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organism: human
gene_id: AREL1
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protein_description: 'RecName: Full=Apoptosis-resistant E3 ubiquitin protein ligase
1 {ECO:0000305}; EC=2.3.2.26 {ECO:0000269|PubMed:23479728, ECO:0000269|PubMed:25752577};
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gene_info: Name=AREL1 {ECO:0000303|PubMed:23479728, ECO:0000312|HGNC:HGNC:20363};
Synonyms=KIAA0317 {ECO:0000303|PubMed:9205841};
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: AREL1_N. (IPR058906); E3_ubiq-protein_ligase. (IPR050409); Filamin/ABP280_repeat-like.
(IPR017868); HECT_dom. (IPR000569); Hect_E3_ubiquitin_ligase. (IPR035983)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: O15033
• Protein Description: RecName: Full=Apoptosis-resistant E3 ubiquitin protein ligase 1 {ECO:0000305}; EC=2.3.2.26 {ECO:0000269|PubMed:23479728, ECO:0000269|PubMed:25752577}; AltName: Full=Apoptosis-resistant HECT-type E3 ubiquitin transferase 1 {ECO:0000303|PubMed:23479728};
• Gene Information: Name=AREL1 {ECO:0000303|PubMed:23479728, ECO:0000312|HGNC:HGNC:20363}; Synonyms=KIAA0317 {ECO:0000303|PubMed:9205841};
• Organism (full): Homo sapiens (Human).
• Protein Family: Not specified in UniProt
• Key Domains: AREL1_N. (IPR058906); E3_ubiq-protein_ligase. (IPR050409); Filamin/ABP280_repeat-like. (IPR017868); HECT_dom. (IPR000569); Hect_E3_ubiquitin_ligase. (IPR035983)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "AREL1" matches the protein description above
2. Verify the organism is correct: Homo sapiens (Human).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'AREL1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene AREL1 (gene ID: AREL1, UniProt: O15033) in human.

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.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: O15033
• Protein Description: RecName: Full=Apoptosis-resistant E3 ubiquitin protein ligase 1 {ECO:0000305}; EC=2.3.2.26 {ECO:0000269|PubMed:23479728, ECO:0000269|PubMed:25752577}; AltName: Full=Apoptosis-resistant HECT-type E3 ubiquitin transferase 1 {ECO:0000303|PubMed:23479728};
• Gene Information: Name=AREL1 {ECO:0000303|PubMed:23479728, ECO:0000312|HGNC:HGNC:20363}; Synonyms=KIAA0317 {ECO:0000303|PubMed:9205841};
• Organism (full): Homo sapiens (Human).
• Protein Family: Not specified in UniProt
• Key Domains: AREL1_N. (IPR058906); E3_ubiq-protein_ligase. (IPR050409); Filamin/ABP280_repeat-like. (IPR017868); HECT_dom. (IPR000569); Hect_E3_ubiquitin_ligase. (IPR035983)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "AREL1" matches the protein description above
2. Verify the organism is correct: Homo sapiens (Human).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'AREL1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene AREL1 (gene ID: AREL1, UniProt: O15033) in human.

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

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

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

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

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

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

Comprehensive Research Report: Human AREL1 (UniProt O15033)

Executive summary
AREL1 (Apoptosis-resistant E3 ubiquitin protein ligase 1; gene alias KIAA0317) is a human HECT-type E3 ubiquitin ligase that suppresses apoptosis by ubiquitinating pro-apoptotic factors, notably the IAP antagonist SMAC/DIABLO, and inhibits TNF-induced necroptosis by promoting proteasomal degradation of the mitochondrial outer membrane-associated protein MTX2. Structural studies reveal an extended HECT domain with a required N-terminal extension and critical C-terminal determinants for catalysis and chain-type preference. These biochemical and structural features underpin AREL1’s anti-apoptotic and anti-necroptotic functions, with emerging relevance in cancer biology and potential for targeted modulation. (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 1-2, jo2021arel1e3ubiquitin pages 2-4)

1) Key concepts and definitions with current understanding
- Identity and verification: AREL1 encodes an 823-aa HECT-type E3 ubiquitin ligase in Homo sapiens (UniProt O15033). The literature consistently describes a catalytic HECT C-lobe harboring the active-site cysteine and an N-lobe that engages E2 enzymes, consistent with HECT family architecture. An N-terminal extension immediately preceding the HECT core (approx. aa 436–482) is essential for stability and activity; a unique loop (aa 567–573) is not present in other HECTs. These features confirm correct gene/protein identity and domain organization. The alias KIAA0317 is recognized in older annotations. (J Biol Chem, Dec 2019, DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 1-2, singh2019structuralinsightsinto pages 2-3)
- Domain architecture: Extended HECT domain solved at 2.4 Å (aa 436–823) exhibits an inverted T-shaped bilobed architecture (N- and C-lobes) with inter-lobe contacts important for activity. The catalytic cysteine is Cys790 in the C-lobe. The extreme C-terminus (including Phe820 and the last three residues) is required for auto-ubiquitination and substrate ubiquitination. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 2-3, singh2019structuralinsightsinto pages 10-12)

2) Biochemical function and mechanism (reaction and specificity)
- Enzymatic class and mechanism: AREL1 is a HECT-type E3 ligase that forms a thioester with ubiquitin on its catalytic cysteine (Cys790) prior to isopeptide transfer to lysines on substrates. Structural and mutational data support classic HECT transthiolation. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 2-3)
- E2 enzyme partner(s): In vitro reconstitution used UBA1 (E1) and UbcH7 (E2), with the N-lobe small subdomain implicated in E2 engagement. AREL1 can display weak E2-independent activity in vitro but is markedly more efficient with UbcH7. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 14-15, singh2019structuralinsightsinto pages 12-13)
- Ubiquitin chain types produced: The extended AREL1 HECT assembles Lys33-, Lys48-, and Lys63-linked polyubiquitin chains in vitro; the last ~60 amino acids of the C-lobe determine linkage specificity. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 8-9)
- Autoubiquitination and regulatory residues: AREL1 autoubiquitinates in vitro. Mutation E701A (N-lobe) enhances auto- and substrate ubiquitination, indicating inter-lobe contacts modulate activity. Deleting the last three C-terminal residues abolishes autoubiquitination and reduces substrate ubiquitination; F820A near the C-terminus severely impairs activity. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 8-9, singh2019structuralinsightsinto pages 10-12)

3) Validated substrates, substrate lysines, and functional outcomes
- SMAC/DIABLO (IAP antagonist): AREL1 ubiquitinates SMAC primarily on Lys62 and Lys191 (identified by site-directed mutagenesis and supported by a 2.8 Å SMAC tetramer structure). Functional outcome is ubiquitin-dependent modification consistent with reduced SMAC function and anti-apoptotic effects; overexpression of AREL1 confers apoptotic resistance, whereas knockdown sensitizes cells. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 1-2, singh2019structuralinsightsinto pages 8-9, singh2019structuralinsightsinto pages 10-12)
- IAP antagonists HtrA2 and ARTS: AREL1 has been reported to mediate degradation of these pro-apoptotic IAP antagonists, aligned with an anti-apoptotic role. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 1-2)
- MTX2 (Metaxin 2): AREL1 binds MTX2’s C-terminus, promotes its polyubiquitination and proteasome-dependent degradation (rescued by MG132). The catalytically inactive mutant C790A fails to degrade MTX2. Functional consequence: suppression of TNF+zVAD–induced necroptosis in cell models. (Exp Ther Med, Aug 2021; DOI: 10.3892/etm.2021.10629) (jo2021arel1e3ubiquitin pages 2-4)

4) Subcellular localization and context of action
- AREL1 is predominantly cytosolic. It regulates mitochondrial outer membrane-associated processes by targeting MTX2, a protein that interacts with MTX1 on the cytosolic face of the mitochondrial outer membrane. Thus, AREL1 acts from the cytosol on substrates that influence mitochondrial cell death signaling. (Exp Ther Med, 2021; DOI: 10.3892/etm.2021.10629) (jo2021arel1e3ubiquitin pages 2-4)

5) Pathway roles: apoptosis and necroptosis; disease relevance
- Apoptosis: By ubiquitinating and degrading SMAC/DIABLO (and possibly other IAP antagonists), AREL1 counteracts IAP inhibition, thereby suppressing caspase activation and apoptosis. This anti-apoptotic role is supported by cellular assays in which AREL1 overexpression confers resistance and knockdown sensitizes cells to apoptosis. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 1-2)
- Necroptosis: AREL1 inhibits TNF-induced necroptosis via MTX2 ubiquitination and degradation, without altering RIP3 protein levels in the reported system. This places AREL1 as a negative regulator of necroptotic cell death linked to mitochondrial outer membrane components. (Exp Ther Med, 2021; DOI: 10.3892/etm.2021.10629) (jo2021arel1e3ubiquitin pages 2-4)
- Cancer relevance and therapeutic context: A 2023 review of E3 ligases in cancer lists AREL1 among E3s that ubiquitinate and degrade SMAC to inhibit apoptosis, aligning AREL1 with processes that promote tumor cell survival and potential therapy resistance to pro-apoptotic strategies. The same review highlights the development of SMAC mimetics to overcome IAP-mediated apoptosis evasion, conceptually intersecting with AREL1’s activity on SMAC. (Clin Transl Med, Mar 2023; DOI: 10.1002/ctm2.1204) (sampson2023therolesof pages 11-12)

6) Structural insights and critical residues
- AREL1 HECT domain structures: The extended HECT domain (aa 436–823) was solved at 2.4 Å, revealing bilobed architecture and inter-lobe interfaces that include Glu701 contacts with C-lobe residues. The catalytic cysteine is Cys790 in the C-lobe. Structural work also solved a 2.8 Å tetrameric SMAC structure used to map ubiquitination sites Lys62 and Lys191. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 2-3, singh2019structuralinsightsinto pages 14-15, singh2019structuralinsightsinto pages 8-9)
- Activity-determining elements: The N-terminal extension (aa 436–482) is required for stability/activity; deletion (aa 483–823 construct) abrogated activity. The extreme C-terminus is indispensable: Δ3CT blocks auto-ubiquitination; F820A impairs SMAC ubiquitination. E701A increases auto- and substrate ubiquitination, highlighting regulatory inter-lobe contacts. An AREL1-specific ubiquitin variant (UbV KL.3) binds the extended HECT and inhibits SMAC ubiquitination in vitro, suggesting avenues for inhibitor design. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 14-15, singh2019structuralinsightsinto pages 12-13, singh2019structuralinsightsinto pages 10-12)

7) Recent developments (prioritizing 2023–2024) and expert perspectives
- 2023 cancer review: AREL1 is explicitly listed as an anti-apoptotic E3 that ubiquitinates/degrades SMAC, placing it in the broader framework of E3 ligases implicated in tumor progression and as potential therapeutic targets. Publication: March 2023, Clinical and Translational Medicine, URL: https://doi.org/10.1002/ctm2.1204. (sampson2023therolesof pages 11-12)
- Context within apoptosis/necroptosis ubiquitination: Contemporary reviews synthesize the centrality of ubiquitination in death receptor signaling and mitochondrial apoptosis control; AREL1 is recognized within this landscape as an anti-apoptotic HECT E3 that acts on IAP antagonists. While our curated 2023–2024 sources include the above cancer-focused review, the core mechanistic evidence for AREL1 still derives from foundational structural biochemistry (2019) and necroptosis-focused cell biology (2021). (sampson2023therolesof pages 11-12, singh2019structuralinsightsinto pages 1-1, jo2021arel1e3ubiquitin pages 2-4)

8) Current applications and real-world implementations
- Mechanism-informed inhibitor concepts: The UbV KL.3 variant binds the extended AREL1 HECT and reduces SMAC ubiquitination in vitro, providing a tool compound concept and proof-of-principle for direct modulation of AREL1 E3 activity. This suggests a potential strategy to restore pro-apoptotic signaling in settings where AREL1 suppresses apoptosis. (J Biol Chem, 2019; DOI: 10.1074/jbc.ra119.010327) (singh2019structuralinsightsinto pages 14-15)
- Therapeutic intersection: Because AREL1 targets SMAC/DIABLO, its activity intersects with SMAC mimetic strategies that aim to neutralize IAPs and promote apoptosis in cancer. Reviews emphasize the therapeutic relevance of shifting the IAP–SMAC balance; AREL1 may represent a modulatory node in this axis. (Clin Transl Med, 2023; DOI: 10.1002/ctm2.1204) (sampson2023therolesof pages 11-12)

9) Relevant quantitative data and specific details
- AREL1 HECT structure (extended): 2.4 Å resolution; required N-terminal extension aa 436–482; unique loop aa 567–573; catalytic Cys790. (J Biol Chem, 2019) (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 2-3)
- Ubiquitin chain linkages: K33, K48, K63 assembled by AREL1 HECT in vitro; last ~60 aa determine linkage specificity. (J Biol Chem, 2019) (singh2019structuralinsightsinto pages 8-9)
- Critical residues and mutants: E701A increases activity; Δ3CT abolishes autoubiquitination; F820A impairs SMAC ubiquitination; catalysis-deficient C790A abolishes MTX2 degradation. (J Biol Chem, 2019; Exp Ther Med, 2021) (singh2019structuralinsightsinto pages 8-9, singh2019structuralinsightsinto pages 10-12, jo2021arel1e3ubiquitin pages 2-4)
- Substrate lysines on SMAC: Lys62 and Lys191 identified as primary ubiquitination sites. (J Biol Chem, 2019) (singh2019structuralinsightsinto pages 8-9)

10) Limitations and open questions
- E2 partner breadth: While UbcH7 supports AREL1 in vitro, broader E2 specificity and in vivo partners remain to be fully defined.
- Chain-type utilization in cells: The physiological predominance of K33/K48/K63 chains on specific substrates and the determinants governing linkage selection in vivo require further study.
- Disease genetics and clinical correlations: Direct clinical-genetic links or large-scale tumor genomic associations specific to AREL1 were not captured in the present evidence set and merit targeted investigation.

Embedded evidence summary table
| Aspect | Key findings | Experimental details/notes | Source (journal, year) | URL/DOI |
|---|---|---|---|---|
| Identity & domains | AREL1 is an 823-aa human HECT-type E3 ubiquitin ligase; N-terminal extended region aa 436–482 required for stability/activity; unique loop aa 567–573; catalytic Cys790; extreme C-terminal residues (F820, Δ3CT) critical for activity | Crystal structure of extended HECT (aa 436–823) solved (2.4 Å); mutational/deletion analyses (F820A, Δ3CT, N-terminal deletions) showing effects on stability and activity | J Biol Chem, 2019 (Singh et al.) (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 2-3, singh2019structuralinsightsinto pages 10-12) | https://doi.org/10.1074/jbc.ra119.010327 |
| Biochemical mechanism | HECT transthiolation mechanism via catalytic Cys790; E2 tested = UbcH7; assembles Lys33-, Lys48-, and Lys63-linked polyubiquitin chains; shows autoubiquitination; E701A increases activity; deletion of last 3 C-term residues abolishes autoubiquitination | In vitro ubiquitination with UBA1 (E1), UbcH7 (E2), single-lysine Ub mutants; site-directed mutants (E701A, F820A, Δ3CT); use of ubiquitin variant (UbV KL.3) to probe mechanism | J Biol Chem, 2019 (Singh et al.) (singh2019structuralinsightsinto pages 8-9, singh2019structuralinsightsinto pages 14-15) | https://doi.org/10.1074/jbc.ra119.010327 |
| Validated substrates | SMAC/DIABLO ubiquitinated (primary sites Lys62 and Lys191); IAP antagonists (HtrA2, ARTS) reported as targets; MTX2 ubiquitinated leading to proteasomal degradation; AREL1 C790A (Cys→Ala) mutant is E3-deficient | SMAC ubiquitination mapped via in vitro assays and SMAC crystal structure; MTX2 ubiquitination and degradation shown in cell co-expression, MG132 rescue, and AREL1 knockdown/AREL1-C790A mutant experiments | SMAC: J Biol Chem, 2019 (singh2019structuralinsightsinto pages 8-9); MTX2: Experimental and Therapeutic Medicine, 2021 (Jo et al.) (jo2021arel1e3ubiquitin pages 2-4) | SMAC DOI https://doi.org/10.1074/jbc.ra119.010327; MTX2 DOI https://doi.org/10.3892/etm.2021.10629 |
| Localization | Predominantly cytosolic localization; functionally acts on mitochondrial outer-membrane–associated substrate MTX2 (AREL1 binds MTX2 C-terminal domain while MTX1 interacts with MTX2 N-terminus) | Co-immunoprecipitation and cellular localization assays; proteasome-dependence of MTX2 loss demonstrated (MG132) | Experimental and Therapeutic Medicine, 2021 (Jo et al.) (jo2021arel1e3ubiquitin pages 2-4) | https://doi.org/10.3892/etm.2021.10629 |
| Pathway roles | Anti-apoptotic role via ubiquitination/degradation of IAP antagonists (reducing caspase activation) and modulation of cell death pathways; inhibits TNF-induced necroptosis by targeting MTX2 for degradation | Cellular assays: AREL1 overexpression confers apoptotic resistance (e.g., H1299 cells) and knockdown sensitizes cells; TNF+zVAD necroptosis assays show AREL1 suppresses necroptosis | J Biol Chem, 2019; Experimental and Therapeutic Medicine, 2021 (singh2019structuralinsightsinto pages 1-2, jo2021arel1e3ubiquitin pages 2-4) | https://doi.org/10.1074/jbc.ra119.010327; https://doi.org/10.3892/etm.2021.10629 |
| Structural insights | Extended HECT adopts an inverted T-shaped bilobed architecture with defined N-lobe/C-lobe interfacial contacts (e.g., Glu701 interactions); catalytic Cys790 located in C-lobe; UbV KL.3 binds extended HECT and inhibits SMAC ubiquitination; PDB deposits reported (6JX5, 6JX6) | X-ray crystallography (AREL1 HECT aa 436–823 at 2.4 Å; SMAC tetramer at 2.8 Å), ITC binding (UbV KL.3), CD and thermal stability, analytical SEC; mutational mapping of active-site and C-terminal determinants | J Biol Chem, 2019 (Singh et al.) (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 14-15, singh2019structuralinsightsinto pages 12-13) | https://doi.org/10.1074/jbc.ra119.010327; PDB: 6JX5, 6JX6 |
| Recent perspectives (2023–2024) | Searches yielded limited AREL1-specific primary studies from 2023–2024 in provided contexts; core mechanistic and structural evidence remains from 2019 and functional follow-up in 2021; E3 ligase reviews discuss E3s in cancer/apoptosis with AREL1 noted in broader context | Review-level literature on E3 ligases and ubiquitination in apoptosis/necroptosis references AREL1 among anti-apoptotic E3s, but direct AREL1-focused clinical/translational studies were not retrieved in the provided evidence set | Primary experimental sources in collected evidence: J Biol Chem, 2019; Exp Ther Med, 2021 (singh2019structuralinsightsinto pages 1-2, jo2021arel1e3ubiquitin pages 2-4) | Core DOI https://doi.org/10.1074/jbc.ra119.010327; functional DOI https://doi.org/10.3892/etm.2021.10629 |

Table: Concise, citable summary of key experimental evidence for human AREL1 (UniProt O15033), covering domains, mechanism, substrates, localization, pathways, structural data, and recent-perspective notes; useful for quick reference and citation in reports.

References (with URLs and dates)
- Singh S, Ng J, Nayak D, Sivaraman J. Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activities in vitro. Journal of Biological Chemistry. Published Dec 2019. DOI: 10.1074/jbc.ra119.010327; URL: https://doi.org/10.1074/jbc.ra119.010327 (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 1-2, singh2019structuralinsightsinto pages 14-15, singh2019structuralinsightsinto pages 12-13, singh2019structuralinsightsinto pages 8-9, singh2019structuralinsightsinto pages 2-3, singh2019structuralinsightsinto pages 10-12)
- Jo Y, Kim B, Shin DY. AREL1 E3 ubiquitin ligase inhibits TNF-induced necroptosis via the ubiquitination of MTX2. Experimental and Therapeutic Medicine. Published Aug 2021. DOI: 10.3892/etm.2021.10629; URL: https://doi.org/10.3892/etm.2021.10629 (jo2021arel1e3ubiquitin pages 2-4)
- Sampson C, Wang Q, Otkur W, Zhao H, Lu Y, Liu X, Piao H. The roles of E3 ubiquitin ligases in cancer progression and targeted therapy. Clinical and Translational Medicine. Published Mar 2023. DOI: 10.1002/ctm2.1204; URL: https://doi.org/10.1002/ctm2.1204 (sampson2023therolesof pages 11-12)

Compliance with mandatory verification steps
1) Gene symbol matches protein description: AREL1 corresponds to apoptosis-resistant HECT-type E3 ubiquitin ligase, consistent with UniProt O15033 and structural/functional literature. (singh2019structuralinsightsinto pages 1-1)
2) Organism verified: All cited primary studies are human AREL1. (singh2019structuralinsightsinto pages 1-1, jo2021arel1e3ubiquitin pages 2-4)
3) Domains/family alignment: HECT domain and unique AREL1-specific N-terminal extension/loop confirmed by crystallography; consistent with E3_ubiquitin-protein_ligase and HECT family annotations. (singh2019structuralinsightsinto pages 1-1, singh2019structuralinsightsinto pages 2-3)
4) Ambiguity check: No conflicting gene symbol usage identified in the retrieved literature; AREL1 is consistently the human HECT E3 discussed. (singh2019structuralinsightsinto pages 1-2)

References

1. (singh2019structuralinsightsinto pages 1-1): Sunil Singh, Joel Ng, Digant Nayak, and J. Sivaraman. Structural insights into a hect-type e3 ligase arel1 and its ubiquitination activities in vitro. Journal of Biological Chemistry, 294:19934-19949, Dec 2019. URL: https://doi.org/10.1074/jbc.ra119.010327, doi:10.1074/jbc.ra119.010327. This article has 25 citations and is from a domain leading peer-reviewed journal.

2. (singh2019structuralinsightsinto pages 1-2): Sunil Singh, Joel Ng, Digant Nayak, and J. Sivaraman. Structural insights into a hect-type e3 ligase arel1 and its ubiquitination activities in vitro. Journal of Biological Chemistry, 294:19934-19949, Dec 2019. URL: https://doi.org/10.1074/jbc.ra119.010327, doi:10.1074/jbc.ra119.010327. This article has 25 citations and is from a domain leading peer-reviewed journal.

3. (jo2021arel1e3ubiquitin pages 2-4): Yongsam Jo, Byeongmok Kim, and Deug Y. Shin. Arel1 e3 ubiquitin ligase inhibits tnf-induced necroptosis via the ubiquitination of mtx2. Experimental and Therapeutic Medicine, Aug 2021. URL: https://doi.org/10.3892/etm.2021.10629, doi:10.3892/etm.2021.10629. This article has 7 citations and is from a peer-reviewed journal.

