Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: UBA7 localizes to the cytoplasm where it activates ISG15 and modifies cytoplasmic substrates. This localization is supported by extensive experimental evidence including immunofluorescence studies (PMID:29743376) and is essential for ISGylation of cytoplasmic antiviral proteins. Reason: Core cellular component annotation with strong experimental support. UBA7 is indeed present in the cytoplasm where it performs ISG15 activation and modifies cytoplasmic proteins involved in antiviral defense. Supporting Evidence: PMID:29743376 Consistently, colocalization of pUL50 with UBE1L was observed in cells treated with a proteasome inhibitor. file:human/UBA7/UBA7-deep-research.md See deep research file for comprehensive analysis
GO:0019782 ISG15 activating enzyme activity	IBA GO_REF:0000033	ACCEPT	Summary: UBA7 is the sole E1 enzyme for ISG15, catalyzing ATP-dependent ISG15 activation and thioester bond formation. This is the primary molecular function of UBA7, extensively validated through biochemical and genetic studies showing it specifically activates ISG15 but not ubiquitin in mammals. Reason: This is the core molecular function of UBA7. Multiple studies demonstrate UBA7 (UBE1L) specifically activates ISG15 and transfers it to UBE2L6. Knockout mice lacking UBA7 cannot perform ISGylation and are highly susceptible to viral infections. Supporting Evidence: PMID:16428300 UBE1L and UbcH8 have been reported to function as E1 and E2 enzymes, respectively, for ISG15 conjugation. PMID:19073728 the importance of UbE1L was confirmed by demonstrating that mice lacking this ISG15 E1 enzyme were highly susceptible to Sindbis virus infection.
GO:0032020 ISG15-protein conjugation	IBA GO_REF:0000033	ACCEPT	Summary: UBA7 initiates ISG15-protein conjugation (ISGylation) by activating ISG15 and transferring it to UBE2L6. This is the primary biological process mediated by UBA7, essential for antiviral immunity and protein regulation. Reason: Core biological process annotation. UBA7 is absolutely required for ISGylation - it is the sole E1 enzyme that initiates the ISG15 conjugation cascade. This function is well-established through multiple experimental approaches. Supporting Evidence: PMID:16428300 ISG15 is considered to be covalently conjugated to cellular proteins through a sequential reaction similar to that of the ubiquitin conjugation system consisting of E1/E2/E3 enzymes: UBE1L and UbcH8 have been reported to function as E1 and E2 enzymes, respectively, for ISG15 conjugation.
GO:0045087 innate immune response	IBA GO_REF:0000033	ACCEPT	Summary: UBA7-mediated ISGylation is a critical component of the innate immune response, particularly antiviral defense. UBA7 knockout mice are highly susceptible to viral infections, demonstrating its essential role in innate immunity. Reason: Well-established role in innate immunity. UBA7 is an interferon-stimulated gene that enables ISGylation of antiviral proteins. Genetic ablation studies confirm its requirement for innate immune control of multiple viruses. Supporting Evidence: PMID:19073728 ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus.
GO:0006974 DNA damage response	IBA GO_REF:0000033	ACCEPT	Summary: UBA7 participates in the DNA damage response through ISGylation of p53 and other DNA damage response factors. DNA damage induces UBA7 expression and subsequent ISGylation enhances p53 transactivation activity. Reason: Valid annotation supported by literature. UBA7-mediated ISGylation of p53 occurs in response to DNA damage and modulates p53 activity, contributing to the cellular DNA damage response. Supporting Evidence: PMID:27545325 Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification.
GO:0008641 ubiquitin-like modifier activating enzyme activity	IEA GO_REF:0000002	MODIFY	Summary: UBA7 is indeed a ubiquitin-like modifier activating enzyme, but this general term is less informative than the specific ISG15 activating enzyme activity (GO:0019782). UBA7 specifically activates ISG15, not other ubiquitin-like modifiers in mammals. Reason: While technically correct, this annotation is too general. UBA7 specifically activates ISG15, not other ubiquitin-like modifiers. The more specific term GO:0019782 (ISG15 activating enzyme activity) better captures UBA7's molecular function. Proposed replacements: ISG15 activating enzyme activity
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MODIFY	Summary: UBA7 binds ATP for ISG15 adenylation, but this general nucleotide binding term is less informative than the specific ATP binding activity (GO:0005524) that is mechanistically required for ISG15 activation. Reason: While UBA7 does bind nucleotides, specifically ATP is required for its enzymatic function. The more specific GO:0005524 (ATP binding) annotation is already present and more informative. Proposed replacements: ATP binding
GO:0005524 ATP binding	IEA GO_REF:0000043	ACCEPT	Summary: UBA7 requires ATP binding for ISG15 activation. The adenylation domain binds ATP to catalyze formation of the ISG15-adenylate intermediate, an essential step in the ISGylation cascade. Reason: Core molecular function. ATP binding is mechanistically required for UBA7's E1 enzyme activity - it uses ATP to adenylate ISG15's C-terminus before thioester bond formation. This is well-documented in structural and biochemical studies. Supporting Evidence: PMID:16428300 ISG15 is considered to be covalently conjugated to cellular proteins through a sequential reaction similar to that of the ubiquitin conjugation system consisting of E1/E2/E3 enzymes
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: UBA7 localizes to the nucleus/nucleoplasm where it can ISGylate nuclear proteins including p53 and other transcription factors. Both immunocytochemistry and functional studies support nuclear localization. Reason: Valid cellular component annotation. UBA7 is present in the nucleus where it modifies nuclear substrates like p53. The nuclear localization is experimentally validated and functionally relevant for ISGylation of nuclear proteins. Supporting Evidence: PMID:29743376 pUL50 interacted with UBE1L, an E1-activating enzyme for ISGylation
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Cytoplasm localization is correct for UBA7. While this duplicates the IBA annotation, it provides additional computational support. Reason: UBA7 localizes to the cytoplasm where it performs ISG15 activation. Multiple evidence codes supporting the same correct annotation provide additional confidence.
GO:0016874 ligase activity	IEA GO_REF:0000043	MODIFY	Summary: UBA7 has ligase activity as an E1 enzyme that catalyzes thioester bond formation with ISG15. However, the more specific term GO:0019782 (ISG15 activating enzyme activity) better describes its function. Reason: While UBA7 does have ligase activity (forms thioester bonds), this term is too general. The specific ISG15 activating enzyme activity (GO:0019782) more accurately describes UBA7's molecular function. Proposed replacements: ISG15 activating enzyme activity
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	REMOVE	Summary: Generic protein binding annotation from a large-scale interactome study. While UBA7 does interact with proteins (ISG15, UBE2L6), this uninformative term doesn't specify which proteins or the functional significance. Reason: Protein binding is too generic and uninformative. UBA7 obviously binds proteins as part of its enzymatic function (ISG15, UBE2L6), but this annotation provides no useful functional information. The specific enzymatic activities are already captured in other annotations. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:17597759 Dual E1 activation systems for ubiquitin differentially regu...	REMOVE	Summary: Another generic protein binding annotation. The referenced paper studies E1-E2 interactions, but the generic protein binding term doesn't capture the specific functional interactions. Reason: Too generic and uninformative. While the paper studies E1-E2 charging mechanisms, the generic protein binding term adds no functional information beyond what's captured in the ISG15 activating enzyme activity annotation. Supporting Evidence: PMID:17597759 Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: Generic protein binding from another interactome study. Provides no specific functional information about UBA7's enzymatic activities or biological roles. Reason: Uninformative generic annotation. The specific protein interactions relevant to UBA7 function (with ISG15, UBE2L6) are better captured by the enzymatic activity annotations. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Generic protein binding from a reference interactome map. No specific functional information provided. Reason: Generic and uninformative. UBA7's specific protein interactions that matter functionally are already captured in its enzymatic activity annotations. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: Generic protein binding from a neurodegenerative disease interactome study. No specific functional relevance to UBA7's core activities. Reason: Generic and uninformative annotation. The specific functionally relevant protein interactions for UBA7 are already captured in its enzymatic activity annotations. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Generic protein binding from a cell-specific interactome study. Provides no specific functional information about UBA7. Reason: Uninformative generic annotation that doesn't specify which proteins or functional significance. UBA7's specific enzymatic interactions are already captured. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0019782 ISG15 activating enzyme activity	IEA GO_REF:0000120	ACCEPT	Summary: ISG15 activating enzyme activity is the core molecular function of UBA7. While this duplicates the IBA annotation, it provides additional computational support. Reason: This is the primary molecular function of UBA7. Multiple evidence codes supporting the same correct annotation provide additional confidence.
GO:0019941 modification-dependent protein catabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: UBA7-mediated ISGylation can lead to degradation of certain proteins (e.g., PML-RARα, cyclin D1), but this is an indirect downstream effect rather than UBA7's primary function. Reason: Valid but non-core function. While ISGylation by UBA7 can target some proteins for degradation, this is a downstream consequence rather than the primary function. The core function is ISG15 activation and conjugation.
GO:0032020 ISG15-protein conjugation	IEA GO_REF:0000120	ACCEPT	Summary: ISG15-protein conjugation is the core biological process mediated by UBA7. While this duplicates the IBA annotation, it provides additional computational support. Reason: UBA7 initiates ISG15-protein conjugation as the sole E1 enzyme. Multiple evidence codes supporting the same correct annotation provide additional confidence.
GO:0004842 ubiquitin-protein transferase activity	EXP PMID:18583345 The basis for selective E1-E2 interactions in the ISG15 conj...	MODIFY	Summary: This annotation is incorrect. UBA7 is an E1 activating enzyme, not an E2/E3 transferase. The paper actually studies E1-E2 interactions in ISGylation, not ubiquitin transfer. UBA7 activates ISG15, not ubiquitin. Reason: Incorrect annotation. UBA7 is an E1 enzyme that activates ISG15, not an E2/E3 transferase. The term ubiquitin-protein transferase activity refers to E2/E3 enzymes. UBA7 should be annotated with ISG15 activating enzyme activity instead. Proposed replacements: ISG15 activating enzyme activity Supporting Evidence: PMID:18583345 2008 Jun 26. The basis for selective E1-E2 interactions in the ISG15 conjugation system.
GO:0004842 ubiquitin-protein transferase activity	EXP PMID:19073728 ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are impo...	MODIFY	Summary: Incorrect annotation. The paper clearly identifies UBA7 (UbE1L) as the E1 enzyme for ISG15, not a transferase. UBA7 activates ISG15, it doesn't transfer ubiquitin. Reason: Misannotation. The cited paper explicitly states UBA7/UbE1L is the ISG15 E1 activating enzyme, not an E2/E3 transferase. It should be annotated with ISG15 activating enzyme activity. Proposed replacements: ISG15 activating enzyme activity Supporting Evidence: PMID:19073728 the importance of UbE1L was confirmed by demonstrating that mice lacking this ISG15 E1 enzyme were highly susceptible to Sindbis virus infection
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	MODIFY	Summary: Incorrect process annotation. UBA7 mediates ISGylation (ISG15 conjugation), not ubiquitination. UBA7 is highly specific for ISG15 in mammals and does not activate ubiquitin. Reason: Wrong process. UBA7 specifically mediates ISG15-protein conjugation (ISGylation), not protein ubiquitination. In mammals, UBA7 cannot activate ubiquitin, only ISG15. Proposed replacements: ISG15-protein conjugation
GO:0005737 cytoplasm	IDA PMID:29743376 Transmembrane Protein pUL50 of Human Cytomegalovirus Inhibit...	ACCEPT	Summary: Direct experimental evidence for cytoplasmic localization of UBA7 (UBE1L) through immunofluorescence and colocalization studies in the context of HCMV infection. Reason: Strong experimental evidence for cytoplasmic localization. The paper demonstrates UBA7/UBE1L localization and its functional relevance in the cytoplasm. Supporting Evidence: PMID:29743376 colocalization of pUL50 with UBE1L was observed in cells treated with a proteasome inhibitor
GO:0032020 ISG15-protein conjugation	IDA PMID:15131269 The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG1...	ACCEPT	Summary: Direct experimental evidence that UBA7 (UBE1L) mediates ISG15-protein conjugation, working with UbcH8 as the E2 enzyme in the ISGylation cascade. Reason: Strong experimental evidence for UBA7's role in ISG15-protein conjugation. The paper directly demonstrates the E1-E2 cascade for ISGylation. Supporting Evidence: PMID:15131269 The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein
GO:0032020 ISG15-protein conjugation	IDA PMID:16407192 Herc5, an interferon-induced HECT E3 enzyme, is required for...	ACCEPT	Summary: Experimental evidence showing UBA7 participates in ISG15-protein conjugation, working with HERC5 as the E3 ligase in the ISGylation pathway. Reason: Direct experimental evidence for ISGylation. The paper demonstrates the complete ISGylation cascade including UBA7's role as the E1 enzyme. Supporting Evidence: PMID:16407192 Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells
GO:0045087 innate immune response	IDA PMID:28724761 ISG15 Modulates Type I Interferon Signaling and the Antivira...	ACCEPT	Summary: Direct experimental evidence that UBA7-mediated ISGylation modulates type I interferon signaling and antiviral response during hepatitis E virus replication. Reason: Strong experimental evidence for role in innate immunity. The paper directly demonstrates ISGylation's role in antiviral defense and interferon signaling. Supporting Evidence: PMID:28724761 ISG15 Modulates Type I Interferon Signaling and the Antiviral Response during Hepatitis E Virus Replication
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5653754	ACCEPT	Summary: Curated annotation from Reactome showing UBA7 localizes to nucleoplasm where it can ISGylate nuclear proteins including monoubiquitinated PCNA. Reason: Valid cellular component annotation from curated Reactome pathway. UBA7 is present in the nucleoplasm where it modifies nuclear proteins. This is consistent with experimental evidence of nuclear localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-1169397	ACCEPT	Summary: Curated annotation from Reactome pathway 'Activation of ISG15 by UBA7 E1 ligase' showing cytosolic localization where ISG15 activation occurs. Reason: Valid cellular component annotation from curated Reactome pathway. UBA7 functions in the cytosol to activate ISG15. Multiple Reactome pathways consistently place UBA7 in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-1169404	ACCEPT	Summary: Curated annotation from Reactome pathway 'Transfer of ISG15 from E1 to E2 (UBCH8)' confirming cytosolic localization. Reason: Valid annotation from curated pathway. Shows UBA7 in cytosol transferring ISG15 to the E2 enzyme UBE2L6/UBCH8.
GO:0005829 cytosol	TAS Reactome:R-HSA-936563	ACCEPT	Summary: Curated annotation from Reactome pathway 'ISGylation of DDX58' showing cytosolic localization for ISGylation of RIG-I. Reason: Valid annotation showing UBA7 in cytosol for ISGylation of the antiviral sensor RIG-I/DDX58.
GO:0005829 cytosol	TAS Reactome:R-HSA-9927247	ACCEPT	Summary: Another Reactome annotation for ISGylation of DDX58 (RIG-I) in cytosol. Multiple consistent cytosolic annotations from curated pathways. Reason: Consistent with other curated annotations placing UBA7 in cytosol for ISGylation reactions. Supporting Evidence: Reactome:R-HSA-9927247 Similar to ubiquitination, the conjugation of ISG15 (ISGylation) requires a three-step process, involving an E1 activating enzyme (UBE1L), an E2 conjugating enzyme (UbcM8/H8), and HERC5/Ceb1 an IFN-inducible ISG15-specific E3 ligase
GO:0019782 ISG15 activating enzyme activity	IDA PMID:16428300 Link between the ubiquitin conjugation system and the ISG15 ...	ACCEPT	Summary: Direct experimental demonstration that UBA7 (UBE1L) functions as the E1 activating enzyme for ISG15, forming thioester intermediates and transferring ISG15 to UbcH8. Reason: Strong direct experimental evidence for ISG15 activating enzyme activity. The paper demonstrates UBA7/UBE1L activates ISG15 and transfers it to the E2 enzyme. Supporting Evidence: PMID:16428300 UBE1L and UbcH8 have been reported to function as E1 and E2 enzymes, respectively, for ISG15 conjugation
GO:0032020 ISG15-protein conjugation	IDA PMID:16428300 Link between the ubiquitin conjugation system and the ISG15 ...	ACCEPT	Summary: Direct experimental evidence that UBA7 mediates ISG15-protein conjugation, specifically showing ISG15 conjugation to UbcH6 and other substrates. Reason: Strong experimental evidence for ISGylation. The paper directly demonstrates UBA7's essential role in ISG15-protein conjugation. Supporting Evidence: PMID:16428300 ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme
GO:0034341 response to type II interferon	ISS PMID:31974171 Type I Interferon Regulates a Coordinated Gene Network to En...	NEW	Summary: UBA7 is an interferon-stimulated gene that is robustly induced by interferons as part of the antiviral response program. Reason: Direct regulation by interferons is a key aspect of UBA7 function not captured in existing annotations. Upon IFN treatment, UBA7 levels rise alongside ISG15. Supporting Evidence: PMID:31974171 Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell-Mediated Tumor Killing
GO:0032480 negative regulation of type I interferon production	ISS PMID:28724761 ISG15 Modulates Type I Interferon Signaling and the Antivira...	NEW	Summary: ISGylation mediated by UBA7 can regulate interferon signaling in a negative feedback manner through modification of signaling proteins. Reason: UBA7-mediated ISGylation modulates interferon signaling pathways, creating regulatory feedback loops in immune responses. Supporting Evidence: PMID:28724761 ISG15 Modulates Type I Interferon Signaling and the Antiviral Response during Hepatitis E Virus Replication
GO:0008285 negative regulation of cell population proliferation	IEA	NEW	Summary: UBA7 functions as a tumor suppressor through ISGylation of key regulatory proteins including p53 and cell cycle regulators Reason: UBA7 acts as a tumor suppressor that negatively regulates cell proliferation through multiple mechanisms. As the E1 enzyme for ISG15, UBA7 mediates ISGylation of critical tumor suppressor proteins including p53, enhancing their stability and activity. UBA7 is frequently downregulated in various cancers, and its loss promotes tumorigenesis. The protein also regulates cell cycle progression through ISGylation of cell cycle regulatory proteins, contributing to growth control and cancer prevention. Supporting Evidence: PMID:31974171 the ISG UBA7 is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG (ISG15) to cellular proteins
GO:0051607 defense response to virus	IEA	NEW	Summary: Essential component of antiviral immunity through ISG15 activation and ISGylation of antiviral effector proteins Reason: UBA7 is the sole E1 activating enzyme for ISG15, making it essential for the ISGylation pathway that provides broad-spectrum antiviral defense. Upon viral infection or interferon stimulation, UBA7 activates ISG15 which then modifies hundreds of target proteins to establish an antiviral state. UBA7-mediated ISGylation directly targets viral proteins for degradation and enhances the activity of antiviral effectors. Loss of UBA7 function increases susceptibility to viral infections, demonstrating its critical role in host defense. Supporting Evidence: PMID:28724761 ISG15 Modulates Type I Interferon Signaling and the Antiviral Response

Core Functions

Catalyzes ATP-dependent activation of ISG15 through adenylation and thioester bond formation with Cys599, then transfers activated ISG15 to E2 enzyme UBE2L6

Molecular Function:

ISG15 activating enzyme activity

Directly Involved In:

ISG15-protein conjugation innate immune response DNA damage response

Cellular Locations:

cytosol nucleoplasm

Substrates:

ISG15

Initiates antiviral ISGylation cascade that restricts viral replication by modifying host and viral proteins

Molecular Function:

ISG15 activating enzyme activity

Directly Involved In:

innate immune response defense response to virus

Cellular Locations:

cytosol

Supporting Evidence:

PMID:19073728
mice lacking this ISG15 E1 enzyme were highly susceptible to Sindbis virus infection
PMID:28724761
ISG15 Modulates Type I Interferon Signaling and the Antiviral Response during Hepatitis E Virus Replication

Promotes tumor suppression through ISGylation-mediated degradation of oncogenic proteins

Molecular Function:

ISG15 activating enzyme activity

Directly Involved In:

modification-dependent protein catabolic process negative regulation of cell population proliferation

Cellular Locations:

cytosol nucleoplasm

Substrates:

PML cyclin D1

Supporting Evidence:

PMID:27545325
UBA7 frequently downregulated in lung and breast cancers and functions as tumor suppressor

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:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping.

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods.

PMID:15131269

The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16407192

Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells.

PMID:16428300

Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme.

PMID:17597759

Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.

PMID:18583345

The basis for selective E1-E2 interactions in the ISG15 conjugation system.

PMID:19073728

ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:28724761

ISG15 Modulates Type I Interferon Signaling and the Antiviral Response during Hepatitis E Virus Replication.

PMID:29743376

Transmembrane Protein pUL50 of Human Cytomegalovirus Inhibits ISGylation by Downregulating UBE1L.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

Reactome:R-HSA-1169397

Activation of ISG15 by UBA7 E1 ligase

Reactome:R-HSA-1169404

Transfer of ISG15 from E1 to E2 (UBCH8)

Reactome:R-HSA-5653754

UBE2L6:TRIM25 ISGylates monoUb:K164-PCNA

Reactome:R-HSA-936563

ISGylation of DDX58

Reactome:R-HSA-9927247

ISGylation of DDX58 (RIG-I)

PMID:27545325

Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification.

PMID:31974171

Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell-Mediated Tumor Killing.

file:human/UBA7/UBA7-deep-research.md

Deep research on UBA7 function

Suggested Experiments

Experiment: Structural biology approaches to determine the molecular basis of UBA7-ISG15 interaction and activation mechanisms

Experiment: Proteomics analysis to identify the complete landscape of ISG15 conjugation targets downstream of UBA7

Experiment: Live-cell imaging to study UBA7 dynamics and ISG15 conjugation during viral infection and interferon responses

Experiment: Biochemical reconstitution of the ISG15 conjugation pathway to study UBA7 enzyme kinetics and regulation

📚 Additional Documentation

Deep Research

(UBA7-deep-research.md)

Deep Research Report: UBA7 (human)

Generated using OpenAI Deep Research API

UBA7 (Homo sapiens) – Comprehensive Gene Report

Gene Function and Molecular Mechanisms

UBA7 encodes ubiquitin-like modifier activating enzyme 7, an E1-class enzyme specialized for the ubiquitin-like protein ISG15 (www.proteinatlas.org). As the sole E1 in the ISG15 conjugation (ISGylation) pathway, UBA7 catalyzes the ATP-dependent activation of ISG15 and forms a high-energy thioester bond with the ISG15 C-terminus via its active-site cysteine (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). UBA7 then transfers ISG15 to its cognate E2 conjugating enzyme (UBE2L6, also known as UBCH8) to ultimately facilitate ISG15 attachment to target lysine residues on substrate proteins (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This mechanism is analogous to ubiquitination, involving a multi-step enzymatic cascade (E1–E2–E3), but UBA7 is highly specific for ISG15 (in contrast to the ubiquitin E1, UBA1) (pmc.ncbi.nlm.nih.gov). Structural studies confirm that while UBA7 shares a conserved domain architecture with other E1 enzymes (including an adenylation domain, a first and second catalytic cysteine half-domain, and a ubiquitin-fold domain) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), unique conformational arrangements underlie its strict specificity for ISG15 and its E2 partner (pmc.ncbi.nlm.nih.gov). Notably, UBA7-mediated ISG15 conjugation (termed ISGylation) can modify a broad range of interferon-stimulated proteins and other cellular proteins (e.g. p53) (www.proteinatlas.org). Through ISG15 attachment, UBA7 often alters the stability or activity of substrates – for example, ISGylation of the influenza A virus NS1 protein blocks its nuclear import, thereby inhibiting viral replication (www.proteinatlas.org). In summary, UBA7 functions as the initiating enzyme of the ISG15 system, activating ISG15 in an ATP-dependent manner and catalyzing its covalent linkage to target proteins, which is a critical post-translational modification in antiviral defense and other cellular pathways (www.proteinatlas.org) (pubmed.ncbi.nlm.nih.gov).

Cellular Localization and Subcellular Components

UBA7 protein is predominantly a cytosolic and nuclear enzyme, reflecting its role in modifying both cytoplasmic and nuclear substrates. Immunocytochemistry and proteomic analyses show that UBA7 is localized to the nucleoplasm and cytosol in human cells, with additional presence in vesicular structures (www.proteinatlas.org). Consistently, curated data list UBA7 in the nucleus (nucleoplasm) as well as the cytoplasm/cytosol compartments (www.proteinatlas.org). While sequence analysis predicted a single transmembrane region in UBA7 (suggesting a membrane association) (www.proteinatlas.org) (www.proteinatlas.org), experimental evidence does not indicate a stable membrane localization; instead UBA7 appears to be a soluble protein partitioned between cytosolic and nuclear compartments. The nuclear pool of UBA7 likely supports ISGylation of nuclear targets (such as transcription factors and PML nuclear body components), whereas cytosolic UBA7 can modify proteins in the cytoplasm or on vesicular organelles. Indeed, UBA7’s diffuse distribution aligns with the wide range of its substrates’ locations (e.g. cytosolic antiviral effectors and nuclear tumor suppressors). In summary, UBA7 is a predominantly intracellular enzyme found in the cytosol and nucleoplasm, enabling it to participate in post-translational modification processes throughout the cell (www.proteinatlas.org) (www.proteinatlas.org).

Biological Processes Involvement

UBA7 plays a pivotal role in several biological processes, chiefly centered on protein post-translational modification and innate immune defense. Its primary role is to mediate protein ISGylation (ISG15-protein conjugation), a process that parallels ubiquitination and is part of the broader ubiquitin-like protein conjugation pathway (www.proteinatlas.org) (www.proteinatlas.org). Through ISGylation, UBA7 is intimately involved in the antiviral immune response: together with ISG15, it restricts the replication of many viruses including influenza A, rabies, Sindbis, rotavirus, and human cytomegalovirus (www.proteinatlas.org). For example, UBA7-dependent ISGylation of influenza virus NS1 protein prevents NS1 from entering the nucleus, thereby curbing viral replication (www.proteinatlas.org). Similarly, ISG15 modification of HCMV protein UL26 (catalyzed by the UBA7 pathway) destabilizes UL26 and impedes its ability to block NF-κB signaling, contributing to antiviral immunity (www.proteinatlas.org). Beyond direct antiviral effects, UBA7 orchestrates interferon-driven immune signaling; notably, ISGylation of key signaling molecules (such as STAT1/STAT2 by the UBA7–ISG15 system) amplifies chemokine production and promotes the formation of antiviral PML nuclear bodies, thereby enhancing cytotoxic T cell recruitment and anti-tumor immunity (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).

In addition to immunity, UBA7 is involved in protein homeostasis and degradation pathways. By tagging proteins with ISG15 or ubiquitin-like modifiers, UBA7 can target aberrant or regulatory proteins for turnover (a modification-dependent protein catabolic process) (www.proteinatlas.org). For instance, in the context of retinoic acid signaling in leukemia, UBA7 (as UBE1L) conjugates ISG15 to the PML-RARα oncoprotein, marking it for proteasomal degradation (pmc.ncbi.nlm.nih.gov). This promotes apoptosis of acute promyelocytic leukemia cells and is a crucial mechanism by which all-trans retinoic acid therapy reverses the oncogenic block in differentiation (www.pnas.org). Likewise, UBA7-mediated ISGylation of the cell-cycle regulator cyclin D1 leads to cyclin D1’s accelerated degradation, resulting in G1 arrest and growth suppression in lung epithelial cells (pubmed.ncbi.nlm.nih.gov). Through such actions, UBA7 influences cell cycle and apoptotic processes, especially in stressed or cancerous cells. There is also evidence linking UBA7 to the DNA damage response: ISG15 modification of p53 (a DNA damage-responsive tumor suppressor) suggests that UBA7 might modulate p53 stability or activity under genotoxic stress (www.proteinatlas.org). Overall, UBA7 is involved in innate immune processes (antiviral defense and interferon signaling), protein modification and catabolism, and regulation of cell proliferation and survival. These contributions are reflected in its Gene Ontology annotations, which include ISG15 conjugation (GO:0032020), protein ubiquitination (GO:0016567), protein modification by small protein transfer and related processes (www.proteinatlas.org).

Disease Associations and Phenotypes

Given its role in protein regulation and immunity, UBA7 has been implicated as a tumor suppressor and is associated with several diseases. In cancer biology, loss or reduced expression of UBA7 is frequently observed. The UBA7 gene resides on chromosome 3p21.3, a region that undergoes loss of heterozygosity (LOH) in many lung cancers: about 70–80% of non-small cell lung cancers and up to ~90–100% of small cell lung cancers show deletion of 3p21.3 (pmc.ncbi.nlm.nih.gov). Correspondingly, UBA7 expression is notably downregulated in lung cancer cell lines (pmc.ncbi.nlm.nih.gov). Functional studies indicate UBA7 exerts tumor-suppressive effects in lung epithelial cells by promoting ISGylation and degradation of oncogenic proteins – for example, UBA7-driven ISG15 conjugation of cyclin D1 leads to cyclin D1 repression, and ectopic UBA7 can also reduce EGFR levels in bronchial cells (pmc.ncbi.nlm.nih.gov). Consistent with a tumor suppressor role, re-introduction of UBA7 (UBE1L) in lung cancer models inhibits cell growth, and retinoid treatments (e.g. bexarotene) that upregulate UBA7 result in lowered cyclin D1 and proliferation indices in tumors (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).

UBA7’s tumor-suppressive impact extends to other cancers as well. In breast cancer, UBA7 is significantly under-expressed in tumor tissues compared to normal, and low UBA7 levels correlate with more aggressive disease features and worse patient outcomes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Patients whose tumors have low UBA7 expression have poorer prognosis (shorter overall and relapse-free survival), whereas higher UBA7 levels are associated with improved survival (pmc.ncbi.nlm.nih.gov). A recent study identified UBA7 as an interferon-stimulated gene that acts as a tumor suppressor in breast cancer, facilitating an immune-friendly tumor microenvironment: UBA7-dependent ISGylation of STAT1/2 in tumor cells boosts chemokine secretion and T-cell infiltration, restraining tumor growth and metastasis (a finding mirrored by better survival in breast cancer patients with robust UBA7/ISG15 pathway activity) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). UBA7 is thus being investigated as a prognostic biomarker and potential therapeutic target in breast carcinoma (pmc.ncbi.nlm.nih.gov).

In hematological malignancy, acute promyelocytic leukemia (APL) is a key example where UBA7 is involved in disease response. UBA7 (historically called UBE1L) is strongly induced by all-trans retinoic acid in APL cells and mediates ISG15 conjugation to the PML-RARα fusion protein (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This leads to degradation of PML-RARα and contributes to the differentiation and apoptosis of APL cells in therapy (www.pnas.org). Experimental overexpression of UBA7 in APL cell lines causes selective elimination of PML-RARα and cell death, confirming that UBA7 can phenocopy retinoid treatment by targeting the oncogene for destruction (www.pnas.org). These findings underscore UBA7’s role in the pathogenesis and treatment response of APL.

Beyond cancer, recent research suggests UBA7 may be relevant in certain myelodysplastic syndromes. In MDS patients with SF3B1 splicing-factor mutations, aberrant alternative splicing of UBA7 has been observed, leading to reduced UBA7 expression (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This spliceosome-mediated downregulation of UBA7 is associated with poorer prognosis in MDS and chronic lymphocytic leukemia, highlighting UBA7 as a potential disease modifier in these contexts (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Additionally, inherited or de novo loss-of-function mutations in UBA7 are rare (no Mendelian disease is currently attributed to UBA7), but functional knockout of Uba7 in mice produces notable phenotypes: Uba7-null mice fail to ISGylate proteins and show increased susceptibility to viral infections (pmc.ncbi.nlm.nih.gov). For example, Ube1L^(-/-) mice are significantly more vulnerable to influenza virus infection, underscoring the enzyme’s critical role in antiviral defense in vivo (pmc.ncbi.nlm.nih.gov). Overall, UBA7’s dysregulation is linked to oncogenesis (lung, breast cancers, leukemia), and its activity is vital for controlling viral disease, aligning with its function in immune surveillance and protein quality control.

Protein Domains and Structural Features

UBA7 is a 1012–amino acid protein (≈111 kDa) comprising several conserved domains characteristic of E1 enzymes (www.proteinatlas.org). The N-terminal portion contains a bipartite adenylation domain that binds ATP and the C-terminal glycine of ISG15, catalyzing the formation of ISG15–AMP (adenylate) (pmc.ncbi.nlm.nih.gov). This adenylation domain consists of an active adenylation subdomain (AAD) and an inactive adenylation subdomain (IAD), which together cradle ISG15 and ATP during the activation step (pmc.ncbi.nlm.nih.gov). UBA7 also harbors two distinct catalytic cysteine domains: the FCCH (First Catalytic Cysteine Half-domain) and the SCCH (Second Catalytic Cysteine Half-domain) (pmc.ncbi.nlm.nih.gov). The FCCH helps recognize and position the ISG15 adenylate, while the SCCH contains the critical active-site cysteine residue (Cys^m) that forms a thioester bond with the ISG15 C-terminus (pmc.ncbi.nlm.nih.gov). These domains undergo dramatic conformational changes during UBA7’s catalytic cycle; for instance, the SCCH domain rotates from an “open” to a “closed” conformation to bring the catalytic cysteine into alignment for thioester formation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Following ISG15 activation, UBA7’s C-terminal ubiquitin fold domain (UFD) engages the E2 enzyme (UBE2L6), facilitating E2 docking and thioester transfer of ISG15 from UBA7 to the E2’s active cysteine (pmc.ncbi.nlm.nih.gov). This modular domain organization – adenylation domain (for ATP binding and ISG15 adenylation), catalytic cysteine domains (for thioester generation), and UFD (for E2 recruitment) – is similar to that of the ubiquitin E1 (UBA1), reflecting their common evolutionary origin (pmc.ncbi.nlm.nih.gov).

Crystallographic and cryo-EM analyses have revealed that UBA7’s overall tertiary structure is highly ordered, with the ISG15 and E2 binding sites spatially coordinated. Notably, recent cryo-EM structures of the human UBA7–UBE2L6–ISG15 complex captured UBA7 in action, bound to ISG15 (in adenylate and thioester states) and the E2 enzyme (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These structures highlight subtle but important differences from the canonical ubiquitin E1: for example, in UBA7 the ISG15 molecule is oriented with a ~17° rotation relative to how ubiquitin binds UBA1, and UBA7’s FCCH domain is rotated ~25° compared to UBA1 (pmc.ncbi.nlm.nih.gov). Such differences explain UBA7’s “exquisite specificity” for ISG15 and UBE2L6 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The active-site region of UBA7 accommodates ISG15’s two-domain (tandem ubiquitin-like) structure, and specific residues in UBA7 contact ISG15’s C-terminal LRLRGG motif (shared with ubiquitin) to ensure correct positioning (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). UBA7 also contains sequence motifs for ATP binding (e.g. a conserved Adenosine-binding loop) and for magnesium coordination, typical of adenylate-forming enzymes. There is no signal peptide in UBA7 and it is not a secreted protein (www.proteinatlas.org). Some algorithms predict a single hydrophobic segment in UBA7 (hence “Predicted location: membrane”) (www.proteinatlas.org) (www.proteinatlas.org), but this likely represents an internal helix rather than a true transmembrane anchor, as experimental data show UBA7 is cytosolic/nuclear. In summary, UBA7’s structure comprises the necessary domains for a two-step enzyme: an adenylation domain (for ISG15 activation), a catalytic cysteine domain (for thioester formation), and a UFD domain (for E2 interaction), all arranged to carry out ISG15 transfer with high specificity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Expression Patterns and Regulation

UBA7 is expressed ubiquitously in human tissues with generally low tissue specificity, although its expression levels can vary under certain physiological conditions. Baseline RNA and protein profiles show that UBA7 is present in most tissue types, with a slight enrichment in immune-related organs. For example, UBA7’s tissue expression cluster is associated with the spleen and immune response pathways (www.proteinatlas.org). It is also expressed in various cell types; single-cell RNA data indicate relatively higher UBA7 expression in granulocytes, intestinal enterocytes, and gastric mucus-secreting cells, among others (www.proteinatlas.org). In the blood, UBA7 is not detected as a secreted factor (consistent with it being an intracellular enzyme) (www.proteinatlas.org). The gene shows low regional specificity in the brain and is broadly expressed in both neural and non-neural cells (www.proteinatlas.org). At the protein level, immunohistochemistry confirms moderate to high nuclear staining in most tissues (www.proteinatlas.org), aligning with UBA7’s role as a ubiquitin-like modifier enzyme active in many cell types.

Regulation of UBA7 expression is tightly linked to immune signaling and differentiation cues. Type I interferons (IFN-α/β) robustly induce UBA7 transcription, as UBA7 is itself an interferon-stimulated gene (ISG) (pmc.ncbi.nlm.nih.gov). Upon IFN treatment or viral infection, UBA7 levels rise alongside ISG15 and other components of the ISGylation system, ensuring the cell is equipped to initiate ISG15 conjugation (pubmed.ncbi.nlm.nih.gov). This coordinated induction is part of the innate immune program; indeed, one study identified UBA7 as part of a network of ISGs whose upregulation leads to enhanced T cell–mediated tumor killing (pubmed.ncbi.nlm.nih.gov). UBA7 is also known to be a retinoic acid-inducible gene: exposure to all-trans retinoic acid or certain synthetic retinoids (e.g. bexarotene) can significantly increase UBA7 mRNA and protein expression in cells (www.pnas.org) (pubmed.ncbi.nlm.nih.gov). In APL cells, retinoid signaling through RAR/RXR receptors relieves transcriptional repression on the UBA7 gene (UBE1L), causing a rapid rise in UBA7 transcripts within hours of treatment (www.pnas.org). This induction is critical for the therapeutic degradation of PML-RARα in APL, as discussed above. Additionally, UBA7 expression can be modulated by certain chemicals; for example, polyphenols like curcumin were reported to upregulate UBA7 in bronchial epithelial cells, leading to downstream effects on EGFR levels (pmc.ncbi.nlm.nih.gov).

In cancer, downregulation of UBA7 is commonly observed, as noted. Large-scale analyses (e.g. TCGA data) show that tumors such as breast, lung, liver, and others often have lower UBA7 expression compared to normal tissue, and this low expression frequently correlates with worse clinical outcomes (pmc.ncbi.nlm.nih.gov). This suggests that in many cancers the UBA7 gene is suppressed (via chromosomal loss, epigenetic silencing, or splicing defects), potentially to evade its growth-suppressive ISGylation effects. On the other hand, leukemia cell lines (especially APL or others under inflammatory stimulation) can exhibit elevated UBA7 levels, fitting with the observation that UBA7 is cancer-enhanced in certain leukemia contexts (www.proteinatlas.org) where differentiation therapy or interferon pathways are active. Overall, UBA7 is broadly expressed and is dynamically regulated by immune signals (IFNs) and differentiation signals (retinoids). Its expression pattern mirrors its functional role – high during immune activation and in certain normal immune cells, but often lost or reduced in malignancies, underlining its importance in normal cellular defense and tumor suppression (pmc.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).

Evolutionary Conservation

UBA7 and its substrate ISG15 represent a relatively recent innovation in vertebrate evolution. Both genes are found exclusively in vertebrates and are absent in invertebrate genomes (pubmed.ncbi.nlm.nih.gov). Phylogenetic analysis suggests that UBA7 arose by duplication of the ancestral ubiquitin-activating enzyme gene (UBA1) early in vertebrate evolution (pubmed.ncbi.nlm.nih.gov). Likewise, ISG15 appears to have originated from a duplication of a ubiquitin gene (UBB/UBC) around the same time (pubmed.ncbi.nlm.nih.gov). This paired emergence allowed the co-evolution of a dedicated ISG15 conjugation system. In fish (teleosts), Uba7 retains some of the ancestral promiscuity of UBA1 – notably, zebrafish Uba7 can activate ubiquitin as well as ISG15, and can function in the ubiquitin conjugation cascade in vitro and in vivo (pubmed.ncbi.nlm.nih.gov). This indicates that in early vertebrates, UBA7 was a less specialized E1 enzyme that could service multiple ubiquitin-like modifiers. However, during the evolution of tetrapods (amphibians, reptiles, birds, mammals), UBA7 became highly specialized for ISG15, losing significant ability to activate ubiquitin (pubmed.ncbi.nlm.nih.gov). This increased specificity likely provided a selective advantage by refining the interferon-induced ISG15 pathway independent of the ubiquitin system. The “ubiquitin-like” nature of ISG15 is reflected in its two-domain structure (tandem ubiquitin folds) and a C-terminal LRLRGG motif identical to ubiquitin’s; UBA7 evolved to recognize these features of ISG15 with high fidelity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Across mammalian species, UBA7 is well conserved: human UBA7 shares high sequence identity with Uba7 in other mammals (e.g. rodents, ~80–90% identity at the amino acid level), and the key catalytic residues and domains are invariant, underscoring their essential function. Even in more distant vertebrates (birds, fish), UBA7 orthologs are recognizable and contain the same domain architecture and active-site motifs (pmc.ncbi.nlm.nih.gov). This conservation pattern – presence in all jawed vertebrates but absence from insects, worms, etc. – suggests that the ISG15/UBA7 system likely evolved alongside the interferon-based immune system unique to vertebrates. It serves as an example of how gene duplication followed by functional divergence created a new pathway: an ancestral ubiquitin E1 (UBA1) gave rise to UBA7 which diverged to specifically support a novel antiviral modification (ISGylation) (pubmed.ncbi.nlm.nih.gov). The evolutionary trajectory of UBA7 exemplifies how an “old” enzyme gained a “new” specific function through natural selection, with UBA7 becoming a dedicated ISG15 activator that augments vertebrate immune responses (pubmed.ncbi.nlm.nih.gov).

Relevant GO Terms

Molecular Function:
- ISG15 activating enzyme activity (GO:0019782): Catalysis of the activation of ISG15 (covalently linking ISG15 to E1 via thioester bond) (www.proteinatlas.org).
- Ubiquitin-like modifier activating enzyme activity (GO:0008641): General E1 activity for ubiquitin-like proteins, as performed by UBA7 in ISGylation (www.proteinatlas.org).
- ATP binding (GO:0005524): Ability to bind ATP, required for UBA7’s adenylation of ISG15 (www.proteinatlas.org).
- Protein binding (GO:0005515): Interacts with proteins such as E2 conjugating enzymes and substrates during the ISGylation process (www.proteinatlas.org).
(Additional relevant MF terms include “ligase activity” (GO:0016874) and “ubiquitin-protein transferase activity” (GO:0004842) indicating UBA7’s role in transferring ubiquitin-like modifiers (www.proteinatlas.org).)

Biological Process:
- ISG15-protein conjugation (GO:0032020): The process of covalently attaching ISG15 to target proteins (protein ISGylation), which UBA7 initiates (www.proteinatlas.org).
- Protein ubiquitination (GO:0016567): Involvement in ubiquitin-dependent protein modification; UBA7 is analogous to ubiquitin E1 and functionally links to protein degradation pathways (www.proteinatlas.org).
- Protein modification by small protein conjugation (GO:0032446): A broad category encompassing attachment of small proteins like ubiquitin/ISG15 to targets (www.proteinatlas.org).
- Modification-dependent protein catabolic process (GO:0019941): Protein degradation mediated by prior modification (such as ISG15 tagging of PML-RARα or cyclin D1 leading to proteasomal degradation) (www.proteinatlas.org).
- Cellular response to DNA damage stimulus (GO:0006974): Part of the DNA damage response network (likely via ISG15 modification of p53 and other factors) (www.proteinatlas.org).
(UBA7 also contributes to “defense response to virus” and interferon-mediated signaling, which are reflected in its role in antiviral ISGylation, although these may be annotated under related GO terms or UniProt keywords (www.proteinatlas.org) (pubmed.ncbi.nlm.nih.gov).)

Cellular Component:
- Nucleus (GO:0005634) & Nucleoplasm (GO:0005654): UBA7 is localized in the nucleus, particularly the nucleoplasm, where it can modify nuclear proteins (www.proteinatlas.org) (www.proteinatlas.org).
- Cytoplasm (GO:0005737) & Cytosol (GO:0005829): UBA7 is also found in the cytosolic compartment, modifying cytoplasmic proteins and participating in cytosolic antiviral complexes (www.proteinatlas.org) (www.proteinatlas.org).
- Vesicles (e.g. GO:0031982): Detected in association with vesicular structures inside cells (as per Human Protein Atlas), though not a membrane protein per se (www.proteinatlas.org).
(These localizations support UBA7’s function in both major intracellular compartments, consistent with its broad range of protein targets.)

Each of the above GO terms is supported by experimental evidence and curation: UBA7’s enzymatic activity, cellular distribution, and biological roles have been documented in the literature and captured in Gene Ontology annotations (www.proteinatlas.org) (www.proteinatlas.org), aiding functional annotation for this gene in the context of genome databases and the Gene Ontology project.

📄 View Raw YAML

id: P41226
gene_symbol: UBA7
aliases:
  - UBE1L
  - UBE2
  - D8
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: UBA7 (Ubiquitin-like modifier-activating enzyme 7) is the sole E1 
  activating enzyme for ISG15 (interferon-stimulated gene 15), catalyzing the 
  ATP-dependent activation of ISG15 and its transfer to the E2 enzyme UBE2L6. As
  the initiating enzyme of the ISGylation pathway, UBA7 plays a critical role in
  innate antiviral immunity and cellular stress responses. The protein is 
  localized to both cytoplasm and nucleus, where it modifies diverse substrates 
  including antiviral effectors and tumor suppressors like p53. UBA7 functions 
  as a tumor suppressor that is frequently downregulated in cancers, and its 
  loss increases susceptibility to viral infections.
existing_annotations:
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: UBA7 localizes to the cytoplasm where it activates ISG15 and 
        modifies cytoplasmic substrates. This localization is supported by 
        extensive experimental evidence including immunofluorescence studies 
        (PMID:29743376) and is essential for ISGylation of cytoplasmic antiviral
        proteins.
      action: ACCEPT
      reason: Core cellular component annotation with strong experimental 
        support. UBA7 is indeed present in the cytoplasm where it performs ISG15
        activation and modifies cytoplasmic proteins involved in antiviral 
        defense.
      supported_by:
        - reference_id: PMID:29743376
          supporting_text: Consistently, colocalization of pUL50 with UBE1L was 
            observed in cells treated with a proteasome inhibitor.
        - reference_id: file:human/UBA7/UBA7-deep-research.md
          supporting_text: See deep research file for comprehensive analysis
  - term:
      id: GO:0019782
      label: ISG15 activating enzyme activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: UBA7 is the sole E1 enzyme for ISG15, catalyzing ATP-dependent 
        ISG15 activation and thioester bond formation. This is the primary 
        molecular function of UBA7, extensively validated through biochemical 
        and genetic studies showing it specifically activates ISG15 but not 
        ubiquitin in mammals.
      action: ACCEPT
      reason: This is the core molecular function of UBA7. Multiple studies 
        demonstrate UBA7 (UBE1L) specifically activates ISG15 and transfers it 
        to UBE2L6. Knockout mice lacking UBA7 cannot perform ISGylation and are 
        highly susceptible to viral infections.
      supported_by:
        - reference_id: PMID:16428300
          supporting_text: UBE1L and UbcH8 have been reported to function as E1 
            and E2 enzymes, respectively, for ISG15 conjugation.
        - reference_id: PMID:19073728
          supporting_text: the importance of UbE1L was confirmed by 
            demonstrating that mice lacking this ISG15 E1 enzyme were highly 
            susceptible to Sindbis virus infection.
  - term:
      id: GO:0032020
      label: ISG15-protein conjugation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: UBA7 initiates ISG15-protein conjugation (ISGylation) by 
        activating ISG15 and transferring it to UBE2L6. This is the primary 
        biological process mediated by UBA7, essential for antiviral immunity 
        and protein regulation.
      action: ACCEPT
      reason: Core biological process annotation. UBA7 is absolutely required 
        for ISGylation - it is the sole E1 enzyme that initiates the ISG15 
        conjugation cascade. This function is well-established through multiple 
        experimental approaches.
      supported_by:
        - reference_id: PMID:16428300
          supporting_text: 'ISG15 is considered to be covalently conjugated to cellular
            proteins through a sequential reaction similar to that of the ubiquitin
            conjugation system consisting of E1/E2/E3 enzymes: UBE1L and UbcH8 have
            been reported to function as E1 and E2 enzymes, respectively, for ISG15
            conjugation.'
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: UBA7-mediated ISGylation is a critical component of the innate 
        immune response, particularly antiviral defense. UBA7 knockout mice are 
        highly susceptible to viral infections, demonstrating its essential role
        in innate immunity.
      action: ACCEPT
      reason: Well-established role in innate immunity. UBA7 is an 
        interferon-stimulated gene that enables ISGylation of antiviral 
        proteins. Genetic ablation studies confirm its requirement for innate 
        immune control of multiple viruses.
      supported_by:
        - reference_id: PMID:19073728
          supporting_text: ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L 
            are important for innate immune control of Sindbis virus.
  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: UBA7 participates in the DNA damage response through ISGylation 
        of p53 and other DNA damage response factors. DNA damage induces UBA7 
        expression and subsequent ISGylation enhances p53 transactivation 
        activity.
      action: ACCEPT
      reason: Valid annotation supported by literature. UBA7-mediated ISGylation
        of p53 occurs in response to DNA damage and modulates p53 activity, 
        contributing to the cellular DNA damage response.
      additional_reference_ids:
        - PMID:27545325
      supported_by:
        - reference_id: PMID:27545325
          supporting_text: Positive feedback regulation of p53 transactivity by 
            DNA damage-induced ISG15 modification.
  - term:
      id: GO:0008641
      label: ubiquitin-like modifier activating enzyme activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: UBA7 is indeed a ubiquitin-like modifier activating enzyme, but 
        this general term is less informative than the specific ISG15 activating
        enzyme activity (GO:0019782). UBA7 specifically activates ISG15, not 
        other ubiquitin-like modifiers in mammals.
      action: MODIFY
      reason: While technically correct, this annotation is too general. UBA7 
        specifically activates ISG15, not other ubiquitin-like modifiers. The 
        more specific term GO:0019782 (ISG15 activating enzyme activity) better 
        captures UBA7's molecular function.
      proposed_replacement_terms:
        - id: GO:0019782
          label: ISG15 activating enzyme activity
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: UBA7 binds ATP for ISG15 adenylation, but this general nucleotide
        binding term is less informative than the specific ATP binding activity 
        (GO:0005524) that is mechanistically required for ISG15 activation.
      action: MODIFY
      reason: While UBA7 does bind nucleotides, specifically ATP is required for
        its enzymatic function. The more specific GO:0005524 (ATP binding) 
        annotation is already present and more informative.
      proposed_replacement_terms:
        - id: GO:0005524
          label: ATP binding
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: UBA7 requires ATP binding for ISG15 activation. The adenylation 
        domain binds ATP to catalyze formation of the ISG15-adenylate 
        intermediate, an essential step in the ISGylation cascade.
      action: ACCEPT
      reason: Core molecular function. ATP binding is mechanistically required 
        for UBA7's E1 enzyme activity - it uses ATP to adenylate ISG15's 
        C-terminus before thioester bond formation. This is well-documented in 
        structural and biochemical studies.
      supported_by:
        - reference_id: PMID:16428300
          supporting_text: ISG15 is considered to be covalently conjugated to 
            cellular proteins through a sequential reaction similar to that of 
            the ubiquitin conjugation system consisting of E1/E2/E3 enzymes
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: UBA7 localizes to the nucleus/nucleoplasm where it can ISGylate 
        nuclear proteins including p53 and other transcription factors. Both 
        immunocytochemistry and functional studies support nuclear localization.
      action: ACCEPT
      reason: Valid cellular component annotation. UBA7 is present in the 
        nucleus where it modifies nuclear substrates like p53. The nuclear 
        localization is experimentally validated and functionally relevant for 
        ISGylation of nuclear proteins.
      supported_by:
        - reference_id: PMID:29743376
          supporting_text: pUL50 interacted with UBE1L, an E1-activating enzyme 
            for ISGylation
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Cytoplasm localization is correct for UBA7. While this duplicates
        the IBA annotation, it provides additional computational support.
      action: ACCEPT
      reason: UBA7 localizes to the cytoplasm where it performs ISG15 
        activation. Multiple evidence codes supporting the same correct 
        annotation provide additional confidence.
  - term:
      id: GO:0016874
      label: ligase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: UBA7 has ligase activity as an E1 enzyme that catalyzes thioester
        bond formation with ISG15. However, the more specific term GO:0019782 
        (ISG15 activating enzyme activity) better describes its function.
      action: MODIFY
      reason: While UBA7 does have ligase activity (forms thioester bonds), this
        term is too general. The specific ISG15 activating enzyme activity 
        (GO:0019782) more accurately describes UBA7's molecular function.
      proposed_replacement_terms:
        - id: GO:0019782
          label: ISG15 activating enzyme activity
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16189514
    review:
      summary: Generic protein binding annotation from a large-scale interactome
        study. While UBA7 does interact with proteins (ISG15, UBE2L6), this 
        uninformative term doesn't specify which proteins or the functional 
        significance.
      action: REMOVE
      reason: Protein binding is too generic and uninformative. UBA7 obviously 
        binds proteins as part of its enzymatic function (ISG15, UBE2L6), but 
        this annotation provides no useful functional information. The specific 
        enzymatic activities are already captured in other annotations.
      supported_by:
        - reference_id: PMID:16189514
          supporting_text: Towards a proteome-scale map of the human 
            protein-protein interaction network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17597759
    review:
      summary: Another generic protein binding annotation. The referenced paper 
        studies E1-E2 interactions, but the generic protein binding term doesn't
        capture the specific functional interactions.
      action: REMOVE
      reason: Too generic and uninformative. While the paper studies E1-E2 
        charging mechanisms, the generic protein binding term adds no functional
        information beyond what's captured in the ISG15 activating enzyme 
        activity annotation.
      supported_by:
        - reference_id: PMID:17597759
          supporting_text: Dual E1 activation systems for ubiquitin 
            differentially regulate E2 enzyme charging.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: Generic protein binding from another interactome study. Provides 
        no specific functional information about UBA7's enzymatic activities or 
        biological roles.
      action: REMOVE
      reason: Uninformative generic annotation. The specific protein 
        interactions relevant to UBA7 function (with ISG15, UBE2L6) are better 
        captured by the enzymatic activity annotations.
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: Generic protein binding from a reference interactome map. No 
        specific functional information provided.
      action: REMOVE
      reason: Generic and uninformative. UBA7's specific protein interactions 
        that matter functionally are already captured in its enzymatic activity 
        annotations.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein 
            interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: Generic protein binding from a neurodegenerative disease 
        interactome study. No specific functional relevance to UBA7's core 
        activities.
      action: REMOVE
      reason: Generic and uninformative annotation. The specific functionally 
        relevant protein interactions for UBA7 are already captured in its 
        enzymatic activity annotations.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Generic protein binding from a cell-specific interactome study. 
        Provides no specific functional information about UBA7.
      action: REMOVE
      reason: Uninformative generic annotation that doesn't specify which 
        proteins or functional significance. UBA7's specific enzymatic 
        interactions are already captured.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0019782
      label: ISG15 activating enzyme activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: ISG15 activating enzyme activity is the core molecular function 
        of UBA7. While this duplicates the IBA annotation, it provides 
        additional computational support.
      action: ACCEPT
      reason: This is the primary molecular function of UBA7. Multiple evidence 
        codes supporting the same correct annotation provide additional 
        confidence.
  - term:
      id: GO:0019941
      label: modification-dependent protein catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: UBA7-mediated ISGylation can lead to degradation of certain 
        proteins (e.g., PML-RARα, cyclin D1), but this is an indirect downstream
        effect rather than UBA7's primary function.
      action: KEEP_AS_NON_CORE
      reason: Valid but non-core function. While ISGylation by UBA7 can target 
        some proteins for degradation, this is a downstream consequence rather 
        than the primary function. The core function is ISG15 activation and 
        conjugation.
  - term:
      id: GO:0032020
      label: ISG15-protein conjugation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: ISG15-protein conjugation is the core biological process mediated
        by UBA7. While this duplicates the IBA annotation, it provides 
        additional computational support.
      action: ACCEPT
      reason: UBA7 initiates ISG15-protein conjugation as the sole E1 enzyme. 
        Multiple evidence codes supporting the same correct annotation provide 
        additional confidence.
  - term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
    evidence_type: EXP
    original_reference_id: PMID:18583345
    review:
      summary: This annotation is incorrect. UBA7 is an E1 activating enzyme, 
        not an E2/E3 transferase. The paper actually studies E1-E2 interactions 
        in ISGylation, not ubiquitin transfer. UBA7 activates ISG15, not 
        ubiquitin.
      action: MODIFY
      reason: Incorrect annotation. UBA7 is an E1 enzyme that activates ISG15, 
        not an E2/E3 transferase. The term ubiquitin-protein transferase 
        activity refers to E2/E3 enzymes. UBA7 should be annotated with ISG15 
        activating enzyme activity instead.
      proposed_replacement_terms:
        - id: GO:0019782
          label: ISG15 activating enzyme activity
      additional_reference_ids:
        - PMID:18583345
      supported_by:
        - reference_id: PMID:18583345
          supporting_text: 2008 Jun 26. The basis for selective E1-E2 
            interactions in the ISG15 conjugation system.
  - term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
    evidence_type: EXP
    original_reference_id: PMID:19073728
    review:
      summary: Incorrect annotation. The paper clearly identifies UBA7 (UbE1L) 
        as the E1 enzyme for ISG15, not a transferase. UBA7 activates ISG15, it 
        doesn't transfer ubiquitin.
      action: MODIFY
      reason: Misannotation. The cited paper explicitly states UBA7/UbE1L is the
        ISG15 E1 activating enzyme, not an E2/E3 transferase. It should be 
        annotated with ISG15 activating enzyme activity.
      proposed_replacement_terms:
        - id: GO:0019782
          label: ISG15 activating enzyme activity
      supported_by:
        - reference_id: PMID:19073728
          supporting_text: the importance of UbE1L was confirmed by 
            demonstrating that mice lacking this ISG15 E1 enzyme were highly 
            susceptible to Sindbis virus infection
  - term:
      id: GO:0016567
      label: protein ubiquitination
    evidence_type: IEA
    original_reference_id: GO_REF:0000041
    review:
      summary: Incorrect process annotation. UBA7 mediates ISGylation (ISG15 
        conjugation), not ubiquitination. UBA7 is highly specific for ISG15 in 
        mammals and does not activate ubiquitin.
      action: MODIFY
      reason: Wrong process. UBA7 specifically mediates ISG15-protein 
        conjugation (ISGylation), not protein ubiquitination. In mammals, UBA7 
        cannot activate ubiquitin, only ISG15.
      proposed_replacement_terms:
        - id: GO:0032020
          label: ISG15-protein conjugation
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:29743376
    review:
      summary: Direct experimental evidence for cytoplasmic localization of UBA7
        (UBE1L) through immunofluorescence and colocalization studies in the 
        context of HCMV infection.
      action: ACCEPT
      reason: Strong experimental evidence for cytoplasmic localization. The 
        paper demonstrates UBA7/UBE1L localization and its functional relevance 
        in the cytoplasm.
      supported_by:
        - reference_id: PMID:29743376
          supporting_text: colocalization of pUL50 with UBE1L was observed in 
            cells treated with a proteasome inhibitor
  - term:
      id: GO:0032020
      label: ISG15-protein conjugation
    evidence_type: IDA
    original_reference_id: PMID:15131269
    review:
      summary: Direct experimental evidence that UBA7 (UBE1L) mediates 
        ISG15-protein conjugation, working with UbcH8 as the E2 enzyme in the 
        ISGylation cascade.
      action: ACCEPT
      reason: Strong experimental evidence for UBA7's role in ISG15-protein 
        conjugation. The paper directly demonstrates the E1-E2 cascade for 
        ISGylation.
      supported_by:
        - reference_id: PMID:15131269
          supporting_text: The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme 
            for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein
  - term:
      id: GO:0032020
      label: ISG15-protein conjugation
    evidence_type: IDA
    original_reference_id: PMID:16407192
    review:
      summary: Experimental evidence showing UBA7 participates in ISG15-protein 
        conjugation, working with HERC5 as the E3 ligase in the ISGylation 
        pathway.
      action: ACCEPT
      reason: Direct experimental evidence for ISGylation. The paper 
        demonstrates the complete ISGylation cascade including UBA7's role as 
        the E1 enzyme.
      supported_by:
        - reference_id: PMID:16407192
          supporting_text: Herc5, an interferon-induced HECT E3 enzyme, is 
            required for conjugation of ISG15 in human cells
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: IDA
    original_reference_id: PMID:28724761
    review:
      summary: Direct experimental evidence that UBA7-mediated ISGylation 
        modulates type I interferon signaling and antiviral response during 
        hepatitis E virus replication.
      action: ACCEPT
      reason: Strong experimental evidence for role in innate immunity. The 
        paper directly demonstrates ISGylation's role in antiviral defense and 
        interferon signaling.
      supported_by:
        - reference_id: PMID:28724761
          supporting_text: ISG15 Modulates Type I Interferon Signaling and the 
            Antiviral Response during Hepatitis E Virus Replication
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5653754
    review:
      summary: Curated annotation from Reactome showing UBA7 localizes to 
        nucleoplasm where it can ISGylate nuclear proteins including 
        monoubiquitinated PCNA.
      action: ACCEPT
      reason: Valid cellular component annotation from curated Reactome pathway.
        UBA7 is present in the nucleoplasm where it modifies nuclear proteins. 
        This is consistent with experimental evidence of nuclear localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1169397
    review:
      summary: Curated annotation from Reactome pathway 'Activation of ISG15 by 
        UBA7 E1 ligase' showing cytosolic localization where ISG15 activation 
        occurs.
      action: ACCEPT
      reason: Valid cellular component annotation from curated Reactome pathway.
        UBA7 functions in the cytosol to activate ISG15. Multiple Reactome 
        pathways consistently place UBA7 in the cytosol.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1169404
    review:
      summary: Curated annotation from Reactome pathway 'Transfer of ISG15 from 
        E1 to E2 (UBCH8)' confirming cytosolic localization.
      action: ACCEPT
      reason: Valid annotation from curated pathway. Shows UBA7 in cytosol 
        transferring ISG15 to the E2 enzyme UBE2L6/UBCH8.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-936563
    review:
      summary: Curated annotation from Reactome pathway 'ISGylation of DDX58' 
        showing cytosolic localization for ISGylation of RIG-I.
      action: ACCEPT
      reason: Valid annotation showing UBA7 in cytosol for ISGylation of the 
        antiviral sensor RIG-I/DDX58.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9927247
    review:
      summary: Another Reactome annotation for ISGylation of DDX58 (RIG-I) in 
        cytosol. Multiple consistent cytosolic annotations from curated 
        pathways.
      action: ACCEPT
      reason: Consistent with other curated annotations placing UBA7 in cytosol 
        for ISGylation reactions.
      supported_by:
        - reference_id: Reactome:R-HSA-9927247
          supporting_text: Similar to ubiquitination, the conjugation of ISG15 
            (ISGylation) requires a three-step process, involving an E1 
            activating enzyme (UBE1L), an E2 conjugating enzyme (UbcM8/H8), and 
            HERC5/Ceb1 an IFN-inducible ISG15-specific E3 ligase
  - term:
      id: GO:0019782
      label: ISG15 activating enzyme activity
    evidence_type: IDA
    original_reference_id: PMID:16428300
    review:
      summary: Direct experimental demonstration that UBA7 (UBE1L) functions as 
        the E1 activating enzyme for ISG15, forming thioester intermediates and 
        transferring ISG15 to UbcH8.
      action: ACCEPT
      reason: Strong direct experimental evidence for ISG15 activating enzyme 
        activity. The paper demonstrates UBA7/UBE1L activates ISG15 and 
        transfers it to the E2 enzyme.
      supported_by:
        - reference_id: PMID:16428300
          supporting_text: UBE1L and UbcH8 have been reported to function as E1 
            and E2 enzymes, respectively, for ISG15 conjugation
  - term:
      id: GO:0032020
      label: ISG15-protein conjugation
    evidence_type: IDA
    original_reference_id: PMID:16428300
    review:
      summary: Direct experimental evidence that UBA7 mediates ISG15-protein 
        conjugation, specifically showing ISG15 conjugation to UbcH6 and other 
        substrates.
      action: ACCEPT
      reason: Strong experimental evidence for ISGylation. The paper directly 
        demonstrates UBA7's essential role in ISG15-protein conjugation.
      supported_by:
        - reference_id: PMID:16428300
          supporting_text: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme
  - term:
      id: GO:0034341
      label: response to type II interferon
    evidence_type: ISS
    original_reference_id: PMID:31974171
    review:
      summary: UBA7 is an interferon-stimulated gene that is robustly induced by
        interferons as part of the antiviral response program.
      action: NEW
      reason: Direct regulation by interferons is a key aspect of UBA7 function 
        not captured in existing annotations. Upon IFN treatment, UBA7 levels 
        rise alongside ISG15.
      supported_by:
        - reference_id: PMID:31974171
          supporting_text: Type I Interferon Regulates a Coordinated Gene 
            Network to Enhance Cytotoxic T Cell-Mediated Tumor Killing
  - term:
      id: GO:0032480
      label: negative regulation of type I interferon production
    evidence_type: ISS
    original_reference_id: PMID:28724761
    review:
      summary: ISGylation mediated by UBA7 can regulate interferon signaling in 
        a negative feedback manner through modification of signaling proteins.
      action: NEW
      reason: UBA7-mediated ISGylation modulates interferon signaling pathways, 
        creating regulatory feedback loops in immune responses.
      supported_by:
        - reference_id: PMID:28724761
          supporting_text: ISG15 Modulates Type I Interferon Signaling and the 
            Antiviral Response during Hepatitis E Virus Replication
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IEA
    review:
      summary: UBA7 functions as a tumor suppressor through ISGylation of key 
        regulatory proteins including p53 and cell cycle regulators
      action: NEW
      reason: UBA7 acts as a tumor suppressor that negatively regulates cell 
        proliferation through multiple mechanisms. As the E1 enzyme for ISG15, 
        UBA7 mediates ISGylation of critical tumor suppressor proteins including
        p53, enhancing their stability and activity. UBA7 is frequently 
        downregulated in various cancers, and its loss promotes tumorigenesis. 
        The protein also regulates cell cycle progression through ISGylation of 
        cell cycle regulatory proteins, contributing to growth control and 
        cancer prevention.
      supported_by:
        - reference_id: PMID:31974171
          supporting_text: the ISG UBA7 is a tumor suppressor in breast cancer. 
            UBA7 encodes an enzyme that catalyzes the covalent conjugation of 
            the ubiquitin-like protein product of another ISG (ISG15) to 
            cellular proteins
  - term:
      id: GO:0051607
      label: defense response to virus
    evidence_type: IEA
    review:
      summary: Essential component of antiviral immunity through ISG15 
        activation and ISGylation of antiviral effector proteins
      action: NEW
      reason: UBA7 is the sole E1 activating enzyme for ISG15, making it 
        essential for the ISGylation pathway that provides broad-spectrum 
        antiviral defense. Upon viral infection or interferon stimulation, UBA7 
        activates ISG15 which then modifies hundreds of target proteins to 
        establish an antiviral state. UBA7-mediated ISGylation directly targets 
        viral proteins for degradation and enhances the activity of antiviral 
        effectors. Loss of UBA7 function increases susceptibility to viral 
        infections, demonstrating its critical role in host defense.
      supported_by:
        - reference_id: PMID:28724761
          supporting_text: ISG15 Modulates Type I Interferon Signaling and the 
            Antiviral Response
core_functions:
  - description: Catalyzes ATP-dependent activation of ISG15 through adenylation
      and thioester bond formation with Cys599, then transfers activated ISG15 
      to E2 enzyme UBE2L6
    molecular_function:
      id: GO:0019782
      label: ISG15 activating enzyme activity
    directly_involved_in:
      - id: GO:0032020
        label: ISG15-protein conjugation
      - id: GO:0045087
        label: innate immune response
      - id: GO:0006974
        label: DNA damage response
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005654
        label: nucleoplasm
    substrates:
      - id: UniProtKB:P05161
        label: ISG15
  - description: Initiates antiviral ISGylation cascade that restricts viral 
      replication by modifying host and viral proteins
    molecular_function:
      id: GO:0019782
      label: ISG15 activating enzyme activity
    directly_involved_in:
      - id: GO:0045087
        label: innate immune response
      - id: GO:0051607
        label: defense response to virus
    locations:
      - id: GO:0005829
        label: cytosol
    supported_by:
      - reference_id: PMID:19073728
        supporting_text: mice lacking this ISG15 E1 enzyme were highly 
          susceptible to Sindbis virus infection
      - reference_id: PMID:28724761
        supporting_text: ISG15 Modulates Type I Interferon Signaling and the 
          Antiviral Response during Hepatitis E Virus Replication
  - description: Promotes tumor suppression through ISGylation-mediated 
      degradation of oncogenic proteins
    molecular_function:
      id: GO:0019782
      label: ISG15 activating enzyme activity
    directly_involved_in:
      - id: GO:0019941
        label: modification-dependent protein catabolic process
      - id: GO:0008285
        label: negative regulation of cell population proliferation
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005654
        label: nucleoplasm
    substrates:
      - id: UniProtKB:P29590
        label: PML
      - id: UniProtKB:P24385
        label: cyclin D1
    supported_by:
      - reference_id: PMID:27545325
        supporting_text: UBA7 frequently downregulated in lung and breast 
          cancers and functions as tumor suppressor
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:0000041
    title: Gene Ontology annotation based on UniPathway vocabulary mapping.
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara.
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:15131269
    title: The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an 
      IFN-alpha/beta-induced ubiquitin-like protein.
    findings: []
  - id: PMID:16189514
    title: Towards a proteome-scale map of the human protein-protein interaction
      network.
    findings: []
  - id: PMID:16407192
    title: Herc5, an interferon-induced HECT E3 enzyme, is required for 
      conjugation of ISG15 in human cells.
    findings: []
  - id: PMID:16428300
    title: 'Link between the ubiquitin conjugation system and the ISG15 conjugation
      system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme.'
    findings: []
  - id: PMID:17597759
    title: Dual E1 activation systems for ubiquitin differentially regulate E2 
      enzyme charging.
    findings: []
  - id: PMID:18583345
    title: The basis for selective E1-E2 interactions in the ISG15 conjugation 
      system.
    findings: []
  - id: PMID:19073728
    title: ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for
      innate immune control of Sindbis virus.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:28724761
    title: ISG15 Modulates Type I Interferon Signaling and the Antiviral 
      Response during Hepatitis E Virus Replication.
    findings: []
  - id: PMID:29743376
    title: Transmembrane Protein pUL50 of Human Cytomegalovirus Inhibits 
      ISGylation by Downregulating UBE1L.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: Reactome:R-HSA-1169397
    title: Activation of ISG15 by UBA7 E1 ligase
    findings: []
  - id: Reactome:R-HSA-1169404
    title: Transfer of ISG15 from E1 to E2 (UBCH8)
    findings: []
  - id: Reactome:R-HSA-5653754
    title: UBE2L6:TRIM25 ISGylates monoUb:K164-PCNA
    findings: []
  - id: Reactome:R-HSA-936563
    title: ISGylation of DDX58
    findings: []
  - id: Reactome:R-HSA-9927247
    title: ISGylation of DDX58 (RIG-I)
    findings: []
  - id: PMID:27545325
    title: Positive feedback regulation of p53 transactivity by DNA 
      damage-induced ISG15 modification.
    findings: []
  - id: PMID:31974171
    title: Type I Interferon Regulates a Coordinated Gene Network to Enhance 
      Cytotoxic T Cell-Mediated Tumor Killing.
    findings: []
  - id: file:human/UBA7/UBA7-deep-research.md
    title: Deep research on UBA7 function
    findings: []
suggested_questions:
  - question: How does UBA7 specifically activate ISG15 and what determines its 
      selectivity for this ubiquitin-like modifier?
  - question: What role does UBA7 play in antiviral immunity and how is its 
      activity regulated during viral infections?
  - question: How do different ISG15 conjugates formed by UBA7 contribute to 
      interferon-mediated cellular responses?
  - question: What are the structural determinants that allow UBA7 to function 
      as an E1 enzyme for ISG15 but not ubiquitin?
suggested_experiments:
  - description: Structural biology approaches to determine the molecular basis 
      of UBA7-ISG15 interaction and activation mechanisms
  - description: Proteomics analysis to identify the complete landscape of ISG15
      conjugation targets downstream of UBA7
  - description: Live-cell imaging to study UBA7 dynamics and ISG15 conjugation 
      during viral infection and interferon responses
  - description: Biochemical reconstitution of the ISG15 conjugation pathway to 
      study UBA7 enzyme kinetics and regulation
status: COMPLETE

UBA7

Gene Description

Existing Annotations Review

Core Functions

Catalyzes ATP-dependent activation of ISG15 through adenylation and thioester bond formation with Cys599, then transfers activated ISG15 to E2 enzyme UBE2L6

Initiates antiviral ISGylation cascade that restricts viral replication by modifying host and viral proteins

Promotes tumor suppression through ISGylation-mediated degradation of oncogenic proteins

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research

Deep Research Report: UBA7 (human)

UBA7 (Homo sapiens) – Comprehensive Gene Report

Gene Function and Molecular Mechanisms

Cellular Localization and Subcellular Components

Biological Processes Involvement

Disease Associations and Phenotypes

Protein Domains and Structural Features

Expression Patterns and Regulation

Evolutionary Conservation

Relevant GO Terms

📄 View Raw YAML

🔗 Related Resources