id: Q8NBM4
gene_symbol: UBAC2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UBAC2 (ubiquitin-associated domain-containing protein 2, also PHGDHL1) is a
  multi-pass endoplasmic reticulum (ER) membrane protein of the rhomboid
  superfamily. Its N-terminal region adopts a rhomboid-like fold but is a
  catalytically inactive pseudoprotease (it lacks the conserved serine-protease
  catalytic dyad), and its C-terminal cytoplasmic UBA domain binds ubiquitin.
  UBAC2 acts as an ER-membrane scaffolding/adaptor component rather than an
  enzyme. It partners the active rhomboid protease RHBDD1 in the ER-associated
  degradation (ERAD) of membrane substrates, where its UBA domain engages
  ubiquitinated clients. UBAC2 is also the ER receptor that binds FAF2/UBXD8 and
  restricts FAF2 trafficking from the ER to lipid droplets, thereby modulating
  ER-to-cytosol dislocation and lipid-droplet partitioning. Independently, UBAC2
  serves as a selective autophagy (ER-phagy/reticulophagy) receptor; a LIR motif
  in its cytoplasmic domain binds the autophagosomal protein GABARAP, and
  MARK2-mediated phosphorylation at Ser223 promotes UBAC2 dimerization and
  GABARAP binding to drive ER-phagy, which in turn restrains ER-stress-induced
  inflammatory responses. In a complex with LMBR1L and the E3 ubiquitin ligase
  AMFR, UBAC2 also negatively regulates canonical Wnt/beta-catenin signaling in
  lymphocytes by promoting degradation of CTNNB1 and the Wnt receptors FZD6 and
  LRP6.
alternative_products:
- name: '1'
  id: Q8NBM4-1
- name: '2'
  id: Q8NBM4-2
  sequence_note: VSP_023911, VSP_023912
- name: '3'
  id: Q8NBM4-3
  sequence_note: VSP_023910
- name: '4'
  id: Q8NBM4-4
  sequence_note: VSP_023909
- name: '5'
  id: Q8NBM4-5
  sequence_note: VSP_023913, VSP_023914
existing_annotations:
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: UBAC2 belongs to the rhomboid superfamily but is a catalytically inactive pseudoprotease; the UniProt record and ERAD literature describe it as a rhomboid pseudoprotease lacking the serine-protease catalytic dyad. This IBA is propagated from the active-rhomboid branch of the phylogenetic tree and is biologically incorrect for UBAC2.
    action: REMOVE
    reason: UBAC2 is a rhomboid pseudoprotease with no protease activity; the serine-type endopeptidase activity is an over-propagated phylogenetic inference refuted on biological grounds (no catalytic residues).
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: the ER-resident rhomboid pseudoprotease UBAC2
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UBAC2 is a multi-pass ER membrane protein; the electronic subcellular-location assignment is consistent with direct experimental evidence.
    action: ACCEPT
    reason: Core compartment; UBAC2 is an integral ER membrane protein.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: ERAD-network interactome capture of the UBAC2-FAF2 interaction. The bare protein binding term is uninformative; the functional relationship is captured by the FAF2/ER-receptor annotations.
    action: KEEP_AS_NON_CORE
    reason: Real ERAD-network interaction (FAF2) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q96CS3: FAF2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome capture (CALCOCO2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction from a large-scale interactome but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q13137: CALCOCO2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (FAF2) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q96CS3: FAF2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (FAF2) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q96CS3: FAF2'
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Orthology-based assignment of the negative Wnt-regulation role, consistent with the experimental IMP evidence (LMBR1L/AMFR complex promotes degradation of CTNNB1 and Wnt receptors).
    action: ACCEPT
    reason: Correct biological process; redundant with experimental IMP evidence.
    supported_by:
    - reference_id: PMID:31073040
      supporting_text: attenuated Wnt signaling in lymphocytes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39284914
  qualifier: enables
  review:
    summary: IPI interactions from the ER-phagy study (including GABARAP-family/autophagy partners). Bare protein binding is uninformative; the GABARAP binding underpins the ER-phagy receptor function captured by the reticulophagy annotation.
    action: KEEP_AS_NON_CORE
    reason: Real autophagy-partner interactions but uninformative GO term.
    supported_by:
    - reference_id: PMID:39284914
      supporting_text: binds to autophagosomal GABARAP
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:39284914
  qualifier: involved_in
  review:
    summary: By driving ER-phagy, UBAC2 restrains ER-stress-induced inflammatory responses and acute colitis in mice; perturbation of UBAC2 alters the inflammatory response.
    action: ACCEPT
    reason: Directly supported (IMP); a downstream consequence of UBAC2's ER-phagy receptor activity.
    supported_by:
    - reference_id: PMID:39284914
      supporting_text: UBAC2 restrains inflammatory responses and acute ulcerative
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:39284914
  qualifier: involved_in
  review:
    summary: UBAC2 is a selective ER-phagy (reticulophagy) receptor with a LIR motif that binds GABARAP; MARK2-mediated Ser223 phosphorylation drives dimerization and GABARAP binding to mediate selective ER degradation.
    action: ACCEPT
    reason: Directly demonstrated core biological process; UBAC2 functions as an ER-phagy receptor.
    supported_by:
    - reference_id: PMID:39284914
      supporting_text: we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31073040
  qualifier: enables
  review:
    summary: IPI capture of the UBAC2-LMBR1L interaction. Bare protein binding is uninformative; the functional cooperation is captured by the negative Wnt-regulation annotation.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (LMBR1L) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: Interacts with LMBR1L
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:31073040
  qualifier: involved_in
  review:
    summary: With LMBR1L and AMFR, UBAC2 negatively regulates canonical Wnt signaling in lymphocytes by promoting ubiquitin-mediated degradation of CTNNB1 and the Wnt receptors FZD6 and LRP6.
    action: ACCEPT
    reason: Directly supported (IMP) biological process; a distinct UBAC2 regulatory role.
    supported_by:
    - reference_id: PMID:31073040
      supporting_text: attenuated Wnt signaling in lymphocytes
- term:
    id: GO:1904153
    label: negative regulation of retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  qualifier: involved_in
  review:
    summary: UBAC2 negatively regulates ER-to-cytosol dislocation/retrotranslocation, consistent with its role as the ER receptor that restricts FAF2/UBXD8 trafficking and modulates ERAD substrate dislocation.
    action: ACCEPT
    reason: Directly supported (IMP); UBAC2 modulates the ER-to-cytosol retrotranslocation step of ERAD.
    supported_by:
    - reference_id: PMID:25660456
      supporting_text: dislocation, also known as retrotranslocation, of those unwanted proteins from
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: located_in
  review:
    summary: Direct evidence that UBAC2 is an ER-resident protein, the compartment where it acts as an ER receptor for FAF2/UBXD8.
    action: ACCEPT
    reason: Core compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: the ER-resident rhomboid pseudoprotease UBAC2
- term:
    id: GO:0070972
    label: protein localization to endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: acts_upstream_of_or_within
  review:
    summary: UBAC2 retains FAF2/UBXD8 at the ER (restricting its trafficking to lipid droplets), thereby controlling FAF2 protein localization to the ER.
    action: ACCEPT
    reason: Directly supported; UBAC2 acts as an ER receptor that governs partner localization at the ER.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: restricts trafficking of UBXD8 to LDs
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: UBAC2 interacts with FAF2/UBXD8 within the human ERAD interaction network.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ERAD interactome mapping; source of a UBAC2-FAF2 IPI annotation.
- id: PMID:23297223
  title: Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet
    turnover.
  findings:
  - statement: UBAC2 is an ER-resident rhomboid pseudoprotease that acts as a selective FAF2/UBXD8 ER receptor, restricting trafficking of FAF2 from the ER to lipid droplets.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes UBAC2 as an ER-resident pseudoprotease and FAF2 ER receptor; source of ER localization and protein-localization-to-ER annotations.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome; source of a UBAC2-CALCOCO2 IPI annotation.
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong
    Kong variant of α-1-antitrypsin (NHK).
  findings:
  - statement: ERAD requires dislocation/retrotranslocation of substrates from the ER lumen to the cytosol; UBAC2 negatively regulates this dislocation step.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the IMP negative-regulation-of-ER-to-cytosol-retrograde-transport annotation.
- 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 UBAC2-FAF2 IPI annotation.
- id: PMID:31073040
  title: LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling.
  findings:
  - statement: UBAC2 (with LMBR1L and AMFR) attenuates canonical Wnt/beta-catenin signaling in lymphocytes by promoting degradation of CTNNB1 and Wnt receptors FZD6/LRP6.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes UBAC2's negative regulation of canonical Wnt signaling.
- id: PMID:39284914
  title: ER-phagy restrains inflammatory responses through its receptor UBAC2.
  findings:
  - statement: UBAC2 is a receptor for ER-phagy and a negative regulator of inflammatory responses; its LIR motif binds GABARAP and MARK2-mediated Ser223 phosphorylation drives dimerization to facilitate selective ER degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive study establishing UBAC2 as an ER-phagy receptor; source of reticulophagy and negative-regulation-of-inflammatory-response annotations.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of a UBAC2-FAF2 IPI annotation.