4. (singh2019structuralinsightsinto pages 2-3): Sunil Singh, Joel Ng, Digant Nayak, and J. Sivaraman. Structural insights into a hect-type e3 ligase arel1 and its ubiquitination activities in vitro. Journal of Biological Chemistry, 294:19934-19949, Dec 2019. URL: https://doi.org/10.1074/jbc.ra119.010327, doi:10.1074/jbc.ra119.010327. This article has 25 citations and is from a domain leading peer-reviewed journal.

5. (singh2019structuralinsightsinto pages 10-12): Sunil Singh, Joel Ng, Digant Nayak, and J. Sivaraman. Structural insights into a hect-type e3 ligase arel1 and its ubiquitination activities in vitro. Journal of Biological Chemistry, 294:19934-19949, Dec 2019. URL: https://doi.org/10.1074/jbc.ra119.010327, doi:10.1074/jbc.ra119.010327. This article has 25 citations and is from a domain leading peer-reviewed journal.

6. (singh2019structuralinsightsinto pages 14-15): Sunil Singh, Joel Ng, Digant Nayak, and J. Sivaraman. Structural insights into a hect-type e3 ligase arel1 and its ubiquitination activities in vitro. Journal of Biological Chemistry, 294:19934-19949, Dec 2019. URL: https://doi.org/10.1074/jbc.ra119.010327, doi:10.1074/jbc.ra119.010327. This article has 25 citations and is from a domain leading peer-reviewed journal.

7. (singh2019structuralinsightsinto pages 12-13): Sunil Singh, Joel Ng, Digant Nayak, and J. Sivaraman. Structural insights into a hect-type e3 ligase arel1 and its ubiquitination activities in vitro. Journal of Biological Chemistry, 294:19934-19949, Dec 2019. URL: https://doi.org/10.1074/jbc.ra119.010327, doi:10.1074/jbc.ra119.010327. This article has 25 citations and is from a domain leading peer-reviewed journal.

8. (singh2019structuralinsightsinto pages 8-9): Sunil Singh, Joel Ng, Digant Nayak, and J. Sivaraman. Structural insights into a hect-type e3 ligase arel1 and its ubiquitination activities in vitro. Journal of Biological Chemistry, 294:19934-19949, Dec 2019. URL: https://doi.org/10.1074/jbc.ra119.010327, doi:10.1074/jbc.ra119.010327. This article has 25 citations and is from a domain leading peer-reviewed journal.

9. (sampson2023therolesof pages 11-12): Chibuzo Sampson, Qiu-ming Wang, Wuxiyar Otkur, Haifeng Zhao, Yun Lu, Xiaolong Liu, and Hai-long Piao. The roles of e3 ubiquitin ligases in cancer progression and targeted therapy. Clinical and Translational Medicine, Mar 2023. URL: https://doi.org/10.1002/ctm2.1204, doi:10.1002/ctm2.1204. This article has 145 citations and is from a peer-reviewed journal.

Citations

1. singh2019structuralinsightsinto pages 2-3
2. singh2019structuralinsightsinto pages 8-9
3. singh2019structuralinsightsinto pages 1-2
4. sampson2023therolesof pages 11-12
5. singh2019structuralinsightsinto pages 14-15
6. singh2019structuralinsightsinto pages 1-1
7. singh2019structuralinsightsinto pages 10-12
8. singh2019structuralinsightsinto pages 12-13
9. https://doi.org/10.1002/ctm2.1204.
10. https://doi.org/10.1074/jbc.ra119.010327
11. https://doi.org/10.1074/jbc.ra119.010327;
12. https://doi.org/10.3892/etm.2021.10629
13. https://doi.org/10.1002/ctm2.1204
14. https://doi.org/10.1074/jbc.ra119.010327,
15. https://doi.org/10.3892/etm.2021.10629,
16. https://doi.org/10.1002/ctm2.1204,