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Showing AREL1 — FIEL1 is a alias.

AREL1

Apoptosis-resistant E3 ubiquitin protein ligase 1 · UniProt O15033

Length
823 aa
Mass
94.2 kDa
Annotated
2026-06-09
22 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AREL1 is a HECT-family E3 ubiquitin ligase that preferentially assembles non-canonical K33- and K11-linked (and also K27/K29) polyubiquitin chains to control apoptosis, inflammatory signaling, and lysosomal organization (PMID:25723849, PMID:25752577). Crystallographic analysis of its extended HECT domain reveals an inverted T-shaped bilobed fold with a unique loop absent from other HECT members and an N-terminal extension required for catalytic activity, with catalysis depending on its C-terminal active-site residues (PMID:31732561). Its earliest defined role is anti-apoptotic: upon apoptotic stimulation, AREL1 binds and ubiquitinates the cytosolic IAP antagonists SMAC, HtrA2, and ARTS to drive their degradation, thereby blocking caspase-3 activation (PMID:23479728, PMID:31732561). AREL1 additionally degrades regulatory substrates across signaling pathways—PIAS4 to potentiate TGF-β signaling and pulmonary fibrosis (PMID:27162139), SOCS1 and SOCS2 to amplify JAK/STAT and proinflammatory cytokine signaling (PMID:31578312, PMID:36938956), MTX2 to restrain TNF-induced necroptosis (PMID:34584540), and pro-IL-1β (with TRIP12 and UBE2L3) to limit inflammasome-driven inflammation (PMID:37474493). As an ER-resident ligase, AREL1 establishes ER–lysosome contacts via the V-ATPase Voa subunit and K33-ubiquitinates the V1B2 subunit, recruiting UBAC2 to promote perinuclear lysosome clustering, V-ATPase assembly, and acidification; this activity, antagonized by the deubiquitylase ZRANB1, is required for Purkinje cell survival, as Arel1 knockout mice develop age-dependent ataxia and lysosomal dysfunction (PMID:41331534).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2013 Medium

    Established AREL1 as a functional E3 ligase with a defined biological output by showing it targets IAP antagonists for degradation to suppress apoptosis.

    Evidence Co-IP, cellular ubiquitination assays, and siRNA knockdown with caspase-3/XIAP apoptosis readouts

    PMID:23479728

    Open questions at the time
    • Chain linkage type not yet defined
    • Ubiquitination sites on substrates not mapped
    • Single lab, no structural basis
  2. 2015 High

    Defined the biochemical signature of AREL1 by demonstrating it preferentially builds non-canonical K33- and K11-linked chains, distinguishing it from canonical degradative ligases.

    Evidence In vitro reconstitution with purified enzyme, linkage-selective DUBs, mass spectrometry, and NMR of chain conformation; replicated across two labs

    PMID:25723849 PMID:25752577

    Open questions at the time
    • Physiological substrates of K33/K11 chains not linked to specific outcomes here
    • Connection between linkage type and proteasomal fate unresolved
  3. 2016 High

    Extended AREL1 beyond apoptosis by showing it degrades PIAS4 through a phosphorylation-gated double-lock mechanism to potentiate TGF-β-driven fibrosis.

    Evidence Co-IP, ubiquitination and kinase-dependent phosphorylation assays, bleomycin murine fibrosis model with small-molecule inhibitor

    PMID:27162139

    Open questions at the time
    • Chain linkage on PIAS4 not specified
    • Generalizability of phospho-gating to other substrates unknown
  4. 2019 High

    Showed AREL1 amplifies inflammatory signaling by degrading SOCS2, and that genetic or pharmacological inhibition is protective in vivo, establishing therapeutic relevance.

    Evidence Co-IP, ubiquitination assays, KIAA0317 knockout mice in LPS/P. aeruginosa lung inflammation models, BC-1365 inhibitor

    PMID:31578312

    Open questions at the time
    • Linkage type on SOCS2 not defined
    • Whether SOCS2 degradation is the sole driver of the inflammatory phenotype unclear
  5. 2019 High

    Provided the structural basis for AREL1 catalysis, identifying a unique HECT-domain loop, an essential N-terminal extension, and the SMAC ubiquitination sites and active-site residues.