- id: PMID:22455605
  title: Replication study confirms the association between UBAC2 and Behçet's disease
    in two independent Chinese sets of patients and controls.
  findings:
  - statement: UBAC2 is a confirmed Behçet's disease susceptibility locus in Han Chinese; the risk T allele of promoter SNP rs3825427 has lower promoter activity and is associated with decreased expression of UBAC2 transcript variant 1, implicating transcriptional modulation of UBAC2 in disease risk.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:22455605, doi:10.1186/ar3789). Disease-genetics/regulatory evidence linking UBAC2 to Behçet's disease via a functional promoter polymorphism; supports medical relevance of the locus but does not define UBAC2 protein biochemical mechanism. Not tied to a specific GO annotation.
- id: PMID:21700618
  title: Genome-wide association study identifies novel alleles associated with risk
    of cutaneous basal cell carcinoma and squamous cell carcinoma.
  findings:
  - statement: A variant (rs7335046) at the 13q32 locus near UBAC2 confers susceptibility to cutaneous basal cell carcinoma and squamous cell carcinoma.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:21700618, doi:10.1093/hmg/ddr287). Locus-level GWAS association of the UBAC2 region with non-melanoma skin cancer; medical relevance only, does not establish UBAC2 as the causal effector gene or define function.
- id: file:human/UBAC2/UBAC2-uniprot.txt
  title: UniProt entry Q8NBM4 (UBAC2_HUMAN), ubiquitin-associated domain-containing protein 2
  findings:
  - statement: UBAC2 is a multi-pass ER membrane rhomboid pseudoprotease with a cytoplasmic UBA domain; it is an ER-phagy receptor (LIR/GABARAP), restricts FAF2 trafficking to lipid droplets, and negatively regulates canonical Wnt signaling with LMBR1L and AMFR.
    reference_section_type: OTHER
core_functions:
- description: ER-membrane scaffolding/adaptor pseudoprotease of the rhomboid superfamily that, via its cytoplasmic UBA domain, engages ubiquitinated substrates as a component of the ER-associated degradation (ERAD) machinery and acts as the ER receptor restricting FAF2/UBXD8 trafficking from the ER to lipid droplets.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:1904153
    label: negative regulation of retrograde protein transport, ER to cytosol
  supported_by:
  - reference_id: PMID:23297223
    supporting_text: the ER-resident rhomboid pseudoprotease UBAC2
  - reference_id: PMID:25660456
    supporting_text: dislocation, also known as retrotranslocation, of those unwanted proteins from
- description: Selective autophagy (ER-phagy/reticulophagy) receptor whose cytoplasmic LIR motif binds autophagosomal GABARAP; MARK2-driven Ser223 phosphorylation promotes dimerization and GABARAP binding to mediate selective ER degradation, thereby restraining ER-stress-induced inflammatory responses.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0061709
    label: reticulophagy
  - id: GO:0050728
    label: negative regulation of inflammatory response
  supported_by:
  - reference_id: PMID:39284914
    supporting_text: we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy
  - reference_id: PMID:39284914
    supporting_text: binds to autophagosomal GABARAP
- description: Negative regulator of canonical Wnt/beta-catenin signaling that, in a complex with LMBR1L and the E3 ligase AMFR, promotes ubiquitin-mediated degradation of CTNNB1 and the Wnt receptors FZD6 and LRP6 in lymphocytes.
  directly_involved_in:
  - id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  supported_by:
  - reference_id: PMID:31073040
    supporting_text: attenuated Wnt signaling in lymphocytes
proposed_new_terms: []
suggested_questions:
- question: Does the UBAC2 cytoplasmic UBA domain directly bind ubiquitinated ERAD substrates handed off by the active rhomboid protease RHBDD1, and what substrate range does the RHBDD1-UBAC2 module degrade?
- question: How are UBAC2's ERAD-component, FAF2 ER-receptor, ER-phagy receptor, and Wnt-regulatory activities coordinated or partitioned, and do they share the same UBAC2 pool or distinct membrane microdomains?
suggested_experiments:
- description: Reconstitute or co-immunoprecipitate the RHBDD1-UBAC2 module and test whether UBAC2 UBA-domain mutants lose binding to ubiquitinated membrane ERAD substrates, dissociating the scaffolding role from RHBDD1 catalysis.
- description: Use Ser223-phospho (S223A and S223D) and LIR-motif (W275A/L278A) UBAC2 mutants in ER-phagy flux assays (RFP-GFP ER reporters) with and without ER stress to quantify the contribution of MARK2-driven dimerization to selective ER degradation.
- description: Perform comparative proteomics of UBAC2 interactomes under basal, ER-stress, and starvation conditions to map how its ERAD, ER-phagy, and Wnt-regulatory partner networks are remodeled.