Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: ER membrane is the principal compartment where AUP1 acts as an ERAD E2 adaptor; well supported by orthology and direct experiments. Reason: AUP1 is a monotopic ER membrane protein with both termini in the cytosol, where it recruits UBE2G2 to the HRD1-SEL1L/gp78 ERAD machinery. This is a core localization. Supporting Evidence: PMID:23197321 AUP1 is inserted into the membrane of the ER in a monotopic
GO:0036503 ERAD pathway	IBA GO_REF:0000033	ACCEPT	Summary: ERAD participation is the core biological process of AUP1, supported by direct loss-of-function evidence and orthology. Reason: AUP1 associates with the HRD1-SEL1L complex and recruits UBE2G2; depletion impairs degradation of misfolded ER proteins. Supporting Evidence: PMID:21857022 AUP1) physically associates with
GO:0005776 autophagosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Autophagosome localization is only seen upon Dengue/flavivirus infection, when NS4A relocalizes AUP1 from lipid droplets to autophagosomes; it is not a constitutive localization of the normal protein. Reason: This is a context-dependent (virus-induced) localization rather than the core ER/lipid-droplet residence of AUP1. Supporting Evidence: file:human/AUP1/AUP1-uniprot.txt virus infection, relocates from lipid droplets to autophagosomes.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: ER membrane is the principal site of AUP1 ERAD activity; well supported. Reason: AUP1 is a monotopic ER membrane protein where it recruits UBE2G2 to the ERAD machinery. Supporting Evidence: PMID:23197321 AUP1 is inserted into the membrane of the ER in a monotopic
GO:0005811 lipid droplet	IEA GO_REF:0000044	ACCEPT	Summary: Lipid droplet surface localization is a core, directly demonstrated localization for AUP1. Reason: AUP1 integrates into the LD surface monolayer in a monotopic fashion with both termini in the cytosol. Supporting Evidence: PMID:21127063 integrates into the LD surface in a monotopic fashion with both termini facing
GO:0036503 ERAD pathway	IEA GO_REF:0000002	ACCEPT	Summary: ERAD participation is the core biological process of AUP1. Reason: AUP1 associates with the HRD1-SEL1L complex and recruits UBE2G2; depletion impairs degradation of misfolded ER proteins. Supporting Evidence: PMID:21857022 AUP1) physically associates with
GO:0043130 ubiquitin binding	IEA GO_REF:0000002	ACCEPT	Summary: AUP1 binds ubiquitin through its internal CUE domain, a known ubiquitin-binding domain; this is a core molecular function underlying its ERAD and LD-clustering roles. Reason: The CUE domain is directly demonstrated as a ubiquitin-binding domain required for ubiquitination and LD clustering. Supporting Evidence: PMID:24039768 its internal CUE domain, which is a known ubiquitin-binding
GO:0005515 protein binding	IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ...	MARK AS OVER ANNOTATED	Summary: Generic protein-binding annotation from a proteome-scale ERAD interaction map; uninformative as a molecular function term. Reason: Bare protein binding does not convey AUP1's specific adaptor function; more informative terms (ubiquitin conjugating enzyme binding) are captured elsewhere.
GO:0005515 protein binding	IPI PMID:23840749 MOR is not enough: identification of novel mu-opioid recepto...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a mu-opioid receptor membrane yeast two-hybrid interactome; uninformative. Reason: Bare protein binding from a high-throughput screen does not identify a physiologically interpretable AUP1 function.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a binary interactome reference map; uninformative. Reason: Bare protein binding is too general to represent AUP1 function.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:12042322 Ancient ubiquitous protein 1 binds to the conserved membrane...	ACCEPT	Summary: Early experimental support for AUP1 ER/membrane association; consistent with the well-established core ER membrane localization. Reason: ER membrane is a core localization for AUP1 ERAD activity. Supporting Evidence: file:human/AUP1/AUP1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	EXP PMID:18711132 SEL1L nucleates a protein complex required for dislocation o...	ACCEPT	Summary: AUP1 is part of the SEL1L-nucleated ER membrane ERAD complex; supports core ER membrane localization. Reason: AUP1 was identified as a functionally important component of the SEL1L-nucleated ER dislocation complex. Supporting Evidence: PMID:18711132 We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important components of this degradation complex in mammalian cells
GO:0005789 endoplasmic reticulum membrane	EXP PMID:21857022 Dual role of ancient ubiquitous protein 1 (AUP1) in lipid dr...	ACCEPT	Summary: Direct evidence places AUP1 at the ER membrane within the HRD1-SEL1L complex. Reason: ER membrane is the core compartment for AUP1 ERAD function. Supporting Evidence: PMID:21857022 AUP1) physically associates with
GO:0005811 lipid droplet	EXP PMID:28183703 AUP1 (Ancient Ubiquitous Protein 1) Is a Key Determinant of ...	ACCEPT	Summary: AUP1 is demonstrated at the lipid droplet surface in hepatic VLDL studies; core localization. Reason: LD surface localization is a directly demonstrated core localization of AUP1. Supporting Evidence: PMID:28183703 also localizes to the surface of lipid
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9921605	ACCEPT	Summary: Reactome traceable assertion of ER membrane localization is consistent with the established core localization. Reason: ER membrane localization is well supported by direct experimental evidence. Supporting Evidence: file:human/AUP1/AUP1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:29902443 Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigg...	MARK AS OVER ANNOTATED	Summary: The underlying interaction is the specific AUP1-Dengue NS4A association, but the GO term used is generic protein binding. Reason: Bare protein binding is uninformative; the meaningful (virus-specific) interaction is with NS4A and is not a core physiological function.
GO:0005776 autophagosome	IDA PMID:29902443 Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigg...	KEEP AS NON CORE	Summary: Autophagosome localization is observed only after Dengue virus infection, when NS4A relocalizes AUP1 from LDs. Reason: A virus-induced relocalization, not the constitutive site of AUP1 action. Supporting Evidence: PMID:29902443 relocalized from lipid droplets to autophagosomes upon infection
GO:0005811 lipid droplet	IDA PMID:29902443 Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigg...	ACCEPT	Summary: AUP1 is directly observed as a lipid droplet-localized membrane protein; core localization. Reason: LD surface residence is the well-established core localization of AUP1. Supporting Evidence: PMID:29902443 AUP1, a lipid droplet-localized type-III membrane protein
GO:0009615 response to virus	IMP PMID:29902443 Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigg...	KEEP AS NON CORE	Summary: AUP1 is exploited by flaviviruses to drive virus production; this is a host factor role hijacked by the virus rather than an antiviral/defense function of AUP1. Reason: The phenotype is virus production dependent on AUP1, a context-specific host-pathogen role, not a core conserved physiological function. Supporting Evidence: PMID:29902443 Virus production was abolished in cells deleted for AUP1
GO:0061724 lipophagy	IMP PMID:29902443 Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigg...	KEEP AS NON CORE	Summary: AUP1 is required for Dengue-induced lipophagy; demonstrated only in the virus-infection context. Reason: Lipophagy induction is a virus-triggered process exploiting AUP1's acyltransferase activity, not a core constitutive function. Supporting Evidence: PMID:29902443 exploits the acyltransferase activity of AUP1 to trigger lipophagy
GO:0005789 endoplasmic reticulum membrane	IDA PMID:23223569 Ancient ubiquitous protein-1 mediates sterol-induced ubiquit...	ACCEPT	Summary: AUP1 acts at lipid droplet-associated ER membranes; core localization. Reason: AUP1 functions in sterol-regulated HMGCR ubiquitination at LD-associated ER membranes. Supporting Evidence: PMID:23223569 lipid droplet-associated ER membranes
GO:0005811 lipid droplet	IDA PMID:23223569 Ancient ubiquitous protein-1 mediates sterol-induced ubiquit...	ACCEPT	Summary: AUP1 is a lipid droplet-associated protein recruiting Ubc7/UBE2G2 there; core localization. Reason: LD localization is directly demonstrated and required for AUP1's sterol-regulated ERAD role. Supporting Evidence: PMID:23223569 Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
GO:0031624 ubiquitin conjugating enzyme binding	IPI PMID:23223569 Ancient ubiquitous protein-1 mediates sterol-induced ubiquit...	ACCEPT	Summary: AUP1 binds and recruits the E2 ubiquitin-conjugating enzyme Ubc7/UBE2G2; this is a core molecular function. Reason: AUP1 recruits Ubc7 (UBE2G2) to lipid droplets and facilitates its binding to gp78 and Trc8, central to its adaptor role. Supporting Evidence: PMID:23223569 Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
GO:0031625 ubiquitin protein ligase binding	IPI PMID:23223569 Ancient ubiquitous protein-1 mediates sterol-induced ubiquit...	ACCEPT	Summary: AUP1 binds the E3 ubiquitin ligases gp78/AMFR and Trc8/RNF139, bridging them to the E2; core molecular function. Reason: AUP1 facilitates binding of Ubc7 to both gp78 and Trc8, directly demonstrating ligase association. Supporting Evidence: PMID:23223569 facilitates its binding to both gp78 and Trc8
GO:0036503 ERAD pathway	IMP PMID:23223569 Ancient ubiquitous protein-1 mediates sterol-induced ubiquit...	ACCEPT	Summary: AUP1 is required for sterol-regulated ERAD of HMGCR, INSIG1, and SREBF1/2; core process. Reason: AUP1 knockdown blunts sterol-accelerated ubiquitination and ERAD of HMGCR and other sterol-pathway substrates. Supporting Evidence: PMID:23223569 RNAi-mediated knockdown of Aup1 blunts sterol-accelerated ubiquitination
GO:1990044 protein localization to lipid droplet	IMP PMID:23223569 Ancient ubiquitous protein-1 mediates sterol-induced ubiquit...	ACCEPT	Summary: AUP1 recruits/localizes the E2 Ubc7 to lipid droplets, supporting a role in protein localization to the LD. Reason: AUP1 recruits Ubc7 to lipid droplets, a directly demonstrated protein-targeting function at the LD. Supporting Evidence: PMID:23223569 Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
GO:0005783 endoplasmic reticulum	IDA PMID:21857022 Dual role of ancient ubiquitous protein 1 (AUP1) in lipid dr...	ACCEPT	Summary: ER localization (parent of ER membrane) consistent with core ER membrane residence. Reason: AUP1 is an ER protein within the HRD1-SEL1L complex; the more specific ER membrane term is preferred but this is correct. Supporting Evidence: PMID:21857022 AUP1) physically associates with
GO:0005789 endoplasmic reticulum membrane	IDA PMID:21127063 Ancient ubiquitous protein 1 (AUP1) localizes to lipid dropl...	ACCEPT	Summary: Direct evidence of AUP1 at the ER membrane; core localization. Reason: ER membrane residence is a core localization for AUP1. Supporting Evidence: file:human/AUP1/AUP1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	IDA PMID:23197321 Monotopic topology is required for lipid droplet targeting o...	ACCEPT	Summary: AUP1 inserts into the ER membrane in monotopic hairpin fashion; core localization. Reason: Directly demonstrated monotopic ER membrane insertion. Supporting Evidence: PMID:23197321 AUP1 is inserted into the membrane of the ER in a monotopic
GO:0005811 lipid droplet	IDA PMID:21857022 Dual role of ancient ubiquitous protein 1 (AUP1) in lipid dr...	ACCEPT	Summary: AUP1 localizes to lipid droplets and its level controls LD abundance; core localization. Reason: LD localization is directly demonstrated and central to AUP1's LD-regulatory function. Supporting Evidence: PMID:21127063 ancient ubiquitous protein 1 (AUP1) localizes to LDs
GO:0005811 lipid droplet	IDA PMID:23197321 Monotopic topology is required for lipid droplet targeting o...	ACCEPT	Summary: AUP1 is transported to the LD hemi-membrane in monotopic fashion; core localization. Reason: Monotopic topology is directly shown to be required for LD targeting. Supporting Evidence: PMID:23197321 subsequently transported to the hemi-membrane of LDs
GO:0031624 ubiquitin conjugating enzyme binding	IPI PMID:21857022 Dual role of ancient ubiquitous protein 1 (AUP1) in lipid dr...	ACCEPT	Summary: AUP1 recruits the soluble E2 UBE2G2 in ER quality control; core molecular function. Reason: One of AUP1's functions in ER quality control is to recruit the soluble E2 ubiquitin-conjugating enzyme UBE2G2. Supporting Evidence: PMID:21127063 binds to Ube2g2
GO:0036503 ERAD pathway	IMP PMID:21857022 Dual role of ancient ubiquitous protein 1 (AUP1) in lipid dr...	ACCEPT	Summary: AUP1 depletion impairs degradation of misfolded ER proteins; core process. Reason: Loss-of-function evidence directly supports AUP1 in ERAD. Supporting Evidence: PMID:21857022 AUP1) physically associates with
GO:0140042 lipid droplet formation	IMP PMID:21857022 Dual role of ancient ubiquitous protein 1 (AUP1) in lipid dr...	KEEP AS NON CORE	Summary: AUP1 expression level affects the abundance of cellular lipid droplets; a core LD-regulatory function, though regulation of abundance/clustering is the better-supported framing than de novo formation. Reason: The data show AUP1 controls LD abundance/clustering rather than directly catalyzing LD biogenesis; retained as a supported but secondary LD-regulatory role. Supporting Evidence: PMID:21857022 AUP1) in lipid droplet accumulation
GO:0005811 lipid droplet	IDA PMID:21127063 Ancient ubiquitous protein 1 (AUP1) localizes to lipid dropl...	ACCEPT	Summary: AUP1 integrates into the LD surface monolayer; core localization. Reason: Directly demonstrated monotopic LD surface localization. Supporting Evidence: PMID:21127063 integrates into the LD surface in a monotopic fashion with both termini facing
GO:0031624 ubiquitin conjugating enzyme binding	IPI PMID:21127063 Ancient ubiquitous protein 1 (AUP1) localizes to lipid dropl...	ACCEPT	Summary: AUP1 binds the E2 UBE2G2 via its C-terminal G2BR; core molecular function. Reason: AUP1, by means of its G2BR domain, binds Ube2g2, providing a direct molecular link to the ubiquitination machinery. Supporting Evidence: PMID:21127063 by means of its G2BR
GO:0034389 lipid droplet organization	IDA PMID:24039768 Monoubiquitination of ancient ubiquitous protein 1 promotes ...	ACCEPT	Summary: Monoubiquitinated AUP1 on the LD surface induces lipid droplet clustering; a core LD-regulatory function. Reason: AUP1 induces LD cluster formation in a CUE/monoubiquitination-dependent manner. Supporting Evidence: PMID:24039768 the lipid droplet protein AUP1 induces cluster formation
GO:1990044 protein localization to lipid droplet	IDA PMID:21127063 Ancient ubiquitous protein 1 (AUP1) localizes to lipid dropl...	ACCEPT	Summary: AUP1 brings the AUP1-Ube2g2 complex to lipid droplets, localizing the E2 to the LD; supported. Reason: AUP1 provides the molecular link recruiting Ube2g2 to lipid droplets. Supporting Evidence: PMID:21127063 presence of the AUP1-Ube2g2 complex at LDs
GO:0030970 retrograde protein transport, ER to cytosol	IMP PMID:25660456 Identification of ERAD components essential for dislocation ...	ACCEPT	Summary: AUP1 is required for dislocation (retrotranslocation) of the ERAD substrate NHK from the ER to the cytosol; core process tied to its ERAD adaptor role. Reason: AUP1 was identified as an ERAD component essential for dislocation of NHK, i.e. ER-to-cytosol retrograde transport. Supporting Evidence: PMID:25660456 dislocation, also known as retrotranslocation
GO:0070062 extracellular exosome	HDA PMID:18570454 Proteomic analysis of exosomes from human neural stem cells ...	MARK AS OVER ANNOTATED	Summary: High-throughput exosome proteomics localization; inconsistent with AUP1's monotopic ER/LD membrane topology and not a functionally meaningful localization. Reason: This is a mass-spectrometry co-purification hit, not evidence for a functional extracellular/exosomal role for an ER/LD membrane protein.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Generic membrane from a high-throughput membrane proteome; too unspecific to be informative. Reason: The specific ER membrane and lipid droplet localizations are captured by other annotations; the bare membrane term adds no information.

Core Functions

Acts as a substrate-adaptor/scaffold that recruits the soluble E2 ubiquitin-conjugating enzyme UBE2G2 to ER-associated degradation ubiquitin ligase machinery, coupling substrate ubiquitination to dislocation and proteasomal degradation of misfolded ER proteins.

Molecular Function:

ubiquitin conjugating enzyme binding

Directly Involved In:

ERAD pathway

Supporting Evidence:

PMID:21857022
AUP1) physically associates with
PMID:21127063
by means of its G2BR

Drives sterol-regulated ubiquitination and ERAD of HMGCR and related sterol-pathway substrates by recruiting the E2 Ubc7/UBE2G2 to lipid droplet-associated ER membranes and bridging it to the E3 ligases gp78/AMFR and Trc8/RNF139.

Molecular Function:

ubiquitin protein ligase binding

Directly Involved In:

ERAD pathway

Supporting Evidence:

PMID:23223569
facilitates its binding to both gp78 and Trc8

Binds ubiquitin through its internal CUE domain and, when monoubiquitinated, drives lipid droplet clustering, thereby regulating lipid droplet organization and abundance.

Molecular Function:

ubiquitin binding

Directly Involved In:

lipid droplet organization

Supporting Evidence:

PMID:24039768
the lipid droplet protein AUP1 induces cluster formation

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:12042322

Ancient ubiquitous protein 1 binds to the conserved membrane-proximal sequence of the cytoplasmic tail of the integrin alpha subunits that plays a crucial role in the inside-out signaling of alpha IIbbeta 3.

PMID:18570454

Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry.

PMID:18711132

SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:21127063

Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region.

PMID:21857022

Dual role of ancient ubiquitous protein 1 (AUP1) in lipid droplet accumulation and endoplasmic reticulum (ER) protein quality control.

PMID:22119785

Defining human ERAD networks through an integrative mapping strategy.

PMID:23197321

Monotopic topology is required for lipid droplet targeting of ancient ubiquitous protein 1.

PMID:23223569

Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl CoA reductase in lipid droplet-associated endoplasmic reticulum membranes.

PMID:23840749

MOR is not enough: identification of novel mu-opioid receptor interacting proteins using traditional and modified membrane yeast two-hybrid screens.

PMID:24039768

Monoubiquitination of ancient ubiquitous protein 1 promotes lipid droplet clustering.

PMID:25660456

Identification of ERAD components essential for dislocation of the null Hong Kong variant of α-1-antitrypsin (NHK).

PMID:28183703

AUP1 (Ancient Ubiquitous Protein 1) Is a Key Determinant of Hepatic Very-Low-Density Lipoprotein Assembly and Secretion.

PMID:29902443

Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:34879065

A structurally conserved site in AUP1 binds the E2 enzyme UBE2G2 and is essential for ER-associated degradation.

The 27-residue G2BR of AUP1 binds the backside of the ERAD E2 enzyme UBE2G2 with low-nanomolar affinity; this interaction maintains cellular UBE2G2 levels by preventing its rapid degradation, recruits UBE2G2 to the ER membrane, and allosterically activates ubiquitination in conjunction with ERAD E3 ligases.

PMID:38474353

AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2.

AUP1 interacts with the ER-resident form of the kidney Na-K-2Cl cotransporter NKCC2 (SLC12A1) and with the ER lectin OS9, enhances NKCC2 ER retention and ERAD in a proteasome- and mannosidase-dependent manner, and is required for NKCC2 polyubiquitination; AUP1 also downregulates the related cotransporter NCC, indicating a broader role in ERAD of sodium-dependent chloride cotransporters relevant to antenatal Bartter syndrome type 1.

Reactome:R-HSA-9921605

NS4A binds AUP1

Suggested Experiments

Experiment: Define the substrate repertoire of AUP1-dependent ERAD genome-wide (e.g. proximity labeling or quantitative degradomics in AUP1-knockout vs wild-type cells) to distinguish core ERAD clients from sterol-pathway-specific and lipid-droplet-specific roles.

Experiment: Reconstitute AUP1-UBE2G2-gp78/Trc8 ubiquitination in vitro with defined components to test whether AUP1 is a passive scaffold or actively stimulates E2/E3 activity.

Experiment: Test whether AUP1-dependent ERAD of endogenous polytopic membrane clients such as NKCC2/SLC12A1 and NCC/SLC12A3 requires the G2BR-UBE2G2 interaction and the CUE domain, to determine whether physiological substrate handling uses the same module that maintains UBE2G2 levels and recruits it to the ER membrane.

Deep Research

Falcon

(AUP1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 30 citations 2 artifacts 2026-06-07T05:09:21.195372

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000014 The provided images from the document illustrate the domain architecture and localization of AUP1 as requested: - **AUP1 Domain Arc (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.

Research report: Human AUP1 (UniProt Q9Y679) functional annotation

0) Gene/protein identity verification (mandatory)

The literature retrieved here consistently identifies AUP1 as Ancient ubiquitous protein 1 in Homo sapiens, corresponding to UniProt Q9Y679, a ~410 aa protein that localizes to the endoplasmic reticulum (ER) and lipid droplets (LDs) and links LD biology to ubiquitin-dependent ER protein quality control (ERAD). (spandl2011ancientubiquitousprotein pages 3-4, klemm2011dualroleof pages 1-2)

Two frequently used functional descriptors are consistent with the UniProt entry you provided: (i) lipid droplet-regulating protein and (ii) a factor influencing VLDL assembly in liver/hepatocyte models. (zhang2017aup1(ancientubiquitous pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Lipid droplets (LDs) and ER–LD continuity

LDs are neutral-lipid storage organelles bounded by a phospholipid monolayer, and many LD membrane proteins are inserted first into the ER and then partition to LDs. AUP1 is a prototypical ER/LD “dual-localized” protein, found in LD proteomes and also associated with ER quality-control machinery. (klemm2011dualroleof pages 1-2, spandl2011ancientubiquitousprotein pages 3-4)

1.2 ER-associated degradation (ERAD)

ERAD is a protein quality control pathway in which misfolded or regulated ER proteins are ubiquitinated and then extracted for proteasomal degradation. AUP1 acts as an ERAD accessory factor, coupling substrate handling to the ubiquitination machinery. (klemm2011dualroleof pages 1-1, klemm2011dualroleof pages 11-12)

1.3 AUP1 domain definitions (CUE and G2BR)

AUP1 contains two key functional modules:
- CUE domain (“coupling of ubiquitin conjugation to ER degradation”): a ubiquitin-binding domain that mediates interactions with ubiquitinated proteins and ER quality-control components. (klemm2011dualroleof pages 1-1, klemm2011dualroleof pages 4-5)
- G2BR (UBE2G2-binding region): a short C-terminal region that binds and regulates the E2 enzyme UBE2G2 (also called UBC7). (smith2021astructurallyconserved pages 1-2, klemm2011dualroleof pages 11-12)

A schematic of this domain architecture and the LD recruitment concept is shown in the figures retrieved from Spandl et al. (JBC, 2011). (spandl2011ancientubiquitousprotein media 788c5e23, spandl2011ancientubiquitousprotein media ebcd1b79)

2) Molecular function and mechanism (what AUP1 does)

