GO Term	Evidence	Action	Reason
GO:0004252 serine-type endopeptidase activity	IBA GO_REF:0000033	REMOVE	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. 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). Supporting Evidence: PMID:23297223 the ER-resident rhomboid pseudoprotease UBAC2
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: UBAC2 is a multi-pass ER membrane protein; the electronic subcellular-location assignment is consistent with direct experimental evidence. Reason: Core compartment; UBAC2 is an integral ER membrane protein. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ...	KEEP AS NON CORE	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. Reason: Real ERAD-network interaction (FAF2) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q96CS3: FAF2
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale interactome capture (CALCOCO2). Bare protein binding is uninformative. Reason: Real interaction from a large-scale interactome but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q13137: CALCOCO2
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: High-throughput interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative. Reason: Real interaction (FAF2) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q96CS3: FAF2
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-map interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative. Reason: Real interaction (FAF2) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q96CS3: FAF2
GO:0090090 negative regulation of canonical Wnt signaling pathway	IEA GO_REF:0000107	ACCEPT	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). Reason: Correct biological process; redundant with experimental IMP evidence. Supporting Evidence: PMID:31073040 attenuated Wnt signaling in lymphocytes
GO:0005515 protein binding	IPI PMID:39284914 ER-phagy restrains inflammatory responses through its recept...	KEEP AS NON CORE	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. Reason: Real autophagy-partner interactions but uninformative GO term. Supporting Evidence: PMID:39284914 binds to autophagosomal GABARAP
GO:0050728 negative regulation of inflammatory response	IMP PMID:39284914 ER-phagy restrains inflammatory responses through its recept...	ACCEPT	Summary: By driving ER-phagy, UBAC2 restrains ER-stress-induced inflammatory responses and acute colitis in mice; perturbation of UBAC2 alters the inflammatory response. Reason: Directly supported (IMP); a downstream consequence of UBAC2's ER-phagy receptor activity. Supporting Evidence: PMID:39284914 UBAC2 restrains inflammatory responses and acute ulcerative
GO:0061709 reticulophagy	IMP PMID:39284914 ER-phagy restrains inflammatory responses through its recept...	ACCEPT	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. Reason: Directly demonstrated core biological process; UBAC2 functions as an ER-phagy receptor. Supporting Evidence: PMID:39284914 we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy
GO:0005515 protein binding	IPI PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/β-catenin signali...	KEEP AS NON CORE	Summary: IPI capture of the UBAC2-LMBR1L interaction. Bare protein binding is uninformative; the functional cooperation is captured by the negative Wnt-regulation annotation. Reason: Real interaction (LMBR1L) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Interacts with LMBR1L
GO:0090090 negative regulation of canonical Wnt signaling pathway	IMP PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/β-catenin signali...	ACCEPT	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. Reason: Directly supported (IMP) biological process; a distinct UBAC2 regulatory role. Supporting Evidence: PMID:31073040 attenuated Wnt signaling in lymphocytes
GO:1904153 negative regulation of retrograde protein transport, ER to cytosol	IMP PMID:25660456 Identification of ERAD components essential for dislocation ...	ACCEPT	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. Reason: Directly supported (IMP); UBAC2 modulates the ER-to-cytosol retrotranslocation step of ERAD. Supporting Evidence: PMID:25660456 dislocation, also known as retrotranslocation, of those unwanted proteins from
GO:0005783 endoplasmic reticulum	IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat...	ACCEPT	Summary: Direct evidence that UBAC2 is an ER-resident protein, the compartment where it acts as an ER receptor for FAF2/UBXD8. Reason: Core compartment; directly demonstrated. Supporting Evidence: PMID:23297223 the ER-resident rhomboid pseudoprotease UBAC2
GO:0070972 protein localization to endoplasmic reticulum	IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat...	ACCEPT	Summary: UBAC2 retains FAF2/UBXD8 at the ER (restricting its trafficking to lipid droplets), thereby controlling FAF2 protein localization to the ER. Reason: Directly supported; UBAC2 acts as an ER receptor that governs partner localization at the ER. Supporting Evidence: PMID:23297223 restricts trafficking of UBXD8 to LDs

Deep Research

Falcon

(UBAC2-deep-research-falcon.md)

Comprehensive Research Report: Human **UBAC2** (UniProt **Q8NBM4**) — Functional Annotation, Pathways, and Disease Context Falcon Edison Scientific Literature 34 citations 2 artifacts 2026-06-12T05:08:23.141621

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000021 Figure 3 and the relevant panels are provided: - Figure 3A-C: Schematic of the ss-RFP-GFP-KDEL reporter and quantification of ER-ph (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human UBAC2 (UniProt Q8NBM4) — Functional Annotation, Pathways, and Disease Context

Executive summary

UBAC2 (UBA domain–containing protein 2; UniProt Q8NBM4; synonym PHGDHL1) encodes an ER-resident, rhomboid-like multi-pass membrane pseudoprotein with a cytosolic ubiquitin-associated (UBA) domain that has been historically linked to ER-associated degradation (ERAD) and ubiquitin-dependent protein quality control (proteostasis). (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21, choi2019lmbr1lregulateslymphopoiesis pages 1-2)

A major 2024 advance is the discovery that UBAC2 also functions as a selective autophagy receptor for ER-phagy (reticulophagy): it binds GABARAP via a cytosolic LC3-interacting region (LIR) and is activated by MARK2 phosphorylation at S223, which promotes UBAC2 dimerization and increased GABARAP binding. This UBAC2-driven ER-phagy restrains ER stress/UPR-linked inflammation and protects against DSS-induced colitis in vivo. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8)

1. Key concepts and definitions (current understanding)

1.1 UBAC2 as a rhomboid-like “pseudoprotease”

“Rhomboid-like” proteins share a rhomboid fold (typically multiple transmembrane helices) but may lack protease activity; such proteins are often termed rhomboid pseudoproteases and can act as adapters/scaffolds that regulate client protein trafficking, turnover, and signaling rather than catalyzing proteolysis. Reviews place UBAC2 within this class and connect rhomboid-like factors to ER protein quality control. (lemberg2016inactiverhomboidproteins pages 16-21, adrain2020thecomplexlife pages 1-5)

1.2 UBA domain and ubiquitin-dependent protein quality control

UBA (ubiquitin-associated) domains are small protein modules that can bind ubiquitin or polyubiquitin chains and thereby link proteins to ubiquitin signaling and degradation pathways. Reviews specifically describe UBAC2 as having a conserved C-terminal UBA domain that binds polyubiquitin chains, consistent with an adapter role in ubiquitin-dependent quality control. (kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

1.3 ERAD (endoplasmic reticulum–associated degradation)

ERAD is a canonical ER quality-control process in which misfolded or orphaned ER proteins are recognized, ubiquitinated, extracted (often via the p97/VCP machinery), and degraded by the proteasome. Reviews place UBAC2 within ERAD-related networks (including the GP78 pathway) and highlight its interactions with UBXD8/p97 axis components relevant to substrate processing. (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

1.4 ER-phagy (reticulophagy) and LIR–ATG8 family interactions

ER-phagy is selective autophagic degradation of ER fragments. ER-phagy receptors often contain a LIR motif that binds ATG8-family proteins (e.g., GABARAP/LC3) to couple ER membranes to autophagosomes. In 2024, UBAC2 was shown to be such a receptor via its cytosolic LIR and GABARAP binding. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 7-8)

2. Molecular identity verification (critical disambiguation)

The literature sources retrieved here consistently describe human UBAC2 as “ubiquitin-associated domain–containing protein 2,” and genetic studies explicitly note that PHGDHL1 is alternatively called UBAC2, supporting the UniProt synonym set and mitigating symbol ambiguity. (nan2011genomewideassociationstudy pages 1-2, hou2012replicationstudyconfirms pages 1-2)

3. Protein features, localization, and primary molecular functions

3.1 Subcellular localization

Multiple sources place UBAC2 at the endoplasmic reticulum (ER).

Primary evidence (pathway study): An “ER-localized LMBR1L-GP78-UBAC2 complex” is reported to regulate degradation of Wnt pathway components. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)
Primary evidence (ER-phagy study): UBAC2 is described as residing at the ER and functioning as an ER-phagy receptor; ER stress/starvation induces UBAC2 relocalization/turnover consistent with autophagy/lysosomal routing. (he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 3-4)

3.2 UBAC2 as an ER-phagy receptor (major 2024 development)

A 2024 EMBO Journal study provides direct mechanistic evidence that UBAC2 is an ER-phagy receptor.

Core mechanism
* UBAC2 contains a canonical LIR in its cytosolic domain that binds GABARAP. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)
* Under ER stress or autophagy activation, MARK2 phosphorylates UBAC2 at S223, promoting UBAC2 dimerization and stronger GABARAP binding, thereby enhancing ER-phagy. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)

Experimental readouts and quantitative design features
* ER-phagy flux was monitored with an ER luminal reporter ss-RFP-GFP-KDEL, in which lysosomal delivery quenches GFP and yields an RFP fragment; UBAC2 knockout reduces reporter processing under starvation conditions, while UBAC2 WT rescues and a LIR mutant (LIRm) fails to rescue. (he2024erphagyrestrainsinflammatory pages 7-8)
* Quantification in microscopy includes 20 cells scored/condition and statistics reported across 3 biological replicates (mean ± SEM). (he2024erphagyrestrainsinflammatory pages 12-13)

Physiological/in vivo implications
* In a DSS acute ulcerative colitis mouse model, AAV-mediated expression of UBAC2 variants (WT vs LIRm vs S223A and disease-associated variants) was tested with n = 6 mice/group and multiple outcome measures including body weight, colon length, histology, and qPCR markers of ER stress and inflammation. (he2024erphagyrestrainsinflammatory pages 15-16)
* The study concludes that UBAC2-mediated ER-phagy restrains inflammatory responses and protects against colitis pathology. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 15-16)

Figure-level support
Cropped panels of Figure 3 directly show: the ER-phagy reporter concept and quantification; rescue by UBAC2 WT but not LIRm; immunoblot readouts under starvation; and UBAC2–GABARAP co-immunoprecipitation. (he2024erphagyrestrainsinflammatory media 2051f18f, he2024erphagyrestrainsinflammatory media 4a49bd3c, he2024erphagyrestrainsinflammatory media 87f2e417, he2024erphagyrestrainsinflammatory media a2146745)

3.3 UBAC2 in ERAD-like ubiquitin-mediated degradation and Wnt pathway attenuation

Prior to 2024, UBAC2’s best-supported mechanistic placement was in ER-associated ubiquitin-dependent quality control.

A 2019 Science study reports that UBAC2 participates in an “ER-localized LMBR1L-GP78-UBAC2 complex” that promotes ubiquitin-mediated degradation of Wnt receptors (e.g., FZD and LRP6) and helps attenuate Wnt/β-catenin signaling in lymphocytes. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)
Reviews integrate UBAC2 into the broader ERAD conceptual framework, discussing its interactions with ubiquitin-binding modules and ERAD components (including association with UBXD8/p97-related machinery and GP78-linked pathways). (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

4. Recent developments and latest research (prioritize 2023–2024)

4.1 2024: UBAC2–MARK2 axis links ER stress to ER-phagy and inflammation

The central 2024 discovery is that UBAC2 is a regulated ER-phagy receptor, with an explicit upstream kinase (MARK2) and a defined regulatory site (S223 phosphorylation) that modulates receptor activity through dimerization and strengthened GABARAP binding. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)

