple it to autophagic clearance. Since the current GO cache lacks a dedicated lysophagy process term, autophagy cargo adaptor activity is the most specific supported target.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
      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 | TRIM / unclassified | ringless & SPRY

  • UniProt: O95361
  • In branches: ALP, UPS
  • Signature domains: (none)
  • Auxiliary domains: IPR003877, IPR006574
  • PN references (titles):
    • 33791238 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|TRIM / unclassified|ringless & SPRY
      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|TRIM / unclassified
      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:0160247 autophagy cargo adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Lysophagy
  • 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: 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.