2.1 Subcellular localization and membrane topology

AUP1 is enriched on LDs with additional reticular staining consistent with the ER; this has been supported by confocal microscopy, LD flotation, and immunoelectron microscopy. (spandl2011ancientubiquitousprotein pages 3-4)

Mechanistically, AUP1 is an integral membrane protein that inserts via an N-terminal hydrophobic region in a way that leaves both termini cytosolic (hairpin/monotopic insertion), consistent with its role in recruiting cytosolic ubiquitination factors to ER/LD surfaces. (klemm2011dualroleof pages 1-1)

2.2 Recruitment and regulation of the ERAD E2 enzyme UBE2G2

A central, well-supported mechanism is that AUP1 recruits UBE2G2 to ER/LD-associated membranes via its G2BR, enabling efficient ubiquitination during ERAD. (klemm2011dualroleof pages 11-12, klemm2011dualroleof pages 4-5)

High-resolution mechanistic work (structure-function) showed that AUP1’s 27-aa G2BR binds the “backside” of UBE2G2 with low-nanomolar affinity, stabilizes UBE2G2 levels in cells, recruits it to the ER, and allosterically promotes ubiquitination with ERAD E3 ligases. (smith2021astructurallyconserved pages 1-2, smith2021astructurallyconserved pages 15-17)

2.3 The CUE domain as a ubiquitin/substrate engagement and ERAD-complex interaction module

Klemm et al. (JBC, 2011) provides evidence that AUP1’s CUE domain regulates polyubiquitination and promotes interactions with the HRD1 complex and dislocation substrates; mutation of conserved CUE residues reduces AUP1 association with ERAD/dislocation components such as p97/VCP, SEL1L, OS9, UBXD8, HRD1. (klemm2011dualroleof pages 4-5, klemm2011dualroleof pages 11-12)

2.4 AUP1 as a bridge between ER quality control and lipid droplet biology

AUP1 associates with the HRD1–SEL1L ER quality-control complex; AUP1 depletion impairs degradation of misfolded ER proteins, supporting a direct role in ERAD. (klemm2011dualroleof pages 1-1)

Concurrently, AUP1 localizes to LDs and influences LD abundance/behavior, supporting the concept that ER protein quality control and LD biology are functionally connected. (klemm2011dualroleof pages 1-2, klemm2011dualroleof pages 1-1)

3) Pathways involving AUP1

3.1 Sterol-accelerated degradation of HMG-CoA reductase (cholesterol homeostasis)

Jo et al. (MBoC, 2013) provides direct functional evidence that AUP1 promotes sterol-induced ubiquitination and ERAD of HMG-CoA reductase, and affects ERAD of Insig-1 and SREBP precursors. Mechanistically, AUP1 facilitates E2 recruitment/binding to E3 ligases including gp78 and Trc8, and localizes this process to LD-associated ER membranes. (jo2013ancientubiquitousprotein1 pages 1-2)

3.2 Hepatic ApoB/VLDL assembly and secretion (lipoprotein metabolism)

In hepatocyte models, AUP1 is reported to interact with apoB100 and modulate its ubiquitination and proteasomal degradation, with downstream effects on VLDL output and LD size. (zhang2017aup1(ancientubiquitous pages 1-2, zamani2016roleofancienta pages 53-57)

3.3 Lipophagy and infection-associated lipid remodeling (context for 2023–2024 developments)

Although much mechanistic AUP1 work predates 2023, recent biomedical literature increasingly frames AUP1 as part of an LD ubiquitination axis relevant to lipophagy and pathogen-driven lipid remodeling (often via the AUP1–UBE2G2 functional relationship). (zhu2024aup1transcriptionallyactivated pages 1-2, wu2024identificationandanalysis pages 1-2)

4) Recent developments (prioritizing 2023–2024)

4.1 2024: AUP1 promotes ERAD/polyubiquitination of renal cotransporters (NKCC2, NCC)

A 2024 primary study in Cells identified AUP1 as a novel interactor of NKCC2 (ER-resident form) and OS9. AUP1 overexpression decreased NKCC2 protein by enhancing ER retention and ERAD; this effect was fully abolished by ERAD inhibitors MG132 (proteasome) or kifunensine (α-mannosidase inhibitor), and AUP1 knockdown/dominant-negative strongly reduced NKCC2 polyubiquitination while increasing NKCC2 levels. AUP1 also downregulated the related cotransporter NCC, suggesting a broader role as a regulator of sodium-dependent chloride cotransporters. (frachon2024aup1regulatesthe pages 1-2)

This work exemplifies how AUP1’s core ERAD function is being extended into clinically relevant membrane-protein proteostasis (e.g., Bartter syndrome context). (frachon2024aup1regulatesthe pages 1-2)

4.2 2023–2024: AUP1 as a disease biomarker in cancer and inflammation-rich microenvironments

A 2023 glioma study integrated TCGA multi-omics and experimental validation, reporting that AUP1 is increased in tumor components and associated with tumor grade and inflammatory microenvironment features. The dataset scale was TCGA n=690 with immunohistochemical validation on 78 clinical cases. Functionally, siRNA-mediated downregulation of AUP1 mainly impacted proliferation rather than measurable lipophagy activity in their U87MG assays. (chang2023ancientubiquitousprotein pages 1-2)

A 2024 cervical cancer study proposed a mechanism in which KDM5B transcriptionally activates AUP1, promoting lipid-metabolism reprogramming and malignant behaviors; AUP1 interference reduced malignant phenotypes and lipid-metabolic measures (e.g., LD staining/neutral lipid metrics), and KDM5B overexpression could counteract AUP1 knockdown effects. (zhu2024aup1transcriptionallyactivated pages 1-2)

A 2024 Viruses paper used multiple GEO datasets (bulk RNA-seq and scRNA-seq) and machine-learning feature selection to nominate AUP1 among seven lipophagy-related biomarkers/targets for COVID-19 and reported 47 lipophagy-related differentially expressed genes (DEGs; 27 down, 20 up) under criteria adj. p < 0.05 and log2FC > 0.5. This constitutes computational association rather than direct AUP1 mechanism in infection. (wu2024identificationandanalysis pages 4-7, wu2024identificationandanalysis pages 1-2)

5) Current applications and real-world implementations

5.1 Experimental/biomedical applications

Proteostasis and ERAD model system: AUP1 is used as a mechanistic handle to study how ERAD E2 enzymes are recruited and stabilized at membranes (e.g., structure/function of the AUP1–UBE2G2 interface; PDB noted in COVID-19 docking work). (smith2021astructurallyconserved pages 15-17, wu2024identificationandanalysis pages 4-7)
Membrane-protein folding disease research: The NKCC2/NCC study demonstrates how perturbing AUP1 modulates ERAD of clinically relevant transporters; inhibitor rescue (MG132, kifunensine) is used to validate pathway assignment. (frachon2024aup1regulatesthe pages 1-2)

5.2 Translational/clinical implications (emerging)

Cancer biomarker potential: Glioma datasets suggest prognostic association and correlation with immune/inflammatory context, but mechanistic causality remains uncertain since lipophagy was not clearly altered by AUP1 knockdown in that study’s functional assays. (chang2023ancientubiquitousprotein pages 1-2)
Host-directed antiviral strategies targeting lipid droplet pathways: Reviews and mechanistic infection studies emphasize LD remodeling and lipophagy dependence for viral life cycles; AUP1 is frequently cited as an LD factor in these contexts, though direct AUP1-targeted therapeutics are not yet established in the evidence retrieved here. (wu2024identificationandanalysis pages 1-2)

6) Expert opinions and analysis (authoritative synthesis)

Multiple primary studies converge on the view that AUP1 is a multi-compartment adaptor/accessory factor operating at ER/LD membranes, chiefly by recruiting and regulating ubiquitination machinery (notably UBE2G2) to enable ERAD and regulated degradation events that intersect lipid metabolism. (klemm2011dualroleof pages 1-2, smith2021astructurallyconserved pages 15-17, jo2013ancientubiquitousprotein1 pages 1-2)

A key expert-level mechanistic refinement from structural studies is that AUP1’s G2BR is not merely a tether: it binds UBE2G2 with high specificity/affinity and tunes E2 activity and stability—features that explain why AUP1 can be rate-limiting in specific ERAD branches and why its perturbation can have pronounced effects on membrane protein fate. (smith2021astructurallyconserved pages 15-17)

7) Relevant statistics and data (recent)

Glioma study cohorts: n=690 (TCGA) and n=78 (IHC clinical validation). (chang2023ancientubiquitousprotein pages 1-2)
COVID-19 bioinformatics: 47 lipophagy-related DEGs (27 down, 20 up) using adj. p < 0.05 and log2FC > 0.5; 7 feature proteins were carried forward to docking analyses. (wu2024identificationandanalysis pages 4-7)
Cervical cancer global burden cited: 604,000 new cases and 342,000 deaths in 2020 (as background epidemiology within the study). (zhu2024aup1transcriptionallyactivated pages 1-2)

Importantly, several 2023–2024 disease-focused papers accessible here provide cohort sizes and thresholds but do not expose key numerical effect sizes (e.g., hazard ratios, exact fold-changes of AUP1, or quantified rescue magnitudes) in the snippets available; where absent, this report does not infer them. (frachon2024aup1regulatesthe pages 1-2, chang2023ancientubiquitousprotein pages 1-2)

8) Consolidated evidence map

The following table summarizes core functional annotation and recent (2023–2024) applied contexts.

Aspect	Key points	Representative evidence (with citation IDs)
Identity	Human AUP1 corresponds to UniProt Q9Y679; also called Ancient ubiquitous protein 1 and described as a lipid droplet-regulating VLDL assembly factor. It is a broadly expressed, conserved ~410 aa protein linked to ER protein quality control and lipid droplet biology.	(klemm2011dualroleof pages 1-2, spandl2011ancientubiquitousprotein pages 3-4, zhang2017aup1(ancientubiquitous pages 1-2)
Domains	Domain architecture includes an N-terminal hydrophobic hairpin/membrane-inserting region, a putative acyltransferase domain containing the conserved HX4D motif, a CUE ubiquitin-binding domain, and a C-terminal G2BR/UBE2G2-binding region.	(klemm2011dualroleof pages 1-1, spandl2011ancientubiquitousprotein pages 3-4, spandl2011ancientubiquitousprotein media 788c5e23)
Localization	AUP1 localizes to both the endoplasmic reticulum (ER) and lipid droplets (LDs). Imaging, flotation, and immuno-EM studies show a major LD pool plus reticular ER staining.	(klemm2011dualroleof pages 1-2, spandl2011ancientubiquitousprotein pages 3-4)
Membrane topology	AUP1 is inserted in a monotopic hairpin topology, with both N- and C-termini facing the cytosol; this topology is important for ER-to-LD targeting. A transmembrane-converted mutant loses LD localization.	(klemm2011dualroleof pages 1-1, spandl2011ancientubiquitousprotein media 788c5e23)
Key interacting partners	Experimentally supported partners include UBE2G2/UBC7, HRD1-SEL1L, p97/VCP, OS9, UBXD8, gp78/AMFR, and Trc8/RNF139. AUP1 also interacts with disease-relevant clients such as apoB100, NKCC2, and NCC in specific contexts.	(klemm2011dualroleof pages 4-5, jo2013ancientubiquitousprotein1 pages 1-2, frachon2024aup1regulatesthe pages 1-2, zamani2016roleofancienta pages 53-57)
Core mechanism: CUE domain	The CUE domain mediates ubiquitin/substrate engagement and promotes interaction with ER quality-control/dislocation machinery. CUE mutations reduce AUP1 association with p97, SEL1L, UBXD8, OS9, UBC6e, and HRD1, and impair substrate-related ubiquitination behavior.	(klemm2011dualroleof pages 4-5, klemm2011dualroleof pages 11-12)
Core mechanism: G2BR domain	The G2BR directly binds UBE2G2, recruits it to ER membranes, stabilizes cellular UBE2G2, and allosterically activates ERAD ubiquitination. Structural work showed a conserved interface and low-nanomolar affinity for UBE2G2 binding.	(smith2021astructurallyconserved pages 1-2, smith2021astructurallyconserved pages 15-17, klemm2011dualroleof pages 11-12)
ERAD role	AUP1 is an ERAD accessory factor in the HRD1-SEL1L complex. It recruits E2 activity, supports ubiquitination of misfolded ER proteins, and is required for efficient degradation of selected ERAD substrates.	(klemm2011dualroleof pages 1-1, klemm2011dualroleof pages 11-12, klemm2011dualroleof pages 3-4)
Lipid droplet role	AUP1 links ubiquitination machinery to LDs and can influence LD abundance, clustering, and protein composition. Monoubiquitinated AUP1 promotes LD clustering, and AUP1 expression affects cellular LD levels.	(klemm2011dualroleof pages 1-2, spandl2011ancientubiquitousprotein pages 3-4, klemm2011dualroleof pages 1-1)
Sterol/cholesterol pathway	In lipid droplet-associated ER membranes, AUP1 promotes sterol-induced ubiquitination/ERAD of HMG-CoA reductase, Insig-1, and SREBP precursors by helping recruit E2 activity to gp78 and Trc8 complexes.	(jo2013ancientubiquitousprotein1 pages 1-2)
ApoB/VLDL pathway	In hepatocytes, AUP1 interacts with apoB100, promotes its ubiquitination/degradation, influences LD size, and thereby regulates VLDL assembly and secretion. Knockdown is associated with more VLDL1-sized apoB100 particles and increased TG in VLDL-sized fractions.	(zhang2017aup1(ancientubiquitous pages 1-2, zamani2016roleofancienta pages 53-57, zamani2016roleofancient pages 53-57)
2023–2024 development: viral lipophagy	Recent work reinforced AUP1’s role in virus-triggered lipophagy, especially with UBE2G2 in flaviviral infection. 2023 work showed UBE2G2 is required for replication organelle biogenesis and virus production in conjunction with AUP1.	(zhu2024aup1transcriptionallyactivated pages 1-2, wu2024identificationandanalysis pages 1-2)
2023–2024 development: renal ERAD	A 2024 Cells study identified AUP1 as a regulator of NKCC2 and NCC ERAD/polyubiquitination in renal cells. AUP1 co-expression lowered NKCC2, while MG132 or kifunensine fully abolished the AUP1 effect.	(frachon2024aup1regulatesthe pages 1-2)
2023–2024 application: glioma biomarker	A 2023 glioma study found AUP1 is a poor-prognosis biomarker associated with tumor grade, TP53 status, tumor mutation burden, proliferation, and inflamed microenvironments. Functional knockdown mainly affected proliferation rather than lipophagy in U87MG cells.	(chang2023ancientubiquitousprotein pages 1-2)
2023–2024 application: cervical cancer	A 2024 study reported that KDM5B transcriptionally activates AUP1, promoting lipid-metabolism reprogramming and malignant progression in cervical cancer; AUP1 knockdown reduced malignant behaviors and lipid metabolic outputs.	(zhu2024aup1transcriptionallyactivated pages 1-2)
2023–2024 application: COVID-19 bioinformatics	AUP1 was identified among seven lipophagy-related biomarker/drug-target candidates in COVID-19 transcriptomic analyses, where lipophagy appeared downregulated and lipid-droplet formation upregulated. This is currently computational rather than direct mechanistic validation for AUP1.	(wu2024identificationandanalysis pages 1-2, wu2024identificationandanalysis pages 4-7)
Quantitative data points	Explicit recent numbers available in accessible sources include: glioma study TCGA n=690 plus IHC n=78; COVID-19 study identified 47 lipophagy-related DEGs (27 down, 20 up) and selected 7 feature proteins; cervical cancer methods used 50 nmol/L reagents in 3×10^5 cells/well and viability assays with 2×10^4 cells/well; cervical cancer burden cited 604,000 new cases and 342,000 deaths in 2020.	(zhu2024aup1transcriptionallyactivated pages 1-2, wu2024identificationandanalysis pages 4-7, chang2023ancientubiquitousprotein pages 1-2)

Table: This table summarizes the verified identity, domains, localization, mechanisms, pathways, and recent 2023–2024 applications of human AUP1 (UniProt Q9Y679). It is useful as a compact evidence map linking classic mechanistic studies with newer disease and biomarker contexts.

9) Key references (URLs and publication dates)

Spandl et al., Journal of Biological Chemistry (Feb 2011): AUP1 localizes to LDs and binds UBE2G2 via G2BR. https://doi.org/10.1074/jbc.M110.190785 (spandl2011ancientubiquitousprotein pages 3-4)
Klemm et al., Journal of Biological Chemistry (Oct 2011): Dual role in LD accumulation and ER protein quality control; HRD1–SEL1L association; CUE/G2BR functions. https://doi.org/10.1074/jbc.M111.284794 (klemm2011dualroleof pages 1-1)
Jo et al., Molecular Biology of the Cell (Feb 2013): AUP1 mediates sterol-induced ubiquitination/ERAD of HMGCR; links to gp78/Trc8. https://doi.org/10.1091/mbc.e12-07-0564 (jo2013ancientubiquitousprotein1 pages 1-2)
Smith et al., PLOS Biology (Dec 2021): Structural/functional definition of AUP1 G2BR–UBE2G2 interaction; low-nM affinity; ERAD requirement. https://doi.org/10.1371/journal.pbio.3001474 (smith2021astructurallyconserved pages 1-2)
Frachon et al., Cells (Feb 2024): AUP1 promotes NKCC2/NCC ERAD and polyubiquitination; inhibitor rescue with MG132/kifunensine. https://doi.org/10.3390/cells13050389 (frachon2024aup1regulatesthe pages 1-2)
Chang et al., Cancer Cell International (Apr 2023): AUP1 as glioma prognostic biomarker; TCGA n=690; IHC n=78. https://doi.org/10.1186/s12935-023-02912-y (chang2023ancientubiquitousprotein pages 1-2)
Zhu et al., International Journal of Oncology (Sep 2024): KDM5B activates AUP1; lipid metabolism reprogramming in cervical cancer. https://doi.org/10.3892/ijo.2024.5695 (zhu2024aup1transcriptionallyactivated pages 1-2)
Wu et al., Viruses (Jun 2024): Bioinformatics identifies AUP1 among lipophagy-related COVID-19 biomarkers; 47 lipophagy DEGs. https://doi.org/10.3390/v16060923 (wu2024identificationandanalysis pages 1-2)

References

(spandl2011ancientubiquitousprotein pages 3-4): Johanna Spandl, Daniel Lohmann, Lars Kuerschner, Christine Moessinger, and Christoph Thiele. Ancient ubiquitous protein 1 (aup1) localizes to lipid droplets and binds the e2 ubiquitin conjugase g2 (ube2g2) via its g2 binding region. Journal of Biological Chemistry, 286:5599-5606, Feb 2011. URL: https://doi.org/10.1074/jbc.m110.190785, doi:10.1074/jbc.m110.190785. This article has 154 citations and is from a domain leading peer-reviewed journal.
(klemm2011dualroleof pages 1-2): Elizabeth J. Klemm, Eric Spooner, and Hidde L. Ploegh. Dual role of ancient ubiquitous protein 1 (aup1) in lipid droplet accumulation and endoplasmic reticulum (er) protein quality control. Journal of Biological Chemistry, 286:37602-37614, Oct 2011. URL: https://doi.org/10.1074/jbc.m111.284794, doi:10.1074/jbc.m111.284794. This article has 161 citations and is from a domain leading peer-reviewed journal.
(zhang2017aup1(ancientubiquitous pages 1-2): Jing Zhang, Mostafa Zamani, Christoph Thiele, Jennifer Taher, Mohsen Amir Alipour, Zemin Yao, and Khosrow Adeli. Aup1 (ancient ubiquitous protein 1) is a key determinant of hepatic very-low–density lipoprotein assembly and secretion. Arteriosclerosis, Thrombosis, and Vascular Biology, 37:633–642, Apr 2017. URL: https://doi.org/10.1161/atvbaha.117.309000, doi:10.1161/atvbaha.117.309000. This article has 24 citations and is from a domain leading peer-reviewed journal.
(klemm2011dualroleof pages 1-1): Elizabeth J. Klemm, Eric Spooner, and Hidde L. Ploegh. Dual role of ancient ubiquitous protein 1 (aup1) in lipid droplet accumulation and endoplasmic reticulum (er) protein quality control. Journal of Biological Chemistry, 286:37602-37614, Oct 2011. URL: https://doi.org/10.1074/jbc.m111.284794, doi:10.1074/jbc.m111.284794. This article has 161 citations and is from a domain leading peer-reviewed journal.
(klemm2011dualroleof pages 11-12): Elizabeth J. Klemm, Eric Spooner, and Hidde L. Ploegh. Dual role of ancient ubiquitous protein 1 (aup1) in lipid droplet accumulation and endoplasmic reticulum (er) protein quality control. Journal of Biological Chemistry, 286:37602-37614, Oct 2011. URL: https://doi.org/10.1074/jbc.m111.284794, doi:10.1074/jbc.m111.284794. This article has 161 citations and is from a domain leading peer-reviewed journal.
(klemm2011dualroleof pages 4-5): Elizabeth J. Klemm, Eric Spooner, and Hidde L. Ploegh. Dual role of ancient ubiquitous protein 1 (aup1) in lipid droplet accumulation and endoplasmic reticulum (er) protein quality control. Journal of Biological Chemistry, 286:37602-37614, Oct 2011. URL: https://doi.org/10.1074/jbc.m111.284794, doi:10.1074/jbc.m111.284794. This article has 161 citations and is from a domain leading peer-reviewed journal.
(smith2021astructurallyconserved pages 1-2): Christopher E Smith, Y. Tsai, Yu-He Liang, Domarin Khago, J. Mariano, ID JessLi, S. Tarasov, ID EmmaGergel, B. Tsai, ID MatthewVillaneuva, Michelle E. Clapp, ID ValentinMagidson, R. Chari, ID RAndrewByrd, ID XinhuaJi, ID AllanM.Weissman, and Raquel L. Lieberman. A structurally conserved site in aup1 binds the e2 enzyme ube2g2 and is essential for er-associated degradation. Dec 2021. URL: https://doi.org/10.1371/journal.pbio.3001474, doi:10.1371/journal.pbio.3001474. This article has 23 citations and is from a highest quality peer-reviewed journal.
(spandl2011ancientubiquitousprotein media 788c5e23): Johanna Spandl, Daniel Lohmann, Lars Kuerschner, Christine Moessinger, and Christoph Thiele. Ancient ubiquitous protein 1 (aup1) localizes to lipid droplets and binds the e2 ubiquitin conjugase g2 (ube2g2) via its g2 binding region. Journal of Biological Chemistry, 286:5599-5606, Feb 2011. URL: https://doi.org/10.1074/jbc.m110.190785, doi:10.1074/jbc.m110.190785. This article has 154 citations and is from a domain leading peer-reviewed journal.
(spandl2011ancientubiquitousprotein media ebcd1b79): Johanna Spandl, Daniel Lohmann, Lars Kuerschner, Christine Moessinger, and Christoph Thiele. Ancient ubiquitous protein 1 (aup1) localizes to lipid droplets and binds the e2 ubiquitin conjugase g2 (ube2g2) via its g2 binding region. Journal of Biological Chemistry, 286:5599-5606, Feb 2011. URL: https://doi.org/10.1074/jbc.m110.190785, doi:10.1074/jbc.m110.190785. This article has 154 citations and is from a domain leading peer-reviewed journal.
(smith2021astructurallyconserved pages 15-17): Christopher E Smith, Y. Tsai, Yu-He Liang, Domarin Khago, J. Mariano, ID JessLi, S. Tarasov, ID EmmaGergel, B. Tsai, ID MatthewVillaneuva, Michelle E. Clapp, ID ValentinMagidson, R. Chari, ID RAndrewByrd, ID XinhuaJi, ID AllanM.Weissman, and Raquel L. Lieberman. A structurally conserved site in aup1 binds the e2 enzyme ube2g2 and is essential for er-associated degradation. Dec 2021. URL: https://doi.org/10.1371/journal.pbio.3001474, doi:10.1371/journal.pbio.3001474. This article has 23 citations and is from a highest quality peer-reviewed journal.
(jo2013ancientubiquitousprotein1 pages 1-2): Youngah Jo, Isamu Z. Hartman, and Russell A. DeBose-Boyd. Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl coa reductase in lipid droplet–associated endoplasmic reticulum membranes. Molecular Biology of the Cell, 24:169-183, Feb 2013. URL: https://doi.org/10.1091/mbc.e12-07-0564, doi:10.1091/mbc.e12-07-0564. This article has 105 citations and is from a domain leading peer-reviewed journal.
(zamani2016roleofancienta pages 53-57): M Zamani. Role of ancient ubiquitous protein 1 in hepatic apob degradation and vldl production. Unknown journal, 2016.
(zhu2024aup1transcriptionallyactivated pages 1-2): Yingping Zhu, Wenjuan Yang, Xinyan Wang, and Mengmeng Chen. Aup1 transcriptionally activated by kdm5b reprograms lipid metabolism to promote the malignant progression of cervical cancer. International Journal of Oncology, Sep 2024. URL: https://doi.org/10.3892/ijo.2024.5695, doi:10.3892/ijo.2024.5695. This article has 6 citations and is from a peer-reviewed journal.
(wu2024identificationandanalysis pages 1-2): Yujia Wu, Zhenlin Wu, Qiying Jin, Jinyuan Liu, and Peiping Xu. Identification and analysis of biomarkers associated with lipophagy and therapeutic agents for covid-19. Viruses, 16:923, Jun 2024. URL: https://doi.org/10.3390/v16060923, doi:10.3390/v16060923. This article has 6 citations.
(frachon2024aup1regulatesthe pages 1-2): Nadia Frachon, Sylvie Demaretz, Elie Seaayfan, Lydia Chelbi, Dalal Bakhos-Douaihy, and Kamel Laghmani. Aup1 regulates the endoplasmic reticulum-associated degradation and polyubiquitination of nkcc2. Cells, 13:389, Feb 2024. URL: https://doi.org/10.3390/cells13050389, doi:10.3390/cells13050389. This article has 7 citations.
(chang2023ancientubiquitousprotein pages 1-2): Pei-Chi Chang, Yu-Chieh Lin, Hui-Ju Yen, Dueng-Yuan Hueng, Shih-Ming Huang, and Yao-Feng Li. Ancient ubiquitous protein 1 (aup1) is a prognostic biomarker connected with tp53 mutation and the inflamed microenvironments in glioma. Cancer Cell International, Apr 2023. URL: https://doi.org/10.1186/s12935-023-02912-y, doi:10.1186/s12935-023-02912-y. This article has 15 citations and is from a peer-reviewed journal.
(wu2024identificationandanalysis pages 4-7): Yujia Wu, Zhenlin Wu, Qiying Jin, Jinyuan Liu, and Peiping Xu. Identification and analysis of biomarkers associated with lipophagy and therapeutic agents for covid-19. Viruses, 16:923, Jun 2024. URL: https://doi.org/10.3390/v16060923, doi:10.3390/v16060923. This article has 6 citations.
(klemm2011dualroleof pages 3-4): Elizabeth J. Klemm, Eric Spooner, and Hidde L. Ploegh. Dual role of ancient ubiquitous protein 1 (aup1) in lipid droplet accumulation and endoplasmic reticulum (er) protein quality control. Journal of Biological Chemistry, 286:37602-37614, Oct 2011. URL: https://doi.org/10.1074/jbc.m111.284794, doi:10.1074/jbc.m111.284794. This article has 161 citations and is from a domain leading peer-reviewed journal.
(zamani2016roleofancient pages 53-57): M Zamani. Role of ancient ubiquitous protein 1 in hepatic apob degradation and vldl production. Unknown journal, 2016.