4.2 2023: UBAC2 in updated ER quality-control frameworks

A 2023 Cold Spring Harbor Perspectives in Biology review summarizes the roles of rhomboid superfamily members in ER protein quality control and includes UBAC2 within this proteostasis context, providing a recent synthesis that anticipates why a rhomboid-like ER membrane factor may integrate multiple quality-control outputs (e.g., ubiquitin pathways and autophagy). (OpenTargets Search: -UBAC2)

5. Current applications and real-world implementations

5.1 Translational hypothesis generation: inflammation and IBD

Because UBAC2-driven ER-phagy restrains ER stress/UPR-linked inflammation and mitigates colitis phenotypes in vivo (DSS model), the UBAC2–MARK2–GABARAP axis provides a mechanistically grounded target pathway for therapeutic exploration in inflammatory disease contexts where ER stress contributes to pathology. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 15-16)

5.2 Signaling pathway modulation: Wnt/β-catenin brake

The LMBR1L–GP78–UBAC2 complex was proposed as a second “brake” on Wnt signaling in lymphocytes by promoting ER-localized ubiquitination and degradation of Wnt receptors and β-catenin, suggesting a potential lever for contexts where Wnt signaling needs to be constrained. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)

5.3 Human genetics and biomarker context

UBAC2 is implicated as a susceptibility locus across several diseases by genetics and aggregated evidence.

Behçet’s disease: Fine-mapped promoter variants modulate UBAC2 transcription, supporting a plausible regulatory mechanism for disease risk. (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6, hou2012replicationstudyconfirms pages 1-2)
Skin cancers: The UBAC2 region shows genome-wide significant associations with basal cell carcinoma risk, suggesting clinical relevance as a locus (while not proving causality of UBAC2 protein function). (nan2011genomewideassociationstudy pages 1-2)
Database aggregation: Open Targets lists UBAC2 associations with asthma, psoriasis, actinic keratosis, hypothyroidism, etc., which is useful for target prioritization and hypothesis generation. (OpenTargets Search: -UBAC2)

6. Expert synthesis and analysis (authoritative interpretations)

6.1 UBAC2 as an integrator of ER proteostasis pathways

Across authoritative reviews, UBAC2 is repeatedly positioned as an ER membrane rhomboid-like factor with a ubiquitin-binding UBA module that participates in ER quality control, including ERAD-linked networks and lipid-droplet related trafficking (via UBXD8). (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

The 2024 identification of UBAC2 as an ER-phagy receptor provides a coherent functional extension: UBAC2 appears capable of routing ER components to both proteasome-associated and autophagy-associated disposal pathways depending on stress context and regulatory state (e.g., MARK2 phosphorylation), consistent with modern views that ER proteostasis involves coordinated and partially redundant degradation systems. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)

6.2 Caution on mechanistic specificity vs locus association

Genetic associations at the UBAC2/PHGDHL1 locus (e.g., skin cancer GWAS) establish medical relevance but do not alone demonstrate UBAC2 as the causal gene or define causal mechanisms; mechanistic interpretation should primarily rely on direct experiments such as the 2019 Science and 2024 EMBO Journal studies. (nan2011genomewideassociationstudy pages 1-2, choi2019lmbr1lregulateslymphopoiesis pages 1-2, he2024erphagyrestrainsinflammatory pages 1-2)

7. Relevant statistics and data (selected)

7.1 Behçet’s disease (Chinese Han cohorts) — UBAC2 locus

In a two-stage study totaling 477 BD cases and 1,334 controls, UBAC2 showed replicated association, including (selected examples):

rs3825427: combined Pc = 6.9 × 10^-6, OR = 1.5; promoter risk T allele had lower promoter activity than G allele (P = 0.002) and was associated with decreased UBAC2 transcript variant 1 expression in PBMCs and skin (Bonferroni-corrected P = 0.045 and P = 0.025). (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6)
rs9517668: combined Pc = 3.3 × 10^-4, OR = 1.4. (hou2012replicationstudyconfirms pages 4-5)
rs9517701: combined Pc = 2.9 × 10^-5, OR = 1.4. (hou2012replicationstudyconfirms pages 4-5)

7.2 Skin cancer GWAS (UBAC2 region)

For basal cell carcinoma (BCC), rs7335046 near UBAC2 showed combined OR 1.26 (95% CI 1.18–1.34) with P = 2.9 × 10^-8 (genome-wide significant) in a discovery + replication GWAS design. (nan2011genomewideassociationstudy pages 1-2)

7.3 2024 ER-phagy functional statistics (selected)

The EMBO Journal 2024 study reports multiple statistically significant effects of UBAC2 perturbation/mutants on ER-phagy and inflammation-linked phenotypes, including comparisons with p < 0.0001 in several assays; in vivo DSS colitis experiments used n = 6 mice/group. (he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8)

Evidence map (key sources)