    Evidence X-ray crystallography of HECT domain and SMAC tetramer, active-site mutagenesis (E701A, C-terminal deletion), ubiquitin-variant inhibitor assay

    PMID:31732561

    Open questions at the time
    • Full-length structure including N-terminal substrate-recognition region not resolved
    • Structural determinant of K33/K11 linkage selectivity not defined
  6. 2021 Medium

    Added necroptosis control to AREL1's repertoire by showing catalysis-dependent degradation of MTX2 restrains TNF-induced necroptosis.

    Evidence Domain-mapping Co-IP, catalytic mutant (C790A), siRNA knockdown, TNF necroptosis assay

    PMID:34584540

    Open questions at the time
    • In vivo relevance not tested
    • Chain linkage on MTX2 not characterized
  7. 2023 High

    Demonstrated AREL1 acts as a multi-ligase that, with TRIP12 and UBE2L3, K27/K29/K33-ubiquitinates pro-IL-1β to dampen inflammasome output, and separately degrades SOCS1 to dysregulate colonic JAK/STAT signaling.

    Evidence RNAi screen, ubiquitination assays with MS linkage determination, Ube2l3 knockout mice, macrophage inflammasome assays; Co-IP and JAK/STAT readouts for SOCS1

    PMID:36938956 PMID:37474493

    Open questions at the time
    • Relative contributions of AREL1 versus TRIP12 to pro-IL-1β turnover not partitioned
    • SOCS1 study is single-lab Medium-confidence without in vivo model
  8. 2025 High

    Redefined AREL1 as an ER-resident organizer of ER–lysosome contacts, linking its K33-ubiquitination of V-ATPase V1B2 to lysosome positioning, acidification, and Purkinje cell survival.

    Evidence Co-IP, in vitro ubiquitination with linkage ID, live-cell imaging/fractionation for lysosome positioning, lysosomal pH measurement, Arel1 knockout mice with behavior and histology, ZRANB1 knockdown

    PMID:41331534

    Open questions at the time
    • Mechanism by which V1B2 ubiquitination drives UBAC2 binding and clustering at atomic level unresolved
    • Relationship between this ER-resident pool and prior cytosolic/apoptotic roles unclear
    • Whether neurodegeneration is purely lysosomal or involves other substrates not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AREL1 selects among its many substrates, and how its non-canonical chain linkages dictate proteasomal degradation versus signaling/contact-site assembly, remains unresolved.
  • No unifying substrate-recognition logic established across SMAC, PIAS4, SOCS1/2, MTX2, pro-IL-1β, and V1B2
  • Functional distinction between K33 chains that target degradation versus those that nucleate ER-lysosome contacts unclear
  • Reconciliation of cytosolic versus ER-resident localization across studies not addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
MTX2PIAS4SMACSOCS1SOCS2TRIP12UBAC2ZRANB1

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 AREL1 is a cytosolic HECT-family E3 ubiquitin ligase that interacts with and ubiquitinates IAP antagonists SMAC, HtrA2, and ARTS specifically after apoptotic stimulation releases them from mitochondria into the cytosol, promoting their degradation and thereby suppressing caspase-3 cleavage, XIAP degradation, and apoptosis. Co-immunoprecipitation, ubiquitination assays in cells, siRNA knockdown with apoptosis readouts (caspase-3 cleavage, XIAP degradation), subcellular fractionation/localization The Journal of biological chemistry Medium 23479728
2015 AREL1 HECT E3 ligase preferentially assembles K33- and K11-linked polyubiquitin chains in vitro. In vitro ubiquitination assay using purified AREL1 combined with linkage-selective DUBs; mass spectrometry to confirm chain linkage The Biochemical journal High 25723849 25752577
2015 AREL1 assembles K11/K33-linked ubiquitin chains, and in combination with linkage-selective DUBs can be used to generate pure K33-linked chains; these chains adopt an open, dynamic solution conformation. In vitro ubiquitination assay, mass spectrometry for linkage determination, NMR solution studies Molecular cell High 25752577
2016 AREL1 (FIEL1/KIAA0317) ubiquitinates the SUMO E3 ligase PIAS4, targeting it for proteasomal degradation via a double-locking mechanism requiring PKCζ-mediated phosphorylation of PIAS4 and GSK3β-mediated phosphorylation of FIEL1, thereby potentiating TGF-β signaling and promoting pulmonary fibrosis. Co-immunoprecipitation, ubiquitination assays, phosphorylation assays with kinase inhibitors/knockdown, overexpression and knockdown in cells and bleomycin murine fibrosis model The Journal of experimental medicine High 27162139
2019 KIAA0317 (AREL1) mediates the ubiquitination and proteasomal degradation of SOCS2, exacerbating proinflammatory cytokine signaling; KIAA0317 knockout mice are resistant to LPS-induced pulmonary inflammation, and a small molecule inhibitor (BC-1365) prevents SOCS2 degradation and attenuates lung inflammation in vivo. Co-immunoprecipitation, ubiquitination assays, KIAA0317 knockout mice, LPS and P. aeruginosa lung inflammation models, small molecule inhibitor JCI insight High 31578312
2019 Crystal structure of the extended HECT domain of AREL1 (aa 436–823) at 2.4 Å resolution reveals an inverted T-shaped bilobed conformation with a unique loop (aa 567–573) absent in all other HECT members; the N-terminal extended region (aa 436–482) is indispensable for HECT domain stability and activity. AREL1 ubiquitinates SMAC primarily on Lys62 and Lys191. The AREL1 HECT domain assembles K33-, K48-, and K63-linked chains; E701A substitution increases autopolyubiquitination and SMAC ubiquitination, while deletion of the C-terminal three residues abrogates autoubiquitination and reduces SMAC ubiquitination. X-ray crystallography (2.4 Å HECT domain; 2.8 Å SMAC tetramer), in vitro ubiquitination assays, active-site mutagenesis (E701A, C-terminal deletion), ubiquitin variant inhibitor assay The Journal of biological chemistry High 31732561
2021 AREL1 interacts with Metaxin 2 (MTX2) via the C-terminal domain of MTX2 (distinct from the N-terminal domain that binds MTX1) and ubiquitinates MTX2, promoting its proteasomal degradation; catalytically inactive AREL1-C790A does not degrade MTX2. By degrading MTX2, AREL1 inhibits TNF-induced necroptosis. Co-immunoprecipitation with domain-mapping constructs, AREL1 catalytic mutant (C790A), siRNA knockdown, necroptosis assay (TNF stimulation) Experimental and therapeutic medicine Medium 34584540
2023 AREL1 and TRIP12 E3 ligases, together with UBE2L3, add K27-, K29-, and K33-linked polyubiquitin chains to pro-IL-1β, promoting its proteasomal degradation and thereby limiting inflammasome-driven mature IL-1β production and neutrophilic inflammation. RNAi screen, ubiquitination assays, Ube2l3 knockout mice, macrophage inflammasome activation assays, mass spectrometry for chain linkage Nature communications High 37474493
2023 KIAA0317 (AREL1) ubiquitinates SOCS1 and promotes its proteasomal degradation, thereby dysregulating JAK/STAT inflammatory signaling in the colon; modulation of SOCS1 protein levels markedly affects colonic inflammatory responses. Co-immunoprecipitation, ubiquitination assays, protein-protein interaction domain characterization, siRNA knockdown with JAK/STAT signaling readouts The FEBS journal Medium 36938956
2023 AREL1 interacts with SMAC in TGF-β-treated HUVECs and its overexpression inhibits caspase-3 and caspase-9 activation and apoptosis; miR-320b suppresses AREL1 expression, and AREL1 overexpression rescues miR-320b-induced apoptosis. Co-immunoprecipitation, overexpression, caspase activity assays, miRNA mimic/inhibitor transfection in HUVECs Journal of biochemical and molecular toxicology Low 37522329
2025 ER-resident AREL1 establishes membrane contacts between the ER and lysosomes by directly interacting with the Voa subunit of V-ATPase. AREL1 catalyzes K33-linked polyubiquitylation of the V-ATPase V1B2 subunit, inducing its binding to perinuclear ER-localized UBAC2, thereby promoting perinuclear lysosome clustering, lysosomal acidification, and degradative capacity. Loss of AREL1 increases peripheral lysosomes with partially assembled V-ATPase, elevated luminal pH, and reduced degradation. Arel1 knockout mice develop age-dependent Purkinje cell loss, ataxia, motor impairment, and lysosomal dysfunction (lipofuscin accumulation). The deubiquitylase ZRANB1 antagonizes AREL1-mediated V1B2 ubiquitylation. Co-immunoprecipitation, in vitro ubiquitination assays with linkage identification, live-cell imaging and fractionation for lysosome positioning, lysosomal pH measurements, Arel1 knockout mice with behavioral phenotyping and histology, ZRANB1 knockdown The EMBO journal High 41331534