Artifacts

Edison artifact artifact-00

Citations

spandl2011ancientubiquitousprotein pages 3-4
klemm2011dualroleof pages 1-1
chang2023ancientubiquitousprotein pages 1-2
wu2024identificationandanalysis pages 1-2
smith2021astructurallyconserved pages 15-17
wu2024identificationandanalysis pages 4-7
smith2021astructurallyconserved pages 1-2
klemm2011dualroleof pages 1-2
klemm2011dualroleof pages 11-12
klemm2011dualroleof pages 4-5
zamani2016roleofancienta pages 53-57
klemm2011dualroleof pages 3-4
zamani2016roleofancient pages 53-57
https://doi.org/10.1074/jbc.M110.190785
https://doi.org/10.1074/jbc.M111.284794
https://doi.org/10.1091/mbc.e12-07-0564
https://doi.org/10.1371/journal.pbio.3001474
https://doi.org/10.3390/cells13050389
https://doi.org/10.1186/s12935-023-02912-y
https://doi.org/10.3892/ijo.2024.5695
https://doi.org/10.3390/v16060923
https://doi.org/10.1074/jbc.m110.190785,
https://doi.org/10.1074/jbc.m111.284794,
https://doi.org/10.1161/atvbaha.117.309000,
https://doi.org/10.1371/journal.pbio.3001474,
https://doi.org/10.1091/mbc.e12-07-0564,
https://doi.org/10.3892/ijo.2024.5695,
https://doi.org/10.3390/v16060923,
https://doi.org/10.3390/cells13050389,
https://doi.org/10.1186/s12935-023-02912-y,

📚 Additional Documentation

Notes

(AUP1-notes.md)

AUP1 (Ancient Ubiquitous Protein 1) — research notes

UniProt: Q9Y679 (AUP1_HUMAN), 410 aa. RecName now "Lipid droplet-regulating VLDL assembly factor AUP1".
HGNC:891. Chromosome 2.

Domain architecture / topology

Monotopic (hairpin) membrane protein. N-terminal hydrophobic region (~21-41) inserts as a hairpin so that BOTH termini face the cytosol. Dual-localizes to ER membrane and lipid droplet (LD) surface monolayer.
PMID:21127063
PMID:23197321
A single N-terminal domain enables ER residence, monotopic insertion, and LD localization; a topology-changing mutation (PVG->LLL at 33-35) abolishes LD localization.
PMID:23197321
CUE domain (296-338): ubiquitin-binding (UBA-like). Required for interaction with ERAD machinery and misfolded substrates, ubiquitination, LD clustering, and AMFR binding; NOT required for LD localization.
[file:human/AUP1/AUP1-uniprot.txt "The CUE domain is required for interaction with the ER quality control machinery and misfolded substrates, ubiquitination, lipid clustering and interaction with AMFR but is not required for localization to lipid droplets."]
C-terminal G2BR (G2 binding region, ~379-410): binds and recruits the E2 conjugase UBE2G2. Distinct from CUE.
PMID:21127063

Core molecular/cellular function: ERAD E2 adaptor

AUP1 is a component of the mammalian HRD1-SEL1L ER quality control (ERAD) complex; depletion impairs degradation of misfolded ER proteins. Recruits the soluble E2 UBE2G2.
PMID:21857022
Identified in the SEL1L-nucleated complex (SEL1L, AUP1, UBXD8/FAF2, UBC6e/UBE2J1, OS9) required for dislocation of misfolded glycoproteins.
PMID:18711132
CUE domain facilitates AUP1's interaction with the HRD1 complex and with dislocation substrates and regulates polyubiquitylation.
PMID:21857022
Required for ERAD dislocation of NHK (null Hong Kong alpha-1-antitrypsin), confirming a role in retrograde ER-to-cytosol transport. PMID:25660456

HMGCR / sterol-regulated ERAD on LD-associated ER membranes

AUP1 recruits UBE2G2 (Ubc7) to lipid droplets and facilitates its binding to the E3s gp78/AMFR and Trc8/RNF139, driving sterol-induced ubiquitination of HMGCR and its ERAD. Also required for ERAD of INSIG1, SREBF1, SREBF2.
PMID:23223569
PMID:23223569
UBE2G2 interaction maps to the C-terminal G2BR (mutagenesis of L386, K390, L393, R400, R404 abolishes interaction). [file:human/AUP1/AUP1-uniprot.txt]

Lipid droplet biology

AUP1 expression level affects abundance of cellular LDs; first LD-regulatory protein linked to ER quality control.
PMID:21857022
Monoubiquitinated AUP1 (CUE-dependent) on the LD surface induces LD clustering; likely homophilic/heterophilic ubiquitin-mediated interaction.
PMID:24039768
PMID:24039768
Hepatic VLDL assembly/secretion and APOB stability: AUP1 is a key determinant; interacts with APOB. PMID:28183703

Other / contextual

Integrin alpha cytoplasmic-tail binding (yeast two-hybrid; low affinity Kd ~90 uM), proposed inside-out signaling in platelets. Reported as cytoplasmic in that early study (before LD/ER role established). Contextual, not core.
PMID:12042322
Dengue/flavivirus (microbial infection): DENV NS4A binds AUP1, relocates it from LDs to autophagosomes, triggers lipophagy to drive virus production. Host-virus, non-core for normal physiology.
[file:human/AUP1/AUP1-uniprot.txt "Following Dengue virus infection, required for induction of lipophagy which facilitates production of virus progeny particles."]
[file:human/AUP1/AUP1-uniprot.txt "Upon Dengue virus infection, relocates from lipid droplets to autophagosomes."]
Extracellular exosome / generic membrane: high-throughput proteomics localizations (HDA). Non-core.

Assessment summary (core vs non-core)

CORE: ER membrane location; LD location; ERAD pathway; ubiquitin-conjugating enzyme binding (UBE2G2 recruitment); ubiquitin protein ligase binding (gp78/AMFR, Trc8); ubiquitin binding (CUE); lipid droplet organization/formation; protein localization to LD; retrograde ER-to-cytosol transport.
NON-CORE / contextual: autophagosome + lipophagy + response to virus (DENV-specific); VLDL/APOB (tissue-specific hepatic); integrin binding (early, low-affinity).
OVER-ANNOTATED / uninformative: protein binding (GO:0005515) generic IPI; extracellular exosome; generic membrane.

protein binding IPI references

PMID:22119785 (ERAD network mapping), PMID:23840749 (MOR interactome Y2H), PMID:32296183 (binary interactome), PMID:29902443 (DENV NS4A). The 29902443 protein-binding maps to the specific NS4A interaction (host-virus); others are generic.

Falcon deep research findings (2026-06-07)

Source: AUP1-deep-research-falcon.md (Edison/Falcon). PMIDs resolved via PubMed by DOI; exact titles verified.

CONFIRMS (no change needed): Falcon reproduces the established core picture — ER/LD dual monotopic localization, CUE (ubiquitin-binding) and C-terminal G2BR (UBE2G2-binding) domains, HRD1-SEL1L ERAD adaptor role, recruitment/bridging of UBE2G2 to gp78/AMFR and Trc8/RNF139, sterol-regulated HMGCR/INSIG1/SREBF ERAD, LD clustering via monoubiquitinated AUP1, and hepatic apoB/VLDL role. All already captured in the review.
NEW (primary, mechanistic): Smith et al. 2021 PLoS Biology [PMID:34879065 "A structurally conserved site in AUP1 binds the E2 enzyme UBE2G2 and is essential for ER-associated degradation"; DOI 10.1371/journal.pbio.3001474]. Structure of the 27-aa G2BR–UBE2G2 complex: binds the E2 "backside" with low-nanomolar affinity, is required to maintain cellular UBE2G2 levels (prevents its rapid degradation), recruits UBE2G2 to the ER membrane, and allosterically activates ubiquitination with ERAD E3s — structurally analogous to the gp78 G2BR. This strengthens the existing GO:0031624 (ubiquitin conjugating enzyme binding) annotation with high-resolution structural evidence. Not previously in references.
NEW (primary, substrate scope): Frachon et al. 2024 Cells [PMID:38474353 "AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2"; DOI 10.3390/cells13050389]. AUP1 is a novel interactor of ER-resident NKCC2 (SLC12A1) and of OS9; AUP1 co-expression enhances NKCC2 ER retention and ERAD, fully abolished by MG132 or kifunensine; AUP1 knockdown/dominant-negative reduces NKCC2 polyubiquitination and raises NKCC2 levels. AUP1 also downregulates the related cotransporter NCC (SLC12A3), suggesting a broader role as a regulator of Na-dependent Cl- cotransporters. Disease link: antenatal Bartter syndrome type 1. This extends the core ERAD adaptor function to specific physiological membrane-protein clients; consistent with existing GO:0036503 (ERAD pathway) annotation rather than warranting a new term.
PROVISIONAL / low-confidence (notes only, NOT used to change annotations): Several 2023-2024 disease-association papers — glioma prognostic biomarker (Chang 2023, Cancer Cell Int, DOI 10.1186/s12935-023-02912-y), KDM5B-driven AUP1 activation in cervical cancer lipid reprogramming (Zhu 2024, Int J Oncol, DOI 10.3892/ijo.2024.5695), and COVID-19 lipophagy-biomarker bioinformatics (Wu 2024, Viruses, DOI 10.3390/v16060923). These are largely correlative/computational (TCGA cohorts, ML feature selection, IHC) and do not establish new conserved molecular functions; in the glioma study AUP1 knockdown mainly affected proliferation, not lipophagy. Not added to annotations.
Zamani 2016 (thesis, "Role of ancient ubiquitous protein 1 in hepatic apoB degradation and VLDL production") is grey literature (no PMID resolved); the same hepatic apoB/VLDL conclusions are already covered by the peer-reviewed Zhang/Adeli 2017 paper PMID:28183703. Kept in notes only.

Pn Notes

(AUP1-pn-notes.md)

AUP1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9Y679
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/AUP1/AUP1-ai-review.yaml
AIGR review HTML: present - genes/human/AUP1/AUP1-ai-review.html
Gene notes: present - genes/human/AUP1/AUP1-notes.md
GOA TSV: present - genes/human/AUP1/AUP1-goa.tsv
UniProt record: present - genes/human/AUP1/AUP1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/AUP1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/AUP1.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/AUP1/AUP1-deep-research-falcon.md

AIGR Review Snapshot

Description: AUP1 (Ancient Ubiquitous Protein 1) is a conserved, ubiquitously expressed monotopic membrane protein that resides on the cytosolic face of the endoplasmic reticulum membrane and on the lipid droplet surface monolayer, inserting via an N-terminal hydrophobic hairpin so that both termini face the cytosol. Its principal molecular role is to act as an adaptor that recruits the soluble E2 ubiquitin-conjugating enzyme UBE2G2 (via a C-terminal G2 binding region) to ER-associated degradation (ERAD) ubiquitin ligase machinery, including the HRD1-SEL1L complex and the lipid-droplet/ER E3 ligases gp78/AMFR and TRC8/RNF139. Through this activity AUP1 couples substrate ubiquitination to dislocation and proteasomal degradation of misfolded ER proteins, and drives sterol-regulated ubiquitination and ERAD of HMGCR, INSIG1, SREBF1 and SREBF2. AUP1 also has lipid-droplet-regulatory functions: it binds ubiquitin through an internal CUE domain, is itself monoubiquitinated in a CUE-dependent manner to promote lipid droplet clustering, and its level controls lipid droplet abundance. Additional reported roles include hepatic VLDL/apolipoprotein B assembly and secretion. AUP1 is exploited by flaviviruses, whose NS4A protein relocalizes it to autophagosomes to trigger lipophagy.
Existing/core annotation action counts: ACCEPT: 30; KEEP_AS_NON_CORE: 5; MARK_AS_OVER_ANNOTATED: 6

PN Consistency Summary

Consistency: Strong agreement across all sources. Deep research (falcon), review YAML, and PN annotations all converge on AUP1 as an ER/lipid-droplet monotopic membrane adaptor that recruits the E2 UBE2G2 (via G2BR) and binds ubiquitin (CUE) to drive ERAD, with secondary LD-clustering and (virus-induced) lipophagy roles. No contradictions. The three PN branch rows (ER/ALP/UPS) each map to a function the review independently accepts as core (ERAD, ubiquitin binding/E2 recruitment) or non-core (lipophagy).
PN story / NEW pressure: No NEW GO pressure. All three projected terms are already captured. GO:0036503 ERAD pathway and GO:0061724 lipophagy are present in GOA and ACCEPT/KEEP_AS_NON_CORE in the review (lipophagy correctly flagged virus-context, non-core). GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway (verified real) is NOT in GOA and is more specific; the review does not list it but its parent GO:0036503 is accepted. Review's proposed_new_terms is empty — appropriate.
Evidence alignment: PN row 2 cites Spandl 2011 (PMID:21127063), which is in the review (G2BR/Ube2g2 binding). PN otherwise cites few papers; the review is far richer (Klemm 2011 PMID:21857022, Jo 2013 PMID:23223569, Smith 2021 PMID:34879065, Frachon 2024 PMID:38474353, flavivirus PMID:29902443). No divergence — review is a strict superset.
Verdict: Consistent and well-curated; no NEW term, no mapping change. Optional: GO:0097466 could be added to the review as a more-specific ERAD term but is not required.

Full Consistency Review

UniProt: Q9Y679 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (thorough; 40 annotations reviewed)
PN placement: ER proteostasis|...|ER associated degradation|Retrotranslocation channel complex; ALP|...|Lipophagy|Ubiquitination of lipid droplet surface proteins; UPS|Ubiquitin and UBL binding|protein quality control|ERAD cofactor|CUE. PN-node mappings: ERAD group=mapped/exact GO:0036503; Lipophagy type=mapped/propagation GO:0061724; ERAD-cofactor type=mapped/propagation GO:0097466; broader ancestors=no_mapping or context_only.
Consistency: Strong agreement across all sources. Deep research (falcon), review YAML, and PN annotations all converge on AUP1 as an ER/lipid-droplet monotopic membrane adaptor that recruits the E2 UBE2G2 (via G2BR) and binds ubiquitin (CUE) to drive ERAD, with secondary LD-clustering and (virus-induced) lipophagy roles. No contradictions. The three PN branch rows (ER/ALP/UPS) each map to a function the review independently accepts as core (ERAD, ubiquitin binding/E2 recruitment) or non-core (lipophagy).
PN story / NEW pressure: No NEW GO pressure. All three projected terms are already captured. GO:0036503 ERAD pathway and GO:0061724 lipophagy are present in GOA and ACCEPT/KEEP_AS_NON_CORE in the review (lipophagy correctly flagged virus-context, non-core). GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway (verified real) is NOT in GOA and is more specific; the review does not list it but its parent GO:0036503 is accepted. Review's proposed_new_terms is empty — appropriate.
Mapping strategy: No change warranted. ERAD group=mapped/exact is well justified (AUP1 is a bona fide ERAD factor). The two propagation-scope mappings (lipophagy, glycoprotein-ERAD) are defensible at gene level for AUP1; the no_mapping/context_only calls on broad UPS/ALP ancestors are consistent with the TOMM20/HSPA8 "too broad" precedent.
Evidence alignment: PN row 2 cites Spandl 2011 (PMID:21127063), which is in the review (G2BR/Ube2g2 binding). PN otherwise cites few papers; the review is far richer (Klemm 2011 PMID:21857022, Jo 2013 PMID:23223569, Smith 2021 PMID:34879065, Frachon 2024 PMID:38474353, flavivirus PMID:29902443). No divergence — review is a strict superset.
Verdict: Consistent and well-curated; no NEW term, no mapping change. Optional: GO:0097466 could be added to the review as a more-specific ERAD term but is not required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/AUP1/AUP1-ai-review.yaml
PN workbook rows: 3

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | Retrotranslocation channel complex

UniProt: Q9Y679
In branches: ER, ALP, UPS
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|Retrotranslocation channel complex
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower taxonomy bucket already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
- [group] ER proteostasis|Organelle-specific protein degradation|ER associated degradation
  status=mapped scope=exact GO=[GO:0036503 ERAD pathway]
  rationale: The PN group "ER associated degradation" is a direct lexical and biological match to the GO ERAD pathway term. The additional branch and class context disambiguates the source string from any broader degradation language.
- [class] ER proteostasis|Organelle-specific protein degradation
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | Lipophagy | Ubiquitination of lipid droplet surface proteins

UniProt: Q9Y679
In branches: ER, ALP, UPS
Notes: Recruits E2-ligase UBE2G2 to lipid droplets to ubiquitinate surface proteins for lipophagy
PN references (titles):
- Ancient Ubiquitous Protein 1 (AUP1) Localizes to Lipid Droplets and Binds the E2 Ubiquitin Conjugase G2 (Ube2g2) via Its G2 Binding Region* ♦ - Journal of Biological Chemistry (jbc.org)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Lipophagy|Ubiquitination of lipid droplet surface proteins
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Lipophagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061724 lipophagy]
  rationale: This PN type denotes factors that mark lipid cargo for selective autophagy. The category is narrower than the full lipophagy process, so propagation scope is the correct fit.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | protein quality control | ERAD cofactor | CUE

UniProt: Q9Y679
In branches: ER, ALP, UPS
Signature domains: IPR003892
Auxiliary domains: (none)
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control|ERAD cofactor|CUE
  status=no_mapping scope= GO=[]
  rationale: Reviewed manually as a UPS source node. No single GO term is appropriate for direct propagation from this PN label without narrower context or gene-level evidence.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control|ERAD cofactor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway]
  rationale: This PN type groups ubiquitin/UBL-binding factors that act as ERAD cofactors in protein-quality-control contexts. The best available GO target in the local cache is ubiquitin-dependent glycoprotein ERAD pathway, used here at propagation scope.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control
  status=context_only scope=too_broad_to_propagate GO=[GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process]
  rationale: This PN group is a protein-quality-control context bucket, but its descendants include ERAD cofactors, HSP70 cochaperone context, stalled-chain recognition, and other mixed roles. Direct propagation should come from narrower nodes such as ERAD cofactor.
- [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 (3)

GO:0036503 ERAD pathway | scope=exact | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation
GO:0061724 lipophagy | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Lipophagy
GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control|ERAD cofactor

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: Q9Y679
gene_symbol: AUP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'AUP1 (Ancient Ubiquitous Protein 1) is a conserved, ubiquitously expressed
  monotopic membrane protein that resides on the cytosolic face of the endoplasmic
  reticulum membrane and on the lipid droplet surface monolayer, inserting via an N-terminal
  hydrophobic hairpin so that both termini face the cytosol. Its principal molecular
  role is to act as an adaptor that recruits the soluble E2 ubiquitin-conjugating enzyme
  UBE2G2 (via a C-terminal G2 binding region) to ER-associated degradation (ERAD) ubiquitin
  ligase machinery, including the HRD1-SEL1L complex and the lipid-droplet/ER E3 ligases
  gp78/AMFR and TRC8/RNF139. Through this activity AUP1 couples substrate ubiquitination
  to dislocation and proteasomal degradation of misfolded ER proteins, and drives sterol-regulated
  ubiquitination and ERAD of HMGCR, INSIG1, SREBF1 and SREBF2. AUP1 also has lipid-droplet-regulatory
  functions: it binds ubiquitin through an internal CUE domain, is itself monoubiquitinated
  in a CUE-dependent manner to promote lipid droplet clustering, and its level controls
  lipid droplet abundance. Additional reported roles include hepatic VLDL/apolipoprotein
  B assembly and secretion. AUP1 is exploited by flaviviruses, whose NS4A protein relocalizes
  it to autophagosomes to trigger lipophagy.'
alternative_products:
- name: '1'
  id: Q9Y679-2
- name: '2'
  id: Q9Y679-3
  sequence_note: VSP_059683, VSP_059684
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ER membrane is the principal compartment where AUP1 acts as an ERAD E2
      adaptor; well supported by orthology and direct experiments.
    action: ACCEPT
    reason: AUP1 is a monotopic ER membrane protein with both termini in the cytosol,
      where it recruits UBE2G2 to the HRD1-SEL1L/gp78 ERAD machinery. This is a core
      localization.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: AUP1 is inserted into the membrane of the ER in a monotopic
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ERAD participation is the core biological process of AUP1, supported by
      direct loss-of-function evidence and orthology.
    action: ACCEPT
    reason: AUP1 associates with the HRD1-SEL1L complex and recruits UBE2G2; depletion
      impairs degradation of misfolded ER proteins.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Autophagosome localization is only seen upon Dengue/flavivirus infection,
      when NS4A relocalizes AUP1 from lipid droplets to autophagosomes; it is not a
      constitutive localization of the normal protein.
    action: KEEP_AS_NON_CORE
    reason: This is a context-dependent (virus-induced) localization rather than the
      core ER/lipid-droplet residence of AUP1.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: virus infection, relocates from lipid droplets to autophagosomes.
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane is the principal site of AUP1 ERAD activity; well supported.
    action: ACCEPT
    reason: AUP1 is a monotopic ER membrane protein where it recruits UBE2G2 to the
      ERAD machinery.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: AUP1 is inserted into the membrane of the ER in a monotopic
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Lipid droplet surface localization is a core, directly demonstrated localization
      for AUP1.
    action: ACCEPT
    reason: AUP1 integrates into the LD surface monolayer in a monotopic fashion with
      both termini in the cytosol.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: integrates into the LD surface in a monotopic fashion with both
        termini facing
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ERAD participation is the core biological process of AUP1.
    action: ACCEPT
    reason: AUP1 associates with the HRD1-SEL1L complex and recruits UBE2G2; depletion
      impairs degradation of misfolded ER proteins.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: AUP1 binds ubiquitin through its internal CUE domain, a known ubiquitin-binding
      domain; this is a core molecular function underlying its ERAD and LD-clustering
      roles.
    action: ACCEPT
    reason: The CUE domain is directly demonstrated as a ubiquitin-binding domain required
      for ubiquitination and LD clustering.
    supported_by:
    - reference_id: PMID:24039768
      supporting_text: its internal CUE domain, which is a known ubiquitin-binding
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale ERAD interaction
      map; uninformative as a molecular function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not convey AUP1's specific adaptor function;
      more informative terms (ubiquitin conjugating enzyme binding) are captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23840749
  qualifier: enables
  review:
    summary: Generic protein binding from a mu-opioid receptor membrane yeast two-hybrid
      interactome; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput screen does not identify a
      physiologically interpretable AUP1 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding from a binary interactome reference map; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is too general to represent AUP1 function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:12042322
  qualifier: located_in
  review:
    summary: Early experimental support for AUP1 ER/membrane association; consistent
      with the well-established core ER membrane localization.
    action: ACCEPT
    reason: ER membrane is a core localization for AUP1 ERAD activity.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:18711132
  qualifier: located_in
  review:
    summary: AUP1 is part of the SEL1L-nucleated ER membrane ERAD complex; supports
      core ER membrane localization.
    action: ACCEPT
    reason: AUP1 was identified as a functionally important component of the SEL1L-nucleated
      ER dislocation complex.
    supported_by:
    - reference_id: PMID:18711132
      supporting_text: We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important
        components of this degradation complex in mammalian cells
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:21857022
  qualifier: located_in
  review:
    summary: Direct evidence places AUP1 at the ER membrane within the HRD1-SEL1L complex.
    action: ACCEPT
    reason: ER membrane is the core compartment for AUP1 ERAD function.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: EXP
  original_reference_id: PMID:28183703
  qualifier: located_in
  review:
    summary: AUP1 is demonstrated at the lipid droplet surface in hepatic VLDL studies;
      core localization.
    action: ACCEPT
    reason: LD surface localization is a directly demonstrated core localization of
      AUP1.
    supported_by:
    - reference_id: PMID:28183703
      supporting_text: also localizes to the surface of lipid
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9921605
  qualifier: located_in
  review:
    summary: Reactome traceable assertion of ER membrane localization is consistent
      with the established core localization.
    action: ACCEPT
    reason: ER membrane localization is well supported by direct experimental evidence.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29902443
  qualifier: enables
  review:
    summary: The underlying interaction is the specific AUP1-Dengue NS4A association,
      but the GO term used is generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; the meaningful (virus-specific)
      interaction is with NS4A and is not a core physiological function.
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IDA
  original_reference_id: PMID:29902443
  qualifier: located_in
  review:
    summary: Autophagosome localization is observed only after Dengue virus infection,
      when NS4A relocalizes AUP1 from LDs.
    action: KEEP_AS_NON_CORE
    reason: A virus-induced relocalization, not the constitutive site of AUP1 action.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: relocalized
        from lipid droplets to autophagosomes upon infection
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:29902443
  qualifier: located_in
  review:
    summary: AUP1 is directly observed as a lipid droplet-localized membrane protein;
      core localization.
    action: ACCEPT
    reason: LD surface residence is the well-established core localization of AUP1.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: AUP1, a lipid droplet-localized type-III membrane
        protein
      reference_section_type: ABSTRACT
- term:
    id: GO:0009615
    label: response to virus
  evidence_type: IMP
  original_reference_id: PMID:29902443
  qualifier: involved_in
  review:
    summary: AUP1 is exploited by flaviviruses to drive virus production; this is a
      host factor role hijacked by the virus rather than an antiviral/defense function
      of AUP1.
    action: KEEP_AS_NON_CORE
    reason: The phenotype is virus production dependent on AUP1, a context-specific
      host-pathogen role, not a core conserved physiological function.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: Virus production was
        abolished in cells deleted for AUP1
      reference_section_type: ABSTRACT
- term:
    id: GO:0061724
    label: lipophagy
  evidence_type: IMP
  original_reference_id: PMID:29902443
  qualifier: involved_in
  review:
    summary: AUP1 is required for Dengue-induced lipophagy; demonstrated only in the
      virus-infection context.
    action: KEEP_AS_NON_CORE
    reason: Lipophagy induction is a virus-triggered process exploiting AUP1's acyltransferase
      activity, not a core constitutive function.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: exploits the acyltransferase
        activity of AUP1 to trigger lipophagy
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:23223569
  qualifier: located_in
  review:
    summary: AUP1 acts at lipid droplet-associated ER membranes; core localization.
    action: ACCEPT
    reason: AUP1 functions in sterol-regulated HMGCR ubiquitination at LD-associated
      ER membranes.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: lipid droplet-associated ER membranes
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:23223569
  qualifier: located_in
  review:
    summary: AUP1 is a lipid droplet-associated protein recruiting Ubc7/UBE2G2 there;
      core localization.
    action: ACCEPT
    reason: LD localization is directly demonstrated and required for AUP1's sterol-regulated
      ERAD role.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
      reference_section_type: ABSTRACT
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:23223569
  qualifier: enables
  review:
    summary: AUP1 binds and recruits the E2 ubiquitin-conjugating enzyme Ubc7/UBE2G2;
      this is a core molecular function.
    action: ACCEPT
    reason: AUP1 recruits Ubc7 (UBE2G2) to lipid droplets and facilitates its binding
      to gp78 and Trc8, central to its adaptor role.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
      reference_section_type: ABSTRACT
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:23223569
  qualifier: enables
  review:
    summary: AUP1 binds the E3 ubiquitin ligases gp78/AMFR and Trc8/RNF139, bridging
      them to the E2; core molecular function.
    action: ACCEPT
    reason: AUP1 facilitates binding of Ubc7 to both gp78 and Trc8, directly demonstrating
      ligase association.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: facilitates its binding to both gp78 and Trc8
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:23223569
  qualifier: involved_in
  review:
    summary: AUP1 is required for sterol-regulated ERAD of HMGCR, INSIG1, and SREBF1/2;
      core process.
    action: ACCEPT
    reason: AUP1 knockdown blunts sterol-accelerated ubiquitination and ERAD of HMGCR
      and other sterol-pathway substrates.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: RNAi-mediated knockdown of Aup1 blunts sterol-accelerated ubiquitination
      reference_section_type: ABSTRACT
- term:
    id: GO:1990044
    label: protein localization to lipid droplet
  evidence_type: IMP
  original_reference_id: PMID:23223569
  qualifier: involved_in
  review:
    summary: AUP1 recruits/localizes the E2 Ubc7 to lipid droplets, supporting a role
      in protein localization to the LD.
    action: ACCEPT
    reason: AUP1 recruits Ubc7 to lipid droplets, a directly demonstrated protein-targeting
      function at the LD.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
      reference_section_type: ABSTRACT
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:21857022
  qualifier: located_in
  review:
    summary: ER localization (parent of ER membrane) consistent with core ER membrane
      residence.
    action: ACCEPT
    reason: AUP1 is an ER protein within the HRD1-SEL1L complex; the more specific
      ER membrane term is preferred but this is correct.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:21127063
  qualifier: located_in
  review:
    summary: Direct evidence of AUP1 at the ER membrane; core localization.
    action: ACCEPT
    reason: ER membrane residence is a core localization for AUP1.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:23197321
  qualifier: located_in
  review:
    summary: AUP1 inserts into the ER membrane in monotopic hairpin fashion; core localization.
    action: ACCEPT
    reason: Directly demonstrated monotopic ER membrane insertion.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: AUP1 is inserted into the membrane of the ER in a monotopic
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21857022
  qualifier: located_in
  review:
    summary: AUP1 localizes to lipid droplets and its level controls LD abundance;
      core localization.
    action: ACCEPT
    reason: LD localization is directly demonstrated and central to AUP1's LD-regulatory
      function.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: ancient ubiquitous protein 1 (AUP1) localizes to LDs
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:23197321
  qualifier: located_in
  review:
    summary: AUP1 is transported to the LD hemi-membrane in monotopic fashion; core
      localization.
    action: ACCEPT
    reason: Monotopic topology is directly shown to be required for LD targeting.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: subsequently transported to the hemi-membrane of LDs
      reference_section_type: ABSTRACT
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:21857022
  qualifier: enables
  review:
    summary: AUP1 recruits the soluble E2 UBE2G2 in ER quality control; core molecular
      function.
    action: ACCEPT
    reason: One of AUP1's functions in ER quality control is to recruit the soluble
      E2 ubiquitin-conjugating enzyme UBE2G2.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: binds to Ube2g2
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:21857022
  qualifier: involved_in
  review:
    summary: AUP1 depletion impairs degradation of misfolded ER proteins; core process.
    action: ACCEPT
    reason: Loss-of-function evidence directly supports AUP1 in ERAD.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0140042
    label: lipid droplet formation
  evidence_type: IMP
  original_reference_id: PMID:21857022
  qualifier: involved_in
  review:
    summary: AUP1 expression level affects the abundance of cellular lipid droplets;
      a core LD-regulatory function, though regulation of abundance/clustering is the
      better-supported framing than de novo formation.
    action: KEEP_AS_NON_CORE
    reason: The data show AUP1 controls LD abundance/clustering rather than directly
      catalyzing LD biogenesis; retained as a supported but secondary LD-regulatory
      role.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) in lipid droplet accumulation
      reference_section_type: TITLE
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21127063
  qualifier: located_in
  review:
    summary: AUP1 integrates into the LD surface monolayer; core localization.
    action: ACCEPT
    reason: Directly demonstrated monotopic LD surface localization.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: integrates into the LD surface in a monotopic fashion with both
        termini facing
      reference_section_type: ABSTRACT
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:21127063
  qualifier: enables
  review:
    summary: AUP1 binds the E2 UBE2G2 via its C-terminal G2BR; core molecular function.
    action: ACCEPT
    reason: AUP1, by means of its G2BR domain, binds Ube2g2, providing a direct molecular
      link to the ubiquitination machinery.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: by means of its G2BR
      reference_section_type: ABSTRACT
- term:
    id: GO:0034389
    label: lipid droplet organization
  evidence_type: IDA
  original_reference_id: PMID:24039768
  qualifier: involved_in
  review:
    summary: Monoubiquitinated AUP1 on the LD surface induces lipid droplet clustering;
      a core LD-regulatory function.
    action: ACCEPT
    reason: AUP1 induces LD cluster formation in a CUE/monoubiquitination-dependent
      manner.
    supported_by:
    - reference_id: PMID:24039768
      supporting_text: the lipid droplet protein AUP1 induces cluster formation
      reference_section_type: ABSTRACT
- term:
    id: GO:1990044
    label: protein localization to lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21127063
  qualifier: involved_in
  review:
    summary: AUP1 brings the AUP1-Ube2g2 complex to lipid droplets, localizing the
      E2 to the LD; supported.
    action: ACCEPT
    reason: AUP1 provides the molecular link recruiting Ube2g2 to lipid droplets.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: presence of the AUP1-Ube2g2 complex at LDs
      reference_section_type: ABSTRACT
- term:
    id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  qualifier: involved_in
  review:
    summary: AUP1 is required for dislocation (retrotranslocation) of the ERAD substrate
      NHK from the ER to the cytosol; core process tied to its ERAD adaptor role.
    action: ACCEPT
    reason: AUP1 was identified as an ERAD component essential for dislocation of NHK,
      i.e. ER-to-cytosol retrograde transport.
    supported_by:
    - reference_id: PMID:25660456
      supporting_text: dislocation, also known as retrotranslocation
      reference_section_type: ABSTRACT
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:18570454
  qualifier: located_in
  review:
    summary: High-throughput exosome proteomics localization; inconsistent with AUP1's
      monotopic ER/LD membrane topology and not a functionally meaningful localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a mass-spectrometry co-purification hit, not evidence for a functional
      extracellular/exosomal role for an ER/LD membrane protein.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: Generic membrane from a high-throughput membrane proteome; too unspecific
      to be informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific ER membrane and lipid droplet localizations are captured by
      other annotations; the bare membrane term adds no information.
core_functions:
- description: Acts as a substrate-adaptor/scaffold that recruits the soluble E2 ubiquitin-conjugating
    enzyme UBE2G2 to ER-associated degradation ubiquitin ligase machinery, coupling
    substrate ubiquitination to dislocation and proteasomal degradation of misfolded
    ER proteins.
  supported_by:
  - reference_id: PMID:21857022
    supporting_text: AUP1) physically associates with
    reference_section_type: ABSTRACT
  - reference_id: PMID:21127063
    supporting_text: by means of its G2BR
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: Drives sterol-regulated ubiquitination and ERAD of HMGCR and related
    sterol-pathway substrates by recruiting the E2 Ubc7/UBE2G2 to lipid droplet-associated
    ER membranes and bridging it to the E3 ligases gp78/AMFR and Trc8/RNF139.
  supported_by:
  - reference_id: PMID:23223569
    supporting_text: facilitates its binding to both gp78 and Trc8
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: Binds ubiquitin through its internal CUE domain and, when monoubiquitinated,
    drives lipid droplet clustering, thereby regulating lipid droplet organization
    and abundance.
  supported_by:
  - reference_id: PMID:24039768
    supporting_text: the lipid droplet protein AUP1 induces cluster formation
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0043130
    label: ubiquitin binding
  directly_involved_in:
  - id: GO:0034389
    label: lipid droplet organization
proposed_new_terms: []
suggested_questions:
- question: Does AUP1 have an intrinsic enzymatic (acyltransferase) activity, and if
    so what is its physiological substrate? The flavivirus study refers to an AUP1
    acyltransferase domain whose activity is required for lipophagy, but a defined
    enzymatic function and substrate are not established outside the infection context.
suggested_experiments:
- description: Define the substrate repertoire of AUP1-dependent ERAD genome-wide (e.g.
    proximity labeling or quantitative degradomics in AUP1-knockout vs wild-type cells)
    to distinguish core ERAD clients from sterol-pathway-specific and lipid-droplet-specific
    roles.
- description: Reconstitute AUP1-UBE2G2-gp78/Trc8 ubiquitination in vitro with defined
    components to test whether AUP1 is a passive scaffold or actively stimulates E2/E3
    activity.
- description: Test whether AUP1-dependent ERAD of endogenous polytopic membrane clients
    such as NKCC2/SLC12A1 and NCC/SLC12A3 requires the G2BR-UBE2G2 interaction and
    the CUE domain, to determine whether physiological substrate handling uses the
    same module that maintains UBE2G2 levels and recruits it to the ER membrane.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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: PMID:12042322
  title: Ancient ubiquitous protein 1 binds to the conserved membrane-proximal sequence
    of the cytoplasmic tail of the integrin alpha subunits that plays a crucial role
    in the inside-out signaling of alpha IIbbeta 3.
  findings: []
- id: PMID:18570454
  title: Proteomic analysis of exosomes from human neural stem cells by flow field-flow
    fractionation and nanoflow liquid chromatography-tandem mass spectrometry.
  findings: []
- id: PMID:18711132
  title: SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21127063
  title: Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds
    the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region.
  findings: []
- id: PMID:21857022
  title: Dual role of ancient ubiquitous protein 1 (AUP1) in lipid droplet accumulation
    and endoplasmic reticulum (ER) protein quality control.
  findings: []
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings: []
- id: PMID:23197321
  title: Monotopic topology is required for lipid droplet targeting of ancient ubiquitous
    protein 1.
  findings: []
- id: PMID:23223569
  title: Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl
    CoA reductase in lipid droplet-associated endoplasmic reticulum membranes.
  findings: []
- id: PMID:23840749
  title: 'MOR is not enough: identification of novel mu-opioid receptor interacting
    proteins using traditional and modified membrane yeast two-hybrid screens.'
  findings: []
- id: PMID:24039768
  title: Monoubiquitination of ancient ubiquitous protein 1 promotes lipid droplet
    clustering.
  findings: []
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong
    Kong variant of α-1-antitrypsin (NHK).
  findings: []
- id: PMID:28183703
  title: AUP1 (Ancient Ubiquitous Protein 1) Is a Key Determinant of Hepatic Very-Low-Density
    Lipoprotein Assembly and Secretion.
  findings: []
- id: PMID:29902443
  title: Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy
    and Drive Virus Production.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:34879065
  title: A structurally conserved site in AUP1 binds the E2 enzyme UBE2G2 and is essential
    for ER-associated degradation.
  full_text_unavailable: true
  findings:
  - statement: The 27-residue G2BR of AUP1 binds the backside of the ERAD E2 enzyme
      UBE2G2 with low-nanomolar affinity; this interaction maintains cellular UBE2G2
      levels by preventing its rapid degradation, recruits UBE2G2 to the ER membrane,
      and allosterically activates ubiquitination in conjunction with ERAD E3 ligases.
- id: PMID:38474353
  title: AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination
    of NKCC2.
  full_text_unavailable: true
  findings:
  - statement: AUP1 interacts with the ER-resident form of the kidney Na-K-2Cl cotransporter
      NKCC2 (SLC12A1) and with the ER lectin OS9, enhances NKCC2 ER retention and ERAD
      in a proteasome- and mannosidase-dependent manner, and is required for NKCC2
      polyubiquitination; AUP1 also downregulates the related cotransporter NCC, indicating
      a broader role in ERAD of sodium-dependent chloride cotransporters relevant to
      antenatal Bartter syndrome type 1.
- id: Reactome:R-HSA-9921605
  title: NS4A binds AUP1
  findings: []