Year	Citation (first author journal)	URL	Evidence type (primary/review/database)	Key findings relevant to UBAC2 (function/pathway/localization/domains)	Key quantitative/statistical data (p-values, ORs, n)	Notes/limitations
2024	He, EMBO Journal	https://doi.org/10.1038/s44318-024-00232-z	Primary	Identifies human UBAC2 as an ER-resident ER-phagy receptor. UBAC2 contains a cytoplasmic canonical LIR that binds GABARAP; MARK2 phosphorylates UBAC2 at S223, promoting dimerization and stronger GABARAP binding. UBAC2-mediated ER-phagy restrains UPR/inflammatory signaling and protects against DSS colitis. UBAC2 also undergoes autophagic turnover during ER stress/starvation. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8, he2024erphagyrestrainsinflammatory pages 14-15, he2024erphagyrestrainsinflammatory pages 3-4)	HeLa ER-phagy reporter quantified across 3 biological replicates; 20 cells scored/condition in microscopy analyses; DSS colitis experiments used n=6 mice/group; multiple comparisons reported including p<0.0001, p=0.0100, p=0.0071, p=0.0012, p=0.0080. (he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8, he2024erphagyrestrainsinflammatory pages 3-4)	Strongest recent mechanistic study; extends UBAC2 function beyond ERAD into selective autophagy. Context excerpts do not provide all effect sizes/fold changes.
2019	Choi, Science	https://doi.org/10.1126/science.aau0812	Primary	Places UBAC2 in an ER-localized LMBR1L-GP78-UBAC2 complex that promotes ubiquitin-mediated degradation of FZD6/LRP6 and helps limit Wnt/β-catenin signaling in lymphocytes. Supports ER quality-control/ERAD-like function and ER localization. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)	Paper reports impaired lymphoid development/function in mutant mice and restoration experiments involving β-catenin knockout, but quantitative values were not present in the available excerpt. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)	Direct primary evidence for pathway-specific UBAC2 function, but excerpt does not state membrane topology or UBA-domain position.
2023	Bhaduri, Cold Spring Harbor Perspectives in Biology	https://doi.org/10.1101/cshperspect.a041248	Review	Reviews rhomboid superfamily roles in ER protein quality control and includes UBAC2 among rhomboid-like proteins linked to ERAD/proteostasis. Helps place UBAC2 in current ER quality-control framework. (OpenTargets Search: -UBAC2)	No UBAC2-specific quantitative statistics in available excerpt.	High-authority recent review; useful for current conceptual understanding, but mostly secondary synthesis rather than direct UBAC2 experiments.
2020	Adrain, FEBS Journal	https://doi.org/10.1111/febs.15548	Review	Describes UBAC2 as an ER-localized rhomboid pseudoprotease with a conserved C-terminal UBA domain; links UBAC2 to UBXD8, GP78-ERAD, delivery of substrates to GP78, and LMBR1L-GP78-UBAC2-mediated Wnt regulation. Notes Derlin-like behavior and unresolved physiology. (adrain2020thecomplexlife pages 15-18, adrain2020thecomplexlife pages 1-5)	No new quantitative UBAC2 statistics in excerpt.	Strong synthesis of mechanistic literature; some claims are review-level interpretations and precise physiological roles remain incompletely established.
2020	Kandel, BBA Mol Cell Res	https://doi.org/10.1016/j.bbamcr.2020.118793	Review	Summarizes UBAC2 as a rhomboid-like multi-pass membrane protein with a C-terminal UBA domain that binds polyubiquitin; UBAC2 knockdown stabilizes mutant α1-antitrypsin (an ERAD substrate) and UBAC2 restricts UBXD8 trafficking from ER to lipid droplets, linking proteostasis to lipid homeostasis. (kandel2020theroleof pages 10-14)	Quantitative values not included in excerpt; cites primary data that recombinant UBA binds polyubiquitin and knockdown stabilizes mutant α1-antitrypsin. (kandel2020theroleof pages 10-14)	Valuable for integrating ERAD and lipid-droplet biology; secondary source.
2016	Lemberg, Seminars in Cell & Developmental Biology	https://doi.org/10.1016/j.semcdb.2016.06.022	Review	Classifies UBAC2 as a rhomboid-family pseudoprotease predicted to bind ubiquitin via a conserved cytoplasmic C-terminal UBA domain; places it in the ERAD network with gp78 and identifies UBAC2 as an ER tether for UBXD8, affecting lipid-droplet trafficking and triglyceride turnover. (lemberg2016inactiverhomboidproteins pages 16-21)	No quantitative UBAC2-specific statistics in excerpt.	Foundational review; older and predates ER-phagy findings.
2013	Olzmann, Cold Spring Harbor Perspectives in Biology	https://doi.org/10.1101/cshperspect.a013185	Review	Early authoritative ERAD review explicitly mentions UBAC2 as a recently identified UBA-domain-containing, rhomboid-like factor in mammalian ERAD, helping establish the historical basis for UBAC2’s ER quality-control annotation. (OpenTargets Search: -UBAC2)	No UBAC2-specific quantitative data in available excerpt.	Important historical context, but limited UBAC2 detail in excerpt.
2012	Hou, Arthritis Research & Therapy	https://doi.org/10.1186/ar3789	Primary genetics/functional	Validates UBAC2 as a Behçet’s disease susceptibility locus in Han Chinese. Promoter SNP rs3825427 risk T allele reduces promoter activity and lowers UBAC2 transcript variant 1 in PBMCs/skin; variant 1 is decreased in BD, while variant 2 is increased in BD skin. (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6, hou2012replicationstudyconfirms pages 1-2, hou2012replicationstudyconfirms pages 2-4, hou2012replicationstudyconfirms pages 6-7)	Two-stage study totaling 477 BD patients and 1,334 controls; rs9513584 Pc=0.018, OR=1.4; rs3825427 combined Pc=6.9×10^-6, OR=1.5; rs9517668 combined Pc=3.3×10^-4, OR=1.4; rs9517701 combined Pc=2.9×10^-5, OR=1.4; rs3825427 promoter assay P=0.002; transcript variant 1 genotype-expression P=0.045 and P=0.025; BD vs control expression P=0.025 and P=0.047; variant 2 in BD skin P=0.004. (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6, hou2012replicationstudyconfirms pages 1-2, hou2012replicationstudyconfirms pages 2-4)	Strong disease-association and functional-regulatory evidence, but does not define biochemical mechanism of UBAC2 protein action.
2011	Nan, Human Molecular Genetics	https://doi.org/10.1093/hmg/ddr287	Primary genetics	GWAS implicates the UBAC2/PHGDHL1 region in skin cancer susceptibility, supporting medical relevance of the locus. (nan2011genomewideassociationstudy pages 1-2)	Discovery 2,045 BCC cases/6,013 controls; replication 1,426 cases/4,845 controls. rs7335046 near UBAC2: BCC OR 1.26 (95% CI 1.18–1.34), P=2.9×10^-8; SCC OR 1.21 (95% CI 1.02–1.44), P=0.03; rs12210050[T] SCC OR 1.35 (95% CI 1.16–1.57), P=7.6×10^-5. (nan2011genomewideassociationstudy pages 1-2)	Locus-level association only; does not establish UBAC2 as the causal effector gene or define function.
Current	Open Targets Platform	https://platform.opentargets.org/target/ENSG00000134882	Database	Aggregates disease-target associations for UBAC2, including asthma, childhood-onset asthma, psoriasis, actinic keratosis, and hypothyroidism, useful for prioritizing translational hypotheses. (OpenTargets Search: -UBAC2)	Example association scores from excerpt: asthma 0.4426; hypothyroidism 0.3475; actinic keratosis 0.3268; psoriasis 0.3055; childhood-onset asthma 0.3054; 5 literature-linked evidences per listed disease. (OpenTargets Search: -UBAC2)	Useful overview, but database evidence is heterogeneous and should not be treated as proof of causality without examining underlying studies.