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Assembly and specific recognition of k29- and k33-linked polyubiquitin. Molecular cell 176 25752577
2015 Assembly and structure of Lys33-linked polyubiquitin reveals distinct conformations. The Biochemical journal 63 25723849
2017 Genome-wide association study and accuracy of genomic prediction for teat number in Duroc pigs using genotyping-by-sequencing. Genetics, selection, evolution : GSE 43 28356075
2013 Identification of a novel anti-apoptotic E3 ubiquitin ligase that ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, and ARTS. The Journal of biological chemistry 40 23479728
2021 Exploring the "Other" subfamily of HECT E3-ligases for therapeutic intervention. Pharmacology & therapeutics 34 33607149
2016 Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4. The Journal of experimental medicine 33 27162139
2020 Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients. Acta neuropathologica communications 24 32151281
2023 IL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation. Nature communications 21 37474493
2021 Insights from the genetic characterization of central precocious puberty associated with multiple anomalies. Human reproduction (Oxford, England) 21 33313884
2021 Knockdown of circ-FURIN suppresses the proliferation and induces apoptosis of granular cells in polycystic ovary syndrome via miR-195-5p/BCL2 axis. Journal of ovarian research 20 34784951
2019 KIAA0317 regulates pulmonary inflammation through SOCS2 degradation. JCI insight 18 31578312
2019 Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activities in vitro. The Journal of biological chemistry 15 31732561
2014 A panel of protein markers for the early detection of lung cancer with bronchial brushing specimens. Cancer cytopathology 14 25045014
2025 Cross-ancestry genome-wide association study and systems-level integrative analyses implicate new risk genes and therapeutic targets for depression. Nature human behaviour 9 39994458
2016 Therapeutic targets in fibrotic pathways. Cytokine 7 27658114
2023 Genome-wide association study using a single-step approach for teat number in Duroc, Landrace and Yorkshire pigs in Korea. Animal genetics 6 37814452
2022 Downregulation of growth plate genes involved with the onset of femoral head separation in young broilers. Frontiers in physiology 6 36003650
2021 AREL1 E3 ubiquitin ligase inhibits TNF-induced necroptosis via the ubiquitination of MTX2. Experimental and therapeutic medicine 6 34584540
2023 KIAA0317 regulates SOCS1 stability to ameliorate colonic inflammation. The FEBS journal 4 36938956
2023 AREL1 resists the apoptosis induced by TGF-β by inhibiting SMAC in vascular endothelial cells. Journal of biochemical and molecular toxicology 4 37522329
2025 Neuroinflammation mediates the progression of neonate hypoxia-ischemia brain damage to Alzheimer's disease: a bioinformatics and experimental study. Frontiers in aging neuroscience 3 39872979
2025 E3 ligase AREL1 controls perinuclear localization of lysosomes and supports Purkinje cell survival. The EMBO journal 0 41331534

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