AUP1

Gene Description

Existing Annotations Review

Core Functions

Acts as a substrate-adaptor/scaffold that recruits the soluble E2 ubiquitin-conjugating enzyme UBE2G2 to ER-associated degradation ubiquitin ligase machinery, coupling substrate ubiquitination to dislocation and proteasomal degradation of misfolded ER proteins.

Drives sterol-regulated ubiquitination and ERAD of HMGCR and related sterol-pathway substrates by recruiting the E2 Ubc7/UBE2G2 to lipid droplet-associated ER membranes and bridging it to the E3 ligases gp78/AMFR and Trc8/RNF139.

Binds ubiquitin through its internal CUE domain and, when monoubiquitinated, drives lipid droplet clustering, thereby regulating lipid droplet organization and abundance.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human AUP1 (UniProt Q9Y679) functional annotation

0) Gene/protein identity verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 Lipid droplets (LDs) and ER–LD continuity

1.2 ER-associated degradation (ERAD)

1.3 AUP1 domain definitions (CUE and G2BR)

2) Molecular function and mechanism (what AUP1 does)

2.1 Subcellular localization and membrane topology

2.2 Recruitment and regulation of the ERAD E2 enzyme UBE2G2

2.3 The CUE domain as a ubiquitin/substrate engagement and ERAD-complex interaction module

2.4 AUP1 as a bridge between ER quality control and lipid droplet biology

3) Pathways involving AUP1

3.1 Sterol-accelerated degradation of HMG-CoA reductase (cholesterol homeostasis)

3.2 Hepatic ApoB/VLDL assembly and secretion (lipoprotein metabolism)

3.3 Lipophagy and infection-associated lipid remodeling (context for 2023–2024 developments)

4) Recent developments (prioritizing 2023–2024)

4.1 2024: AUP1 promotes ERAD/polyubiquitination of renal cotransporters (NKCC2, NCC)

4.2 2023–2024: AUP1 as a disease biomarker in cancer and inflammation-rich microenvironments

4.3 2024: COVID-19 computational biomarker studies implicate AUP1 as a lipophagy-related marker

5) Current applications and real-world implementations

5.1 Experimental/biomedical applications

5.2 Translational/clinical implications (emerging)

6) Expert opinions and analysis (authoritative synthesis)

7) Relevant statistics and data (recent)

8) Consolidated evidence map

9) Key references (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

AUP1 (Ancient Ubiquitous Protein 1) — research notes

Domain architecture / topology

Core molecular/cellular function: ERAD E2 adaptor

HMGCR / sterol-regulated ERAD on LD-associated ER membranes

Lipid droplet biology

Other / contextual

Assessment summary (core vs non-core)

protein binding IPI references

Falcon deep research findings (2026-06-07)

Pn Notes

AUP1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | Retrotranslocation channel complex

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | Lipophagy | Ubiquitination of lipid droplet surface proteins

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | protein quality control | ERAD cofactor | CUE

Projected GO annotations (3)

Note

📄 View Raw YAML