Table: This table summarizes the main evidence base for human UBAC2 (Q8NBM4), highlighting the 2024 ER-phagy discovery paper, the 2019 Wnt/ERAD study, key reviews, and disease-genetics sources. It is useful for quickly separating direct mechanistic evidence from review synthesis and locus-level association data.

Conclusion

The best-supported “primary function” assignment for human UBAC2 has shifted from being primarily an ERAD-associated adapter in ubiquitin-dependent quality control to a broader role as a regulated ER-phagy receptor that connects ER stress to selective autophagy and inflammatory restraint. Mechanistically, the 2024 EMBO Journal work defines actionable molecular features (LIR–GABARAP binding, MARK2 phosphorylation at S223, dimerization) and demonstrates in vivo relevance in a colitis model, while earlier work supports UBAC2’s role in ER-localized ubiquitin-mediated degradation impacting Wnt signaling and immune development. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, choi2019lmbr1lregulateslymphopoiesis pages 1-2)

URLs and publication dates (selected)

He et al., The EMBO Journal — Sep 2024 — https://doi.org/10.1038/s44318-024-00232-z (he2024erphagyrestrainsinflammatory pages 1-2)
Choi et al., Science — May 2019 — https://doi.org/10.1126/science.aau0812 (choi2019lmbr1lregulateslymphopoiesis pages 1-2)
Bhaduri et al., Cold Spring Harbor Perspectives in Biology — Aug 2023 — https://doi.org/10.1101/cshperspect.a041248 (OpenTargets Search: -UBAC2)
Hou et al., Arthritis Research & Therapy — Mar 2012 — https://doi.org/10.1186/ar3789 (hou2012replicationstudyconfirms pages 1-2)
Nan et al., Human Molecular Genetics — Jun 2011 — https://doi.org/10.1093/hmg/ddr287 (nan2011genomewideassociationstudy pages 1-2)
Open Targets: UBAC2 (ENSG00000134882) — https://platform.opentargets.org/target/ENSG00000134882 (OpenTargets Search: -UBAC2)

References

(adrain2020thecomplexlife pages 15-18): Colin Adrain and Miguel Cavadas. The complex life of rhomboid pseudoproteases. The FEBS Journal, 287:4261-4283, Oct 2020. URL: https://doi.org/10.1111/febs.15548, doi:10.1111/febs.15548. This article has 25 citations.
(kandel2020theroleof pages 10-14): Rachel R. Kandel and Sonya E. Neal. The role of rhomboid superfamily members in protein homeostasis: mechanistic insight and physiological implications. Oct 2020. URL: https://doi.org/10.1016/j.bbamcr.2020.118793, doi:10.1016/j.bbamcr.2020.118793. This article has 27 citations and is from a peer-reviewed journal.
(lemberg2016inactiverhomboidproteins pages 16-21): Marius K. Lemberg and Colin Adrain. Inactive rhomboid proteins: new mechanisms with implications in health and disease. Seminars in cell & developmental biology, 60:29-37, Dec 2016. URL: https://doi.org/10.1016/j.semcdb.2016.06.022, doi:10.1016/j.semcdb.2016.06.022. This article has 41 citations and is from a peer-reviewed journal.
(choi2019lmbr1lregulateslymphopoiesis pages 1-2): Jin Huk Choi, Xue Zhong, William McAlpine, Tzu-Chieh Liao, Duanwu Zhang, Beibei Fang, Jamie Russell, Sara Ludwig, Evan Nair-Gill, Zhao Zhang, Kuan-wen Wang, Takuma Misawa, Xiaoming Zhan, Mihwa Choi, Tao Wang, Xiaohong Li, Miao Tang, Qihua Sun, Liyang Yu, Anne R. Murray, Eva Marie Y. Moresco, and Bruce Beutler. Lmbr1l regulates lymphopoiesis through wnt/β-catenin signaling. May 2019. URL: https://doi.org/10.1126/science.aau0812, doi:10.1126/science.aau0812. This article has 66 citations and is from a highest quality peer-reviewed journal.
(he2024erphagyrestrainsinflammatory pages 1-2): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(he2024erphagyrestrainsinflammatory pages 12-13): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(he2024erphagyrestrainsinflammatory pages 15-16): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(he2024erphagyrestrainsinflammatory pages 7-8): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(adrain2020thecomplexlife pages 1-5): Colin Adrain and Miguel Cavadas. The complex life of rhomboid pseudoproteases. The FEBS Journal, 287:4261-4283, Oct 2020. URL: https://doi.org/10.1111/febs.15548, doi:10.1111/febs.15548. This article has 25 citations.
(nan2011genomewideassociationstudy pages 1-2): Hongmei Nan, Mousheng Xu, Peter Kraft, Abrar A. Qureshi, Constance Chen, Qun Guo, Frank B. Hu, Gary Curhan, Christopher I. Amos, Li-E. Wang, Jeffrey E. Lee, Qingyi Wei, David J. Hunter, and Jiali Han. Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma. Human Molecular Genetics, 20:3718-3724, Jun 2011. URL: https://doi.org/10.1093/hmg/ddr287, doi:10.1093/hmg/ddr287. This article has 127 citations and is from a domain leading peer-reviewed journal.
(hou2012replicationstudyconfirms pages 1-2): Shengping Hou, Qinmeng Shu, Zhengxuan Jiang, Yuanyuan Chen, Fuzhen Li, Feilan Chen, Aize Kijlstra, and Peizeng Yang. Replication study confirms the association between ubac2 and behçet's disease in two independent chinese sets of patients and controls. Arthritis Research & Therapy, 14:R70-R70, Mar 2012. URL: https://doi.org/10.1186/ar3789, doi:10.1186/ar3789. This article has 50 citations and is from a domain leading peer-reviewed journal.
(he2024erphagyrestrainsinflammatory pages 3-4): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(he2024erphagyrestrainsinflammatory media 2051f18f): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(he2024erphagyrestrainsinflammatory media 4a49bd3c): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(he2024erphagyrestrainsinflammatory media 87f2e417): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(he2024erphagyrestrainsinflammatory media a2146745): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(OpenTargets Search: -UBAC2): Open Targets Query (-UBAC2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(hou2012replicationstudyconfirms pages 4-5): Shengping Hou, Qinmeng Shu, Zhengxuan Jiang, Yuanyuan Chen, Fuzhen Li, Feilan Chen, Aize Kijlstra, and Peizeng Yang. Replication study confirms the association between ubac2 and behçet's disease in two independent chinese sets of patients and controls. Arthritis Research & Therapy, 14:R70-R70, Mar 2012. URL: https://doi.org/10.1186/ar3789, doi:10.1186/ar3789. This article has 50 citations and is from a domain leading peer-reviewed journal.
(hou2012replicationstudyconfirms pages 5-6): Shengping Hou, Qinmeng Shu, Zhengxuan Jiang, Yuanyuan Chen, Fuzhen Li, Feilan Chen, Aize Kijlstra, and Peizeng Yang. Replication study confirms the association between ubac2 and behçet's disease in two independent chinese sets of patients and controls. Arthritis Research & Therapy, 14:R70-R70, Mar 2012. URL: https://doi.org/10.1186/ar3789, doi:10.1186/ar3789. This article has 50 citations and is from a domain leading peer-reviewed journal.
(he2024erphagyrestrainsinflammatory pages 14-15): Xing He, Haowei He, Zitong Hou, Zheyu Wang, Qinglin Shi, Tao Zhou, Yaoxing Wu, Yunfei Qin, Jun Wang, Zhe Cai, Jun Cui, and Shouheng Jin. Er-phagy restrains inflammatory responses through its receptor ubac2. The EMBO Journal, 43:5057-5084, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00232-z, doi:10.1038/s44318-024-00232-z. This article has 13 citations.
(hou2012replicationstudyconfirms pages 2-4): Shengping Hou, Qinmeng Shu, Zhengxuan Jiang, Yuanyuan Chen, Fuzhen Li, Feilan Chen, Aize Kijlstra, and Peizeng Yang. Replication study confirms the association between ubac2 and behçet's disease in two independent chinese sets of patients and controls. Arthritis Research & Therapy, 14:R70-R70, Mar 2012. URL: https://doi.org/10.1186/ar3789, doi:10.1186/ar3789. This article has 50 citations and is from a domain leading peer-reviewed journal.
(hou2012replicationstudyconfirms pages 6-7): Shengping Hou, Qinmeng Shu, Zhengxuan Jiang, Yuanyuan Chen, Fuzhen Li, Feilan Chen, Aize Kijlstra, and Peizeng Yang. Replication study confirms the association between ubac2 and behçet's disease in two independent chinese sets of patients and controls. Arthritis Research & Therapy, 14:R70-R70, Mar 2012. URL: https://doi.org/10.1186/ar3789, doi:10.1186/ar3789. This article has 50 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

he2024erphagyrestrainsinflammatory pages 7-8
he2024erphagyrestrainsinflammatory pages 12-13
he2024erphagyrestrainsinflammatory pages 15-16
nan2011genomewideassociationstudy pages 1-2
hou2012replicationstudyconfirms pages 4-5
kandel2020theroleof pages 10-14
lemberg2016inactiverhomboidproteins pages 16-21
he2024erphagyrestrainsinflammatory pages 1-2
hou2012replicationstudyconfirms pages 1-2
adrain2020thecomplexlife pages 15-18
adrain2020thecomplexlife pages 1-5
he2024erphagyrestrainsinflammatory pages 3-4
hou2012replicationstudyconfirms pages 5-6
he2024erphagyrestrainsinflammatory pages 14-15
hou2012replicationstudyconfirms pages 2-4
hou2012replicationstudyconfirms pages 6-7
T
https://doi.org/10.1038/s44318-024-00232-z
https://doi.org/10.1126/science.aau0812
https://doi.org/10.1101/cshperspect.a041248
https://doi.org/10.1111/febs.15548
https://doi.org/10.1016/j.bbamcr.2020.118793
https://doi.org/10.1016/j.semcdb.2016.06.022
https://doi.org/10.1101/cshperspect.a013185
https://doi.org/10.1186/ar3789
https://doi.org/10.1093/hmg/ddr287
https://platform.opentargets.org/target/ENSG00000134882
https://doi.org/10.1111/febs.15548,
https://doi.org/10.1016/j.bbamcr.2020.118793,
https://doi.org/10.1016/j.semcdb.2016.06.022,
https://doi.org/10.1126/science.aau0812,
https://doi.org/10.1038/s44318-024-00232-z,
https://doi.org/10.1093/hmg/ddr287,
https://doi.org/10.1186/ar3789,

📚 Additional Documentation

Notes

(UBAC2-notes.md)

UBAC2 (UBA domain-containing protein 2) review notes

UniProt: Q8NBM4 (UBAC2_HUMAN), 344 aa precursor. Synonym PHGDHL1, PSEC0110. HGNC:20486.
Multi-pass ER-membrane protein with an N-terminal rhomboid-like (pseudoprotease) fold and a
C-terminal cytoplasmic UBA domain (304-344). It is a rhomboid-family pseudoprotease — the
catalytic Ser/His dyad of active rhomboid proteases is NOT conserved, so it has no protease activity.

Core biology

ERAD membrane component (RHBDD1/UBAC2 machinery). UBAC2 partners the active rhomboid protease
RHBDD1 in ER-associated degradation of membrane substrates; its cytoplasmic UBA domain binds
ubiquitinated substrates. (This RHBDD1/UBAC2 role is well established in the ERAD literature; note
the current GOA TSV does not contain a direct RHBDD1-co-annotation, so it is captured in the
description/core_functions rather than as an existing annotation review.)
FAF2/UBXD8 ER receptor. UBAC2 is the ER receptor that restricts trafficking of FAF2/UBXD8 from
the ER to lipid droplets.
PMID:23297223
This is the basis of the IDA ER localization and "protein localization to ER" annotations (MGI,
PMID:23297223), and the IMP "negative regulation of retrograde protein transport ER to cytosol"
(PMID:25660456).
ER-phagy receptor. UBAC2 is an ER-phagy (reticulophagy) receptor with a LIR motif that binds
GABARAP; MARK2 phosphorylates UBAC2 at Ser223 to drive dimerization and GABARAP binding, restraining
inflammatory responses.
PMID:39284914
Wnt regulation. With LMBR1L and the E3 ligase AMFR, UBAC2 negatively regulates canonical Wnt
signaling in lymphocytes by promoting degradation of CTNNB1 and Wnt receptors FZD6/LRP6.
PMID:31073040

Annotation assessment summary

serine-type endopeptidase activity (GO:0004252) IBA: UBAC2 is a rhomboid pseudoprotease lacking
the catalytic dyad; this IBA is an over-propagation from the active-rhomboid branch of the PANTHER tree
and is biologically incorrect → REMOVE (IEA/IBA over-propagation, refutable on biological grounds).
ER membrane (GO:0005789 IEA) / ER (GO:0005783 IDA): core compartment → ACCEPT.
protein localization to ER (GO:0070972) / negative regulation of retrograde protein transport ER to
cytosol (GO:1904153): reflect the FAF2/UBXD8 ER-receptor role → ACCEPT.
reticulophagy (GO:0061709) / negative regulation of inflammatory response (GO:0050728) IMP: ER-phagy
receptor role → ACCEPT.
negative regulation of canonical Wnt (GO:0090090) IMP/IEA: LMBR1L/AMFR Wnt role → ACCEPT (non-core
relative to ERAD/ER-phagy, but experimentally supported).
protein binding (GO:0005515) IPI: uninformative term → KEEP_AS_NON_CORE.

Falcon deep-research findings (incorporated 2026-06)

The Falcon report largely corroborates the existing review (ER-phagy receptor / MARK2 / Ser223 /
GABARAP, LMBR1L-AMFR Wnt regulation, FAF2/UBXD8 ER receptor, ERAD, rhomboid pseudoprotease). The
genuinely new, verifiable additions are the disease-genetics references:

UBAC2 is a confirmed Behçet's disease (BD) susceptibility locus in Han Chinese (two-stage study,
477 BD cases / 1,334 controls). The risk T allele of promoter SNP rs3825427 has lower promoter
activity and lowers UBAC2 transcript variant 1 expression, suggesting disease risk acts via
transcriptional modulation of UBAC2. PMID:22455605 (PubMed-verified; doi:10.1186/ar3789). Added as a top-level reference
(relevance MEDIUM) — locus/regulatory evidence, not tied to a specific GO term.
The 13q32 locus near UBAC2 (variant rs7335046) confers susceptibility to cutaneous basal cell
carcinoma and squamous cell carcinoma. PMID:21700618 (PubMed-verified; doi:10.1093/hmg/ddr287). Added as a top-level reference
(relevance LOW) — locus-level GWAS only, does not establish UBAC2 as the causal gene.
Falcon also cites several rhomboid/ERAD reviews (Adrain 2020 FEBS J doi:10.1111/febs.15548; Kandel
2020 BBA-MCR doi:10.1016/j.bbamcr.2020.118793; Lemberg 2016 Semin Cell Dev Biol
doi:10.1016/j.semcdb.2016.06.022) reiterating the UBA-domain/polyubiquitin-binding adapter and
FAF2/UBXD8 lipid-droplet-trafficking role already captured in the review; not added as separate
references since they only restate existing primary-evidence-backed content.
Note: the Falcon report repeatedly cites the ER-phagy paper as "doi:10.1038/s44318-024-00232-z";
this is the same study already in the review as PMID:39284914 (He et al. 2024, EMBO J). No new
ER-phagy finding beyond what is already annotated.

Pn Notes

(UBAC2-pn-notes.md)

UBAC2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8NBM4
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/UBAC2/UBAC2-ai-review.yaml
AIGR review HTML: missing - genes/human/UBAC2/UBAC2-ai-review.html
Gene notes: present - genes/human/UBAC2/UBAC2-notes.md
GOA TSV: present - genes/human/UBAC2/UBAC2-goa.tsv
UniProt record: present - genes/human/UBAC2/UBAC2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/UBAC2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/UBAC2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/UBAC2/UBAC2-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 8; KEEP_AS_NON_CORE: 6; REMOVE: 1

PN Consistency Summary

Consistency: Excellent. Deep research, review and PN concur that UBAC2 is a catalytically inactive rhomboid pseudoprotease (no Ser/His dyad), an ER-membrane scaffold/adaptor — NOT an enzyme. The PN explicitly tags the LMBR1L-GP78-UBAC2 subtype as "noncatalytic / UBA, transmembrane" and assigns the COMPLEX (GO:0000151), not catalytic activity, to the group — exactly matching the review's REMOVE of the IBA serine-type endopeptidase activity (GO:0004252). The PN correctly does NOT project GO:0061630 to UBAC2. No contradictions.
PN story / NEW pressure: PN's only NEW projection is GO:0000151 ubiquitin ligase complex (verified real; NOT in GOA) from the LMBR1L-GP78(AMFR)-UBAC2 idiosyncratic-RING-complex membership (PMID:31073040). UBAC2 is genuinely a non-catalytic subunit of this AMFR/GP78-containing E3 complex, so complex membership is a DEFENSIBLE ADD — and one the review does NOT currently capture (review has the Wnt BP via this complex but no GO:0000151 CC term). Conclude: pseudoprotease/scaffold correctly captured; GO:0000151 a defensible NEW the review missed.
Evidence alignment: Partial. PN complex row cites "31073040" (LMBR1L/Wnt paper) — IS in the review (HIGH/VERIFIED, source of the Wnt + LMBR1L annotations). The ERphagy row carries no PN reference title; the review's ER-phagy evidence (PMID:39284914, HIGH) is gene-specific and richer. Good overlap on the one cited PMID; no divergence.
Verdict: Fully consistent; pseudoprotease status and scaffold role correctly handled by BOTH review (REMOVE GO:0004252) and PN (noncatalytic tag, no GO:0061630). GO:0000151 complex membership is a defensible ADD the review omits.

Full Consistency Review

UniProt: Q8NBM4 · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE (thorough; rhomboid PSEUDOprotease, ERAD scaffold + FAF2 ER receptor + ER-phagy receptor + Wnt)
PN placement: 2 rows — UPS|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|LMBR1L-GP78-UBAC2 complex|noncatalytic / UBA, transmembrane; UPS|Ubiquitin and UBL binding|trafficking|ERphagy|UBA. PN-node mapping: LMBR1L-GP78-UBAC2 subtype/type no_mapping (noncatalytic, covered by parent); idiosyncratic-RING-complex group→GO:0000151 ubiquitin ligase complex (new_to_goa); E3-ligase class context_only GO:0061630 (too_broad); ERphagy/UBA-binding rows all no_mapping/context_only (GO:0140036 too_broad). Projected: GO:0000151 (new).
Consistency: Excellent. Deep research, review and PN concur that UBAC2 is a catalytically inactive rhomboid pseudoprotease (no Ser/His dyad), an ER-membrane scaffold/adaptor — NOT an enzyme. The PN explicitly tags the LMBR1L-GP78-UBAC2 subtype as "noncatalytic / UBA, transmembrane" and assigns the COMPLEX (GO:0000151), not catalytic activity, to the group — exactly matching the review's REMOVE of the IBA serine-type endopeptidase activity (GO:0004252). The PN correctly does NOT project GO:0061630 to UBAC2. No contradictions.
PN story / NEW pressure: PN's only NEW projection is GO:0000151 ubiquitin ligase complex (verified real; NOT in GOA) from the LMBR1L-GP78(AMFR)-UBAC2 idiosyncratic-RING-complex membership (PMID:31073040). UBAC2 is genuinely a non-catalytic subunit of this AMFR/GP78-containing E3 complex, so complex membership is a DEFENSIBLE ADD — and one the review does NOT currently capture (review has the Wnt BP via this complex but no GO:0000151 CC term). Conclude: pseudoprotease/scaffold correctly captured; GO:0000151 a defensible NEW the review missed.
Mapping strategy: Exemplary. Resolves the pseudoprotease trap (no serine endopeptidase MF — matches prior REMOVE precedent), assigns complex membership not catalysis to the non-catalytic subunit, and conservatively leaves the ERphagy/UBA-binding rows unmapped (avoids over-broad GO:0140036 reader propagation). The ER-phagy biology IS captured at the gene level (review GO:0061709 reticulophagy IMP). No node-status change warranted.
Evidence alignment: Partial. PN complex row cites "31073040" (LMBR1L/Wnt paper) — IS in the review (HIGH/VERIFIED, source of the Wnt + LMBR1L annotations). The ERphagy row carries no PN reference title; the review's ER-phagy evidence (PMID:39284914, HIGH) is gene-specific and richer. Good overlap on the one cited PMID; no divergence.
Verdict: Fully consistent; pseudoprotease status and scaffold role correctly handled by BOTH review (REMOVE GO:0004252) and PN (noncatalytic tag, no GO:0061630). GO:0000151 complex membership is a defensible ADD the review omits.
Recommended edits: [YAML] add GO:0000151 ubiquitin ligase complex (part_of; LMBR1L-AMFR/GP78-UBAC2 complex, PMID:31073040) as a non-core CC — currently absent from the review. [MAP] none — node mapping is correct; complex (not catalytic) target for the non-catalytic subunit is the right call.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/UBAC2/UBAC2-ai-review.yaml
PN workbook rows: 2

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | idiosyncratic RING complex | LMBR1L-GP78-UBAC2 complex | noncatalytic / UBA, transmembrane

UniProt: Q8NBM4
In branches: UPS
Signature domains: (none)
Auxiliary domains: IPR015940
PN references (titles):
- 31073040
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|LMBR1L-GP78-UBAC2 complex|noncatalytic / UBA, transmembrane
  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|idiosyncratic RING complex|LMBR1L-GP78-UBAC2 complex
  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|idiosyncratic RING complex
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000151 ubiquitin ligase complex]
  rationale: This PN group is an E3 ligase complex bucket. The safest shared GO target is ubiquitin ligase complex membership rather than assigning catalytic activity to every subunit.
- [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.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | trafficking | ERphagy | UBA

UniProt: Q8NBM4
In branches: UPS
Signature domains: IPR015940
Auxiliary domains: (none)
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|ERphagy|UBA
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a selective-autophagy or trafficking subdivision under a UPS binding context. The autophagy context is real, but this node is too indirect for automatic GO propagation.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|ERphagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [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 (1)

GO:0000151 ubiquitin ligase complex | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex

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: 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.

UBAC2

Gene Description

Existing Annotations Review

Core Functions

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.

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.