UBE2L6 (also known as UBCH8) is an E2 ubiquitin-conjugating enzyme belonging to the UBE2L family. It functions as the principal E2 enzyme in the ISG15 conjugation (ISGylation) pathway, an interferon-stimulated ubiquitin-like modification system that is part of the innate immune defense against viral infection. UBE2L6 accepts activated ISG15 from the E1 enzyme UBA7 and transfers it to target proteins in conjunction with E3 ligases such as HERC5. The protein contains a single UBC catalytic domain with a conserved active-site cysteine that forms a thioester intermediate with ubiquitin or ISG15. While UBE2L6 can also function as an E2 for ubiquitin conjugation in vitro, its primary physiological role is in ISGylation during the type I interferon response.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005524
ATP binding
|
IEA
GO_REF:0000104 |
REMOVE |
Summary: ATP binding is not a direct molecular function of E2 ubiquitin-conjugating enzymes. E2 enzymes accept activated ubiquitin (or ubiquitin-like proteins) from E1 activating enzymes via a transthioesterification reaction; it is the E1 enzyme that requires ATP to adenylate ubiquitin. This annotation likely arose from an automated rule transfer that conflates the ATP requirement of the E1 step with the E2 enzyme itself.
Reason: E2 ubiquitin-conjugating enzymes do not bind or hydrolyze ATP. The ATP dependence belongs to the E1 activating enzyme (UBA7/UBE1L for ISG15, or UBA1 for ubiquitin). This is an erroneous IEA annotation.
Supporting Evidence:
file:RABIT/G1TUN6/G1TUN6-uniprot.txt
S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [E2 ubiquitin-conjugating enzyme]-L-cysteine = [E1 ubiquitin- activating enzyme]-L-cysteine + S-ubiquitinyl-[E2 ubiquitin- conjugating enzyme]-L-cysteine
|
|
GO:0016874
ligase activity
|
IEA
GO_REF:0000104 |
REMOVE |
Summary: The term 'ligase activity' (GO:0016874) is too broad and arguably misleading for an E2 enzyme. E2 enzymes are transferases (EC 2.3.2.23) that transfer ubiquitin or ubiquitin-like modifiers from an E1 thioester to a substrate. True ligase activity in the ubiquitin system is associated with E3 ubiquitin ligases. The EC number 2.3.2.23 assigned to this protein is in the transferase class, not the ligase class.
Reason: E2 enzymes are classified as transferases (EC 2.3.2.23), not ligases. Calling an E2 a ligase is misleading; the ligase function belongs to E3 enzymes that catalyze the final transfer to substrate lysine residues.
Supporting Evidence:
file:RABIT/G1TUN6/G1TUN6-uniprot.txt
EC=2.3.2.23
|
|
GO:0061631
ubiquitin conjugating enzyme activity
|
IEA
GO_REF:0000003 |
KEEP AS NON CORE |
Summary: UBE2L6 is an E2 ubiquitin-conjugating enzyme with a conserved UBC domain and active-site cysteine. While its primary physiological role is in ISGylation rather than ubiquitin conjugation, UBE2L6 retains E2 enzymatic activity for ubiquitin conjugation and is classified under EC 2.3.2.23. This annotation correctly captures the general enzymatic activity of the protein.
Reason: The ubiquitin conjugating enzyme activity is a valid biochemical activity for this E2 enzyme, but the primary physiological role of UBE2L6 is as an ISG15-specific E2, making this a secondary rather than core function.
Supporting Evidence:
file:RABIT/G1TUN6/G1TUN6-uniprot.txt
Belongs to the ubiquitin-conjugating enzyme family
file:RABIT/G1TUN6/G1TUN6-uniprot.txt
EC=2.3.2.23
|
|
GO:0019787
ubiquitin-like protein transferase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: UBE2L6 is indeed a ubiquitin-like protein transferase, as it transfers ISG15 (a ubiquitin-like protein) to substrates. This annotation is correct and captures the broader enzymatic category that encompasses both the ubiquitin and ISG15 transferase activities of this E2 enzyme. It is a parent term of the more specific ISG15 transferase activity.
Reason: This correctly captures UBE2L6 as a transferase for ubiquitin-like proteins. Since the more specific ISG15 transferase activity is also annotated, this parent term is redundant but not incorrect. Keeping it as it accurately represents the general enzymatic class.
Supporting Evidence:
file:RABIT/G1TUN6/G1TUN6-uniprot.txt
Ubl conjugation pathway
|
|
GO:0032020
ISG15-protein conjugation
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ISG15-protein conjugation (ISGylation) is the core biological process that UBE2L6 participates in. This annotation was transferred from the well-characterized human ortholog (O14933/UBE2L6), which has been experimentally demonstrated to be the dedicated E2 enzyme for ISGylation. The rabbit ortholog, identified by Ensembl Compara, would be expected to retain this conserved function.
Reason: ISGylation is the primary biological process for UBE2L6, supported by ortholog transfer from the experimentally characterized human protein.
Supporting Evidence:
file:RABIT/G1TUN6/G1TUN6-goa.tsv
UniProtKB:O14933|ensembl:ENSP00000287156
|
|
GO:0042296
ISG15 transferase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ISG15 transferase activity is the core molecular function of UBE2L6. The human ortholog (O14933) has been experimentally shown to be the dedicated E2 enzyme that transfers ISG15 to substrate proteins in conjunction with E3 ligases. This annotation, transferred via Ensembl Compara and combined automated methods, is well-supported by the conserved UBC domain and orthologous relationship.
Reason: This is the most specific and informative molecular function annotation for UBE2L6, representing its primary enzymatic activity as the ISG15- specific E2 conjugating enzyme.
Supporting Evidence:
file:RABIT/G1TUN6/G1TUN6-uniprot.txt
ISG15 transferase activity; IEA:Ensembl
file:RABIT/G1TUN6/G1TUN6-goa.tsv
UniProtKB:O14933|ensembl:ENSP00000287156|UniProtKB:Q9QZU9|ensembl:ENSMUSP00000099702
|
|
GO:0045087
innate immune response
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: UBE2L6/UBCH8 participates in the innate immune response through its role in ISGylation. ISG15 conjugation is an interferon-stimulated defense mechanism that modifies viral and host proteins as part of the antiviral innate immune response. This annotation, transferred from the human ortholog via Ensembl Compara, correctly places UBE2L6 in the broader biological context of innate immunity.
Reason: While UBE2L6 does participate in the innate immune response through ISGylation, this is a high-level biological process term. The more specific ISG15-protein conjugation term (GO:0032020) more precisely captures the direct biological role. This annotation provides useful biological context but is not the most informative process-level annotation.
Supporting Evidence:
file:RABIT/G1TUN6/G1TUN6-goa.tsv
UniProtKB:O14933|ensembl:ENSP00000287156
|
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.
The gene UBE2L6 (UniProt: G1TUN6) from Oryctolagus cuniculus encodes an E2 ubiquitin-conjugating enzyme homologous to the human UBE2L6 (UbcH8), and is definitively established as a member of the ubiquitin-conjugating enzyme family based on sequence, protein family (UBC domain), and domain annotation (Ub_conjugating_enzyme, IPR000608, IPR050113, PF00179). This protein is unambiguously identified in rabbit and matches the expected domain and structural characteristics seen in mammalian orthologs (chen2024elucidatingthemechanism pages 1-3, kang2022thediverserepertoire pages 2-3, yao2026ubiquitinconjugatingenzymesin pages 1-3).
UBE2L6 serves as a bifunctional E2 enzyme, central to the ISG15 (interferon-stimulated gene 15) conjugation pathway (ISGylation) and capable of performing ubiquitin conjugation under certain circumstances. Its primary cellular role is in ISGylation, a post-translational modification that covalently links ISG15 to substrate proteins in a three-step enzymatic cascade. UBE2L6 specifically receives ISG15 from the E1 enzyme UBA7 (UBE1L) via a trans-thioesterification reaction. Structural and biochemical evidence show high specificity of UBE2L6 for UBA7 in ISGylation (with lower affinity for the canonical ubiquitin E1 enzyme, UBA1) and for E3 ligases such as HERC5, TRIM25, and HHARI/ARIH1, which confer substrate specificity in the ISGylation system (kang2022thediverserepertoire pages 2-3, tecalcocruz2023proteinisgylationa pages 1-3, mathieu2021herc5andthe pages 2-4).
The catalytic process involves:
- Activation of ISG15 by UBA7 (ATP-dependent),
- Transfer of ISG15 onto UBE2L6 catalytic cysteine through transthiolation,
- Handover to an E3 ligase for covalent (isopeptide bond) attachment to lysine residues on target proteins.
UBE2L6 can also catalyze the ubiquitination of substrate proteins, especially in infection and immune contexts, showing preference (experimentally validated) for K48-linked ubiquitination to promote proteasomal degradation of innate immune sensors. However, in vivo, its ISGylation activity dominates due to cellular pathway specialization (zhu2025porcinereproductiveand pages 2-4, kang2022thediverserepertoire pages 4-6).
| Enzymatic Property | Molecular Details | Citations |
|---|---|---|
| Enzyme classification | UBE2L6 (also called UbcH8) is an E2 ubiquitin/ubiquitin-like conjugating enzyme of the ubiquitin-conjugating enzyme family. In the ISG15 pathway it functions as the cognate E2 that receives activated ISG15 from the E1 enzyme UBA7/UBE1L; it can also participate in ubiquitination reactions. | (kang2022thediverserepertoire pages 2-3, sandy2020morethanmeets pages 1-4, mirzalieva2022isg15andisgylation pages 4-5) |
| Core catalytic role | UBE2L6 acts in the middle of the E1-E2-E3 cascade: activated ISG15 is first adenylated and linked to UBA7, then transferred to the active-site cysteine of UBE2L6, and finally passed to an E3 ligase or directly positioned for ligation to substrate lysines. This is the canonical conjugating-enzyme step of ISGylation. | (kang2022thediverserepertoire pages 2-3, tecalcocruz2023proteinisgylationa pages 1-3, mathieu2021herc5andthe pages 2-4) |
| Catalytic mechanism | The mechanism is thiol-based chemistry typical of E2 enzymes: UBA7 forms a thioester with ISG15, UBE2L6 accepts ISG15 by transthiolation/transesterification onto its catalytic cysteine, and downstream transfer yields an isopeptide bond between the C-terminus of ISG15 and a substrate lysine. | (tecalcocruz2023proteinisgylationa pages 1-3, mathieu2021herc5andthe pages 2-4, kang2022thediverserepertoire pages 2-3) |
| E1 enzyme specificity | Biochemical and structural work shows that UBE2L6 has much higher affinity for the ISG15 E1 UBA7/UBE1L than for the canonical ubiquitin E1 UBA1, supporting functional specificity for ISGylation in cells even though the enzyme can catalyze ubiquitin transfer in vitro. | (sandy2020morethanmeets pages 1-4, kang2022thediverserepertoire pages 2-3, chen2024elucidatingthemechanism pages 1-3) |
| UBA7-UBE2L6 structural interface | Cryo-EM and biochemical studies show that UBA7/UBE1L recruits UBE2L6 through its ubiquitin-fold domain (UFD), while additional contacts involve the SCCH domain and crossover loop. These contacts position the active sites for transfer of activated ISG15 and help explain pathway fidelity. | (wallace2023insightsintothe pages 2-3, wallace2023insightsintothe pages 1-2, chen2024elucidatingthemechanism pages 1-3) |
| Structural basis of specificity | Recent structural studies identified determinants that enforce UBA7-UBE2L6 selectivity, including strong UFD-mediated affinity, features of the catalytic cysteine capping loop, and favorable active-site cysteine chemistry. These determinants distinguish UBE2L6 from the closely related UBE2L3. | (chen2024elucidatingthemechanism pages 1-3, wallace2023insightsintothe pages 1-2) |
| Active-site chemistry | UBE2L6 contains the catalytic cysteine required for thioester formation with ISG15 (and ubiquitin in ubiquitination settings). Experimental structural trapping used a C86-only UBE2L6 construct, underscoring that this catalytic cysteine is essential for E1-to-E2 transfer. | (wallace2023insightsintothe pages 2-3, chen2024elucidatingthemechanism pages 1-3) |
| E1-E2 reaction intermediate | Structural capture of a chemically trapped UBE1L-UBE2L6 complex bound to activated ISG15 revealed how the first transfer steps occur and provided evidence for the transient E1-E2 intermediate that precedes substrate modification. | (wallace2023insightsintothe pages 1-2, wallace2023insightsintothe pages 2-3) |
| Disulfide/thioester-related chemistry | In addition to the normal thioester transfer step, UBA7 and UBE2L6 can form a disulfide-linked complex under biochemical conditions; recent work suggests this reflects strong and specific E1-E2 recognition and redox-sensitive control of the ISG15 transfer cascade. | (chen2024elucidatingthemechanism pages 1-3) |
| E3 ligase partners | The main E3 ligases functioning with UBE2L6 in ISGylation are HERC5, TRIM25/EFP, and HHARI/ARIH1. HERC5 is broadly active and relatively promiscuous, whereas TRIM25 and HHARI show more substrate selectivity. | (kang2022thediverserepertoire pages 2-3, sandy2020morethanmeets pages 1-4, mathieu2021herc5andthe pages 2-4) |
| HERC5-associated mechanism | In the HERC5 pathway, the UBE2L6~ISG15 thioester transfers ISG15 onward for covalent attachment to host or viral substrates. HERC5 can act co-translationally at polysomes, making UBE2L6 part of a ribosome-associated antiviral modification system. | (mathieu2021herc5andthe pages 1-2, mathieu2021herc5andthe pages 2-4, tecalcocruz2023proteinisgylationa pages 1-3) |
| Substrate specificity: ISG15 versus ubiquitin | UBE2L6 is best described as bifunctional: it is the principal E2 for ISG15 conjugation but is also capable of ubiquitin conjugation. In cells, its stronger biochemical preference for UBA7 and the interferon-induced ISGylation machinery make ISG15 transfer its dominant defined role. | (sandy2020morethanmeets pages 1-4, zhu2025porcinereproductiveand pages 2-4, mirzalieva2022isg15andisgylation pages 4-5) |
| Substrate attachment chemistry | The final product of UBE2L6-driven ISGylation is typically mono-ISGylation at substrate lysines via an isopeptide bond between the ISG15 C-terminal glycine motif and the ฮต-amino group of lysine on the target protein. | (tecalcocruz2023proteinisgylationa pages 1-3, mathieu2021herc5andthe pages 2-4) |
| Ubiquitination capacity | Beyond ISGylation, UBE2L6 can function as a ubiquitin-conjugating enzyme and has been implicated in ubiquitin-proteasome-mediated degradation of signaling proteins, especially in infection contexts where it promotes K48-linked ubiquitination of innate immune sensors. | (zhu2025porcinereproductiveand pages 2-4, kang2022thediverserepertoire pages 4-6) |
| Ubiquitin chain linkage types | Experimental infection studies indicate that UBE2L6 can promote K48-linked ubiquitination of RIG-I and MDA5, leading to proteasome-dependent degradation. Other literature also supports broader involvement of UBE2L6 in ubiquitin and ISG15 pathway cross-talk, though linkage specificity is best established for K48 in this context. | (zhu2025porcinereproductiveand pages 2-4, kang2022thediverserepertoire pages 4-6) |
| Domain features important for function | UBE2L6 is built around the conserved E2/UBC catalytic core. Its function depends on the canonical E2 fold, catalytic cysteine, and precise E1-recognition surfaces that allow discrimination between ISG15 and ubiquitin pathways. | (sandy2020morethanmeets pages 1-4, yao2026ubiquitinconjugatingenzymesin pages 1-3, chen2024elucidatingthemechanism pages 1-3) |
| Pathway fidelity | Structural and biochemical analyses show that fidelity in ISG15 signaling depends on selective UBA7-UBE2L6 pairing and recognition of the ISG15 C-terminal ubiquitin-like domain, preventing indiscriminate crossover with the ubiquitin system. | (wallace2023insightsintothe pages 1-2, chen2024elucidatingthemechanism pages 1-3, kang2022thediverserepertoire pages 2-3) |
Table: This table summarizes the enzymatic properties and molecular mechanism of UBE2L6, emphasizing its role as a dual ubiquitin/ISG15 E2 enzyme and highlighting structural evidence from recent cryo-EM and biochemical studies.
UBE2L6 is primarily cytoplasmic, with notable enrichment at sites of active protein translation due to interactions with polysome-associated HERC5, suggesting a role in co-translational ISGylation of nascent proteins. Its distribution can be modulated under stress conditions, including viral infection, and phosphorylation of regulatory motifs affects its subcellular localization (tecalcocruz2023proteinisgylationa pages 1-3, kang2022thediverserepertoire pages 4-6, mathieu2021herc5andthe pages 1-2).
UBE2L6 is a key effector of the type I interferon (IFN)โstimulated ISGylation pathway, and plays a crucial role in innate immunity, antiviral defense, inflammation, metabolism, and protein homeostasis. Upon IFN/JAK-STAT pathway activation, UBE2L6 is upregulated alongside ISG15 and E3 ligase partners, underpinning a broad antiviral and cellular stress response.
Mechanisms include:
- Covalent modification of host and viral proteins via ISGylation, suppressing viral replication and propagation.
- UBE2L6-catalyzed ubiquitination of RIG-I/MDA5 (targets of K48-linked ubiquitination and proteasomal degradation) as exploited by specific viruses for immune evasion (e.g., PRRSV, SVA), and modulation of innate sensor stability.
- Promotion of STAT1 ISGylation (in obesity), biasing macrophages toward an M1 inflammatory phenotype.
- Regulation of adipocyte lipid metabolism via ATGL degradation: UBE2L6 ablation in adipose tissue prevents diet-induced obesity and insulin resistance in mice.
- Participation in DNA damage responses and proteostasis, including regulation of newly synthesized and misfolded proteins, partially via cotranslational ISGylation at ribosomes (tecalcocruz2023proteinisgylationa pages 1-3, sandy2020morethanmeets pages 1-4, wei2021adiposespecificknockoutof pages 2-3, mathieu2021herc5andthe pages 2-4).
| Pathway/Process | Specific Role of UBE2L6 | Key Target Proteins/Substrates | Biological Outcome |
|---|---|---|---|
| ISGylation pathway and interferon response | UBE2L6 is the principal E2 enzyme in the ISG15 conjugation cascade induced by type I interferon; it receives activated ISG15 from UBA7/UBE1L and transfers it to substrates with E3 ligases such as HERC5, TRIM25, and HHARI. In cells, UBE2L6 shows higher functional affinity for the ISG15 pathway than for canonical ubiquitin transfer. (kang2022thediverserepertoire pages 2-3, sandy2020morethanmeets pages 1-4, mathieu2021herc5andthe pages 2-4, mirzalieva2022isg15andisgylation pages 4-5) | ISG15; UBA7/UBE1L; HERC5, TRIM25, HHARI; broad host and viral protein substrates | Establishes interferon-stimulated ISGylation, a core antiviral and stress-response pathway that remodels protein stability, interactions, and signaling. (kang2022thediverserepertoire pages 2-3, mathieu2021herc5andthe pages 2-4, mirzalieva2022isg15andisgylation pages 4-5) |
| Innate antiviral immunity | UBE2L6 supports antiviral defense by enabling ISGylation of host and viral proteins and by participating in interferon-stimulated effector programs. Its expression is induced with ISG15 pathway genes downstream of IFN/JAK-STAT signaling. (mathieu2021herc5andthe pages 1-2, mathieu2021herc5andthe pages 2-4, kang2022thediverserepertoire pages 4-6) | Viral proteins such as influenza NP and other newly synthesized viral proteins via HERC5-associated cotranslational ISGylation; host antiviral signaling proteins | Restricts viral protein synthesis, assembly, and replication, and amplifies innate immune responsiveness. In some virus-host contexts, pathogens can hijack UBE2L6 to weaken immunity. (mathieu2021herc5andthe pages 2-4, kang2022thediverserepertoire pages 4-6, zhu2025porcinereproductiveand pages 2-4) |
| Regulation of RIG-I/MDA5 signaling | UBE2L6 modulates RIG-I-like receptor signaling through ubiquitin/ISG15-dependent mechanisms. During PRRSV infection, elevated UBE2L6 promotes K48-linked ubiquitination and proteasomal loss of RIG-I and MDA5, aided by viral NSP5; broader ISG15 literature also links ISGylation to RIG-I/MDA5 regulation. (zhu2025porcinereproductiveand pages 2-4, kang2022thediverserepertoire pages 4-6) | RIG-I, MDA5, PRRSV NSP5, K48-linked ubiquitin, ISG15 | Suppresses type I IFN and ISG expression during PRRSV infection, facilitating viral replication; demonstrates that UBE2L6 can either support host defense or be co-opted by viruses. (zhu2025porcinereproductiveand pages 2-4) |
| STAT1 signaling and macrophage polarization | In obese mouse models, Ube2L6 promotes STAT1 ISGylation/ISG15-dependent activation, increasing STAT1 abundance and phosphorylation and biasing macrophages toward a pro-inflammatory M1 state. (li2024ube2l6promotesm1 pages 2-3, li2024ube2l6promotesm1 pages 3-4) | STAT1, ISG15, macrophage polarization machinery | Enhances M1 macrophage polarization, inflammatory cytokine production, and obesity-associated inflammation; Ube2L6 deficiency shifts macrophages away from the M1 phenotype. (li2024ube2l6promotesm1 pages 2-3, li2024ube2l6promotesm1 pages 3-4) |
| Adipocyte metabolism and lipid regulation | In adipose tissue, Ube2L6 negatively regulates ATGL stability and thereby restrains lipolysis. Adipose-specific Ube2l6 knockout in mice increases ATGL stability and alters adipocyte size and differentiation under high-fat diet conditions. Human obesity datasets/tissues also show inverse UBE2L6-ATGL association and positive correlation with BMI. (wei2021adiposespecificknockoutof pages 2-3) | ATGL/PNPLA2; adipocyte lipid-droplet/lipolysis machinery | Promotes diet-induced obesity, insulin resistance, hepatic steatosis, and adipose expansion when elevated; loss of Ube2L6 improves metabolic phenotype in mice. (wei2021adiposespecificknockoutof pages 2-3) |
| Protein quality control and proteostasis | Through the ISG15 system, UBE2L6 contributes to proteostasis by promoting cotranslational ISGylation of newly synthesized proteins together with HERC5, altering ubiquitin-dependent turnover and helping manage misfolded, viral, or stress-induced substrates. Reduced UBE2L6 lowers ISGylation and can increase ubiquitination in some cancer-cell models. (tecalcocruz2023proteinisgylationa pages 1-3, kang2022thediverserepertoire pages 4-6) | Newly synthesized proteins, ubiquitin, ISG15, HERC5-associated polysome substrates, Ubc13 and other proteostasis-linked factors | Regulates stability and turnover of protein substrates, restricts nascent viral proteins, and contributes to the balance between ISGylation and ubiquitin-proteasome pathways. (tecalcocruz2023proteinisgylationa pages 1-3, kang2022thediverserepertoire pages 4-6) |
| DNA damage response | UBE2L6 participates in the ISG15 system increasingly linked to genome stability. Reviews identify UBE2L6-dependent ISGylation as part of pathways affecting p53 signaling, replication stress responses, and DNA repair-associated proteome remodeling. (sandy2020morethanmeets pages 1-4, kang2022thediverserepertoire pages 4-6) | ISG15 pathway components; DDR-associated proteins including p53-network and replication/repair factors discussed in ISG15 studies | Suggests a role in maintaining genome stability and modulating DNA damage responses, though many UBE2L6-specific substrates in this context remain incompletely defined. (sandy2020morethanmeets pages 1-4, kang2022thediverserepertoire pages 4-6) |
| Autophagy regulation | UBE2L6 contributes indirectly to autophagy-related control through ISGylation-dependent regulation of proteins such as BECN1 and by modulating antiviral signaling nodes that connect to autophagic degradation pathways. ISG15 literature also links ISGylation to RIG-I-associated autophagy control. (tecalcocruz2023proteinisgylationa pages 1-3, kang2022thediverserepertoire pages 4-6) | BECN1, RIG-I-associated complexes, ISG15-modified stress-response proteins | Can influence antiviral autophagy and selective degradation pathways, thereby integrating innate immune signaling with cellular quality-control responses. (tecalcocruz2023proteinisgylationa pages 1-3, kang2022thediverserepertoire pages 4-6) |
Table: This table summarizes experimentally supported and review-backed roles of UBE2L6 across interferon signaling, antiviral immunity, metabolism, inflammation, and proteostasis. It is useful for functional annotation because it links pathway membership to specific substrates and biological outcomes.
Recent in vivo mouse studies demonstrate that:
- Adipose-specific knockout of Ube2l6 reduces obesity and insulin resistance via increased ATGL stability (wei2021adiposespecificknockoutof pages 2-3).
- Ube2l6 knockdown modulates macrophage polarization and inflammation in metabolic disease settings (li2024ube2l6promotesm1 pages 2-3).
- UBE2L6 is upregulated by type I IFN responses and in metabolic and cardiovascular disease risk tissue (kang2022thediverserepertoire pages 4-6).
This comprehensive annotation integrates recent advances (up to 2025), with authoritative structural, biochemical, and physiological evidence contextualized for O. cuniculus UBE2L6. Current literature and data demonstrate its essential cellular roles in ISGylation, metabolism, and antiviral immunity, all underpinned by precise enzymatic mechanisms and pathway integration. Further details and primary data can be found in the referenced publications and database entries (see URLs above).
References
(chen2024elucidatingthemechanism pages 1-3): Pei-Tzu Chen, Jia-Yin Yeh, Jui-Hsia Weng, and Kuen-Phon Wu. Elucidating the mechanism underlying uba7โขube2l6 disulfide complex formation. bioRxiv, Nov 2024. URL: https://doi.org/10.1101/2024.11.07.622398, doi:10.1101/2024.11.07.622398. This article has 1 citations.
(kang2022thediverserepertoire pages 2-3): Ji An Kang, Yoon Jung Kim, and Young Joo Jeon. The diverse repertoire of isg15: more intricate than initially thought. Experimental & Molecular Medicine, 54:1779-1792, Nov 2022. URL: https://doi.org/10.1038/s12276-022-00872-3, doi:10.1038/s12276-022-00872-3. This article has 108 citations and is from a peer-reviewed journal.
(yao2026ubiquitinconjugatingenzymesin pages 1-3): Zhiyang Yao, Ti Peng, Hao Dong, Yong Liao, Kai Miao, Jiang-Jiang Qin, and Xiaoqing Guan. Ubiquitin-conjugating enzymes in cancer. International Journal of Biological Sciences, 22:3244-3271, Mar 2026. URL: https://doi.org/10.7150/ijbs.130297, doi:10.7150/ijbs.130297. This article has 46 citations and is from a peer-reviewed journal.
(tecalcocruz2023proteinisgylationa pages 1-3): Angeles C. Tecalco-Cruz and Jesรบs Zepeda-Cervantes. Protein isgylation: a posttranslational modification with implications for malignant neoplasms. Exploration of Targeted Anti-tumor Therapy, 4:699-715, Aug 2023. URL: https://doi.org/10.37349/etat.2023.00162, doi:10.37349/etat.2023.00162. This article has 14 citations.
(mathieu2021herc5andthe pages 2-4): Nicholas A. Mathieu, Ermela Paparisto, Stephen D. Barr, and Donald E. Spratt. Herc5 and the isgylation pathway: critical modulators of the antiviral immune response. Viruses, 13:1102, Jun 2021. URL: https://doi.org/10.3390/v13061102, doi:10.3390/v13061102. This article has 91 citations.
(zhu2025porcinereproductiveand pages 2-4): Zhenbang Zhu, Lulu Chen, Meng Zhang, Qianwen Lin, Yifan Yan, Wenqiang Wang, Wei Wen, Zhendong Zhang, and Xiangdong Li. Porcine reproductive and respiratory syndrome virus nsp5 exploited ube2l6 to promote viral replication via antagonising host rlrs and isgylation. Veterinary Research, Jul 2025. URL: https://doi.org/10.1186/s13567-025-01558-0, doi:10.1186/s13567-025-01558-0. This article has 5 citations and is from a highest quality peer-reviewed journal.
(kang2022thediverserepertoire pages 4-6): Ji An Kang, Yoon Jung Kim, and Young Joo Jeon. The diverse repertoire of isg15: more intricate than initially thought. Experimental & Molecular Medicine, 54:1779-1792, Nov 2022. URL: https://doi.org/10.1038/s12276-022-00872-3, doi:10.1038/s12276-022-00872-3. This article has 108 citations and is from a peer-reviewed journal.
(sandy2020morethanmeets pages 1-4): Zac Sandy, Isabelle Cristine da Costa, and Christine K. Schmidt. More than meets the isg15: emerging roles in the dna damage response and beyond. Biomolecules, 10:1557, Nov 2020. URL: https://doi.org/10.3390/biom10111557, doi:10.3390/biom10111557. This article has 65 citations.
(mirzalieva2022isg15andisgylation pages 4-5): Oygul Mirzalieva, Meredith Juncker, Joshua Schwartzenburg, and Shyamal Desai. Isg15 and isgylation in human diseases. Cells, 11:538, Feb 2022. URL: https://doi.org/10.3390/cells11030538, doi:10.3390/cells11030538. This article has 130 citations.
(wallace2023insightsintothe pages 2-3): Iona Wallace, Kheewoong Baek, J. Rajan Prabu, Ronnald Vollrath, Susanne von Gronau, Brenda A. Schulman, and Kirby N. Swatek. Insights into the isg15 transfer cascade by the ube1l activating enzyme. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43711-3, doi:10.1038/s41467-023-43711-3. This article has 31 citations and is from a highest quality peer-reviewed journal.
(wallace2023insightsintothe pages 1-2): Iona Wallace, Kheewoong Baek, J. Rajan Prabu, Ronnald Vollrath, Susanne von Gronau, Brenda A. Schulman, and Kirby N. Swatek. Insights into the isg15 transfer cascade by the ube1l activating enzyme. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43711-3, doi:10.1038/s41467-023-43711-3. This article has 31 citations and is from a highest quality peer-reviewed journal.
(mathieu2021herc5andthe pages 1-2): Nicholas A. Mathieu, Ermela Paparisto, Stephen D. Barr, and Donald E. Spratt. Herc5 and the isgylation pathway: critical modulators of the antiviral immune response. Viruses, 13:1102, Jun 2021. URL: https://doi.org/10.3390/v13061102, doi:10.3390/v13061102. This article has 91 citations.
(wei2021adiposespecificknockoutof pages 2-3): Weiping Wei, Yunqian Li, Yongyong Li, and Daoyuan Li. Adipose-specific knockout of ubiquitin-conjugating enzyme e2l6 (ube2l6) reduces diet-induced obesity, insulin resistance, and hepatic steatosis. Journal of pharmacological sciences, 145 4:327-334, Apr 2021. URL: https://doi.org/10.1016/j.jphs.2020.12.008, doi:10.1016/j.jphs.2020.12.008. This article has 18 citations and is from a peer-reviewed journal.
(li2024ube2l6promotesm1 pages 2-3): Yunqian Li, Xiao Dong, Wenqian He, Huibiao Quan, Kaining Chen, Chaoping Cen, and Weiping Wei. Ube2l6 promotes m1 macrophage polarization in high-fat diet-fed obese mice via isgylation of stat1 to trigger stat1 activation. Obesity Facts, 17:24-36, Oct 2024. URL: https://doi.org/10.1159/000533966, doi:10.1159/000533966. This article has 17 citations and is from a peer-reviewed journal.
(li2024ube2l6promotesm1 pages 3-4): Yunqian Li, Xiao Dong, Wenqian He, Huibiao Quan, Kaining Chen, Chaoping Cen, and Weiping Wei. Ube2l6 promotes m1 macrophage polarization in high-fat diet-fed obese mice via isgylation of stat1 to trigger stat1 activation. Obesity Facts, 17:24-36, Oct 2024. URL: https://doi.org/10.1159/000533966, doi:10.1159/000533966. This article has 17 citations and is from a peer-reviewed journal.
id: G1TUN6
gene_symbol: UBE2L6
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:9986
label: Oryctolagus cuniculus
description: >-
UBE2L6 (also known as UBCH8) is an E2 ubiquitin-conjugating enzyme belonging
to the UBE2L family. It functions as the principal E2 enzyme in the ISG15
conjugation (ISGylation) pathway, an interferon-stimulated ubiquitin-like
modification system that is part of the innate immune defense against viral
infection. UBE2L6 accepts activated ISG15 from the E1 enzyme UBA7 and
transfers it to target proteins in conjunction with E3 ligases such as HERC5.
The protein contains a single UBC catalytic domain with a conserved active-site
cysteine that forms a thioester intermediate with ubiquitin or ISG15. While
UBE2L6 can also function as an E2 for ubiquitin conjugation in vitro, its
primary physiological role is in ISGylation during the type I interferon
response.
existing_annotations:
- term:
id: GO:0005524
label: ATP binding
evidence_type: IEA
original_reference_id: GO_REF:0000104
qualifier: enables
review:
summary: >-
ATP binding is not a direct molecular function of E2 ubiquitin-conjugating
enzymes. E2 enzymes accept activated ubiquitin (or ubiquitin-like
proteins) from E1 activating enzymes via a transthioesterification
reaction; it is the E1 enzyme that requires ATP to adenylate ubiquitin.
This annotation likely arose from an automated rule transfer that
conflates the ATP requirement of the E1 step with the E2 enzyme itself.
action: REMOVE
reason: >-
E2 ubiquitin-conjugating enzymes do not bind or hydrolyze ATP. The ATP
dependence belongs to the E1 activating enzyme (UBA7/UBE1L for ISG15, or
UBA1 for ubiquitin). This is an erroneous IEA annotation.
supported_by:
- reference_id: file:RABIT/G1TUN6/G1TUN6-uniprot.txt
supporting_text: >-
S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine +
[E2 ubiquitin-conjugating enzyme]-L-cysteine = [E1 ubiquitin-
activating enzyme]-L-cysteine + S-ubiquitinyl-[E2 ubiquitin-
conjugating enzyme]-L-cysteine
- term:
id: GO:0016874
label: ligase activity
evidence_type: IEA
original_reference_id: GO_REF:0000104
qualifier: enables
review:
summary: >-
The term 'ligase activity' (GO:0016874) is too broad and arguably
misleading for an E2 enzyme. E2 enzymes are transferases (EC 2.3.2.23)
that transfer ubiquitin or ubiquitin-like modifiers from an E1 thioester
to a substrate. True ligase activity in the ubiquitin system is associated
with E3 ubiquitin ligases. The EC number 2.3.2.23 assigned to this
protein is in the transferase class, not the ligase class.
action: REMOVE
reason: >-
E2 enzymes are classified as transferases (EC 2.3.2.23), not ligases.
Calling an E2 a ligase is misleading; the ligase function belongs to E3
enzymes that catalyze the final transfer to substrate lysine residues.
supported_by:
- reference_id: file:RABIT/G1TUN6/G1TUN6-uniprot.txt
supporting_text: "EC=2.3.2.23"
- term:
id: GO:0061631
label: ubiquitin conjugating enzyme activity
evidence_type: IEA
original_reference_id: GO_REF:0000003
qualifier: enables
review:
summary: >-
UBE2L6 is an E2 ubiquitin-conjugating enzyme with a conserved UBC domain
and active-site cysteine. While its primary physiological role is in
ISGylation rather than ubiquitin conjugation, UBE2L6 retains E2 enzymatic
activity for ubiquitin conjugation and is classified under EC 2.3.2.23.
This annotation correctly captures the general enzymatic activity of the
protein.
action: KEEP_AS_NON_CORE
reason: >-
The ubiquitin conjugating enzyme activity is a valid biochemical activity
for this E2 enzyme, but the primary physiological role of UBE2L6 is as an
ISG15-specific E2, making this a secondary rather than core function.
supported_by:
- reference_id: file:RABIT/G1TUN6/G1TUN6-uniprot.txt
supporting_text: "Belongs to the ubiquitin-conjugating enzyme family"
- reference_id: file:RABIT/G1TUN6/G1TUN6-uniprot.txt
supporting_text: "EC=2.3.2.23"
- term:
id: GO:0019787
label: ubiquitin-like protein transferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: >-
UBE2L6 is indeed a ubiquitin-like protein transferase, as it transfers
ISG15 (a ubiquitin-like protein) to substrates. This annotation is
correct and captures the broader enzymatic category that encompasses both
the ubiquitin and ISG15 transferase activities of this E2 enzyme. It is
a parent term of the more specific ISG15 transferase activity.
action: ACCEPT
reason: >-
This correctly captures UBE2L6 as a transferase for ubiquitin-like
proteins. Since the more specific ISG15 transferase activity is also
annotated, this parent term is redundant but not incorrect. Keeping it
as it accurately represents the general enzymatic class.
supported_by:
- reference_id: file:RABIT/G1TUN6/G1TUN6-uniprot.txt
supporting_text: "Ubl conjugation pathway"
- term:
id: GO:0032020
label: ISG15-protein conjugation
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: >-
ISG15-protein conjugation (ISGylation) is the core biological process
that UBE2L6 participates in. This annotation was transferred from the
well-characterized human ortholog (O14933/UBE2L6), which has been
experimentally demonstrated to be the dedicated E2 enzyme for ISGylation.
The rabbit ortholog, identified by Ensembl Compara, would be expected to
retain this conserved function.
action: ACCEPT
reason: >-
ISGylation is the primary biological process for UBE2L6, supported by
ortholog transfer from the experimentally characterized human protein.
supported_by:
- reference_id: file:RABIT/G1TUN6/G1TUN6-goa.tsv
supporting_text: "UniProtKB:O14933|ensembl:ENSP00000287156"
- term:
id: GO:0042296
label: ISG15 transferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: >-
ISG15 transferase activity is the core molecular function of UBE2L6.
The human ortholog (O14933) has been experimentally shown to be the
dedicated E2 enzyme that transfers ISG15 to substrate proteins in
conjunction with E3 ligases. This annotation, transferred via Ensembl
Compara and combined automated methods, is well-supported by the
conserved UBC domain and orthologous relationship.
action: ACCEPT
reason: >-
This is the most specific and informative molecular function annotation
for UBE2L6, representing its primary enzymatic activity as the ISG15-
specific E2 conjugating enzyme.
supported_by:
- reference_id: file:RABIT/G1TUN6/G1TUN6-uniprot.txt
supporting_text: "ISG15 transferase activity; IEA:Ensembl"
- reference_id: file:RABIT/G1TUN6/G1TUN6-goa.tsv
supporting_text: "UniProtKB:O14933|ensembl:ENSP00000287156|UniProtKB:Q9QZU9|ensembl:ENSMUSP00000099702"
- term:
id: GO:0045087
label: innate immune response
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: >-
UBE2L6/UBCH8 participates in the innate immune response through its role
in ISGylation. ISG15 conjugation is an interferon-stimulated defense
mechanism that modifies viral and host proteins as part of the antiviral
innate immune response. This annotation, transferred from the human
ortholog via Ensembl Compara, correctly places UBE2L6 in the broader
biological context of innate immunity.
action: KEEP_AS_NON_CORE
reason: >-
While UBE2L6 does participate in the innate immune response through
ISGylation, this is a high-level biological process term. The more
specific ISG15-protein conjugation term (GO:0032020) more precisely
captures the direct biological role. This annotation provides useful
biological context but is not the most informative process-level
annotation.
supported_by:
- reference_id: file:RABIT/G1TUN6/G1TUN6-goa.tsv
supporting_text: "UniProtKB:O14933|ensembl:ENSP00000287156"
core_functions:
- description: >-
UBE2L6 functions as the dedicated E2 conjugating enzyme for ISG15, an
interferon-stimulated ubiquitin-like modifier. It accepts activated ISG15
from the E1 enzyme UBA7 via a thioester bond at its active-site cysteine
and transfers it to substrate proteins in cooperation with E3 ligases.
molecular_function:
id: GO:0042296
label: ISG15 transferase activity
directly_involved_in:
- id: GO:0032020
label: ISG15-protein conjugation
references:
- id: GO_REF:0000003
title: Gene Ontology annotation based on Enzyme Commission mapping
findings: []
- id: GO_REF:0000104
title: Electronic Gene Ontology annotations created by transferring manual GO annotations
between related proteins based on shared sequence features
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: []