Affinage

ATXN2L

Ataxin-2-like protein · UniProt Q8WWM7

Length
1075 aa
Mass
113.4 kDa
Annotated
2026-06-09
12 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATXN2L is a perinuclear/cytoplasmic RNA-binding protein that organizes ribonucleoprotein assemblies controlling mRNA translation and is essential for embryonic development (PMID:32698485, PMID:40220918, PMID:41273724). Through liquid-liquid phase separation it forms granules that recruit eukaryotic initiation factors and promote translation of target mRNAs such as ADAM9, an activity augmented by co-localization with stress granules (PMID:41273724). It associates with a broad network of RNA-binding proteins—most prominently NUFIP2, along with PABPN1, LARP1, PTBP1, FMR1, HNRNPK and others—and with actin-complex components including SYNE2; oxidative stress remodels these associations, and loss of ATXN2L depletes NUFIP2 and SYNE2 at the proteome level (PMID:40220918). ATXN2L is asymmetrically dimethylated by PRMT1, which physically associates with it and controls its nuclear localization independently of its stress-granule recruitment (PMID:25748791). Its Lsm/LsmAD and PAM2 domains contribute to alternative splicing regulation and neuronal locomotor behavior despite the protein's perinuclear distribution (PMID:41090760), and its interaction with HDAC3 modulates the NRG1-ErbB2-PI3K-AKT axis in the context of Schwann cell myelination (PMID:36218239). In cancer settings ATXN2L promotes migration, EMT and chemoresistance downstream of EGF-driven PI3K/Akt signaling, and supports tumor progression (PMID:30787271, PMID:41273724). Notably, ATXN2L acts independently of its paralog ATXN2, as neither protein cross-regulates the other (PMID:32698485).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2015 Medium

    Established a post-translational regulatory input on ATXN2L by identifying its arginine methylation writer and linking that modification to subcellular partitioning.

    Evidence Co-immunoprecipitation, in vivo methylation analysis, methylation inhibition and arginine-motif mutagenesis with immunofluorescence in cells

    PMID:25748791

    Open questions at the time
    • Functional consequence of nuclear vs cytoplasmic ATXN2L on RNA metabolism not defined
    • Specific methylated arginine residues not mapped
    • Why methylation controls nuclear but not stress-granule localization is unexplained
  2. 2017 Medium

    Showed ATXN2L can be structurally co-opted in disease through a chromosomal fusion linking its domains to a kinase catalytic domain.

    Evidence RNA-sequencing, RT-PCR and Sanger sequencing of a cutaneous CD4+ T-cell lymphoma patient

    PMID:29262599

    Open questions at the time
    • Constitutive kinase activation inferred by analogy, not demonstrated
    • Single patient, no functional oncogenic assay
    • Role of the ATXN2L portion in the fusion unknown
  3. 2019 Medium

    Placed ATXN2L downstream of EGF-PI3K/Akt signaling and assigned it pro-migratory, pro-EMT, and chemoresistance functions in cancer cells.

    Evidence siRNA knockdown with migration/invasion, EMT marker, oxaliplatin resistance, ROS and apoptosis assays plus PI3K/Akt inhibitor experiments in gastric cancer cells

    PMID:30787271

    Open questions at the time
    • Direct molecular mechanism linking ATXN2L to EMT not defined
    • Whether RNA-binding/translation activity drives the phenotype unclear
    • Single cell-line/lab context
  4. 2020 High

    Demonstrated ATXN2L is essential for development and acts independently of its paralog ATXN2, resolving whether the two proteins are functionally redundant.

    Evidence Constitutive CRISPR/Cas9 Atxn2l knockout mouse with prenatal and brain histology and MEF phenotyping

    PMID:32698485

    Open questions at the time
    • Molecular cause of mid-gestational lethality not pinpointed
    • Mechanism of multinucleation in null MEFs unknown
    • Which domains drive the essential function not dissected here
  5. 2022 Medium

    Identified HDAC3 as an ATXN2L interactor and connected this interaction to NRG1-ErbB2-PI3K-AKT signaling in a myelination/neuropathy context.

    Evidence Co-immunoprecipitation and LC-MS/MS with a db/db diabetic mouse model

    PMID:36218239

    Open questions at the time
    • Pathway placement partly inferential
    • Direct vs indirect HDAC3-ATXN2L effect on signaling not resolved
    • Whether ATXN2L is an HDAC3 substrate or scaffold unknown
  6. 2025 High

    Defined the ATXN2L interactome, showing it preferentially binds a network of RNA-binding proteins and actin-complex components that are remodeled by oxidative stress and dependent on ATXN2L for their abundance.

    Evidence Reciprocal co-IP in wild-type vs ATXN2L-null fibroblasts, global proteome mass spectrometry, and SCA2 knock-in mouse tissue analysis

    PMID:40220918

    Open questions at the time
    • Direct vs RNA-bridged nature of individual interactions not separated
    • Functional consequence of NUFIP2/SYNE2 depletion not mechanistically resolved
    • Stoichiometry of a defined complex not established
  7. 2025 Medium

    Assigned ATXN2L's Lsm/LsmAD and PAM2 domains a role in alternative splicing regulation and neuronal behavior, linking domain architecture to function in vivo.

    Evidence Conditional CamK2a-CreERT2 domain-deletion mouse with behavioral locomotion assay and frontal cortex proteome profiling

    PMID:41090760

    Open questions at the time
    • Splicing role inferred from proteome enrichment, no direct splice-event mapping
    • How a perinuclear protein influences splicing unresolved
    • Causal link between splicing changes and behavior not established
  8. 2025 Medium

    Provided a molecular mechanism for ATXN2L in translation, showing it phase-separates into granules that recruit eIFs to promote target mRNA translation and tumor progression.

    Evidence LLPS assays, eIF co-localization, ADAM9 translation readouts, stress granule imaging, and ATXN2L knockdown/knockout in HCC cells and mice

    PMID:41273724

    Open questions at the time
    • Determinants of LLPS within ATXN2L not mapped
    • Breadth of translationally regulated targets beyond ADAM9 unknown
    • Single tumor context
  9. 2025 Low

    Positioned ATXN2L as a downstream target of an m6A-mediated regulatory axis protecting endothelial cells from hyperglycemic stress.

    Evidence Dual-luciferase reporter, RNA immunoprecipitation, knockdown/overexpression, Western blot, ELISA and flow cytometry in retinal microvascular endothelial cells

    PMID:40533826

    Open questions at the time
    • ATXN2L's own mechanism not interrogated beyond being a target
    • Direct m6A site on ATXN2L mRNA not mapped
    • Single lab, indirect pathway placement
  10. 2025 Low

    Listed ATXN2L as a component of stress-granule complexes containing aberrantly translated HSATIII-derived proteins during thermal stress recovery.

    Evidence Immunofluorescence co-localization and co-IP in a preprint focused on HSATIII translation

    PMID:bio_10.1101_2025.11.12.688122

    Open questions at the time
    • Preprint, not peer-reviewed
    • ATXN2L not the focus; its functional role in these complexes unaddressed
    • Single method with limited ATXN2L-specific detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ATXN2L's RNA-binding, phase-separation, and translation-promoting activities mechanistically converge to produce its essential developmental function remains unresolved.
  • No structural model linking domains to LLPS and eIF recruitment
  • The mRNA targets that account for embryonic essentiality are unidentified
  • Whether splicing, translation, or cytoskeletal roles are primary in vivo is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0045182 translation regulator activity 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-392499 Metabolism of proteins 1
Partners
HDAC3HNRNPKLARP1NUFIP2PABPN1PRMT1PTBP1SYNE2
Complex memberships
stress granule

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ATXN2L is asymmetrically dimethylated in vivo, and this arginine methylation is mediated by PRMT1, which physically associates with ATXN2L. Methylation inhibition alters ATXN2L nuclear localization, but mutation of arginine-glycine-rich motifs or methylation inhibition does not alter ATXN2L localization to stress granules. Co-immunoprecipitation, in vivo methylation analysis, methylation inhibition, site-directed mutagenesis, immunofluorescence localization Experimental cell research Medium 25748791
2020 Constitutive deletion of Atxn2l exons 5-8 (encoding Lsm, LsmAD, and PAM2 domains) in mice causes mid-gestational embryonic lethality with brain lamination defects and apoptosis, demonstrating that ATXN2L is essential for embryonic development. ATXN2L-null mouse embryonic fibroblasts show increased multinucleated giant cells. Neither ATXN2L depletion dysregulates ATXN2 nor vice versa. CRISPR/Cas9 knockout mouse, prenatal histology, brain histological analysis, cell culture phenotyping International journal of molecular sciences High 32698485
2017 A chromosomal translocation t(9;13;16) creates an ATXN2L-JAK2 fusion gene encoding a chimeric protein containing all domains of ATXN2L fused to the catalytic (kinase) domain of JAK2, identified in cutaneous CD4+ T-cell lymphoma. RNA-sequencing, RT-PCR, Sanger sequencing Oncotarget Medium 29262599
2019 In gastric cancer cells, ATXN2L promotes cell migration and invasion via epithelial-to-mesenchymal transition, confers intrinsic and acquired oxaliplatin resistance (silencing ATXN2L increases ROS and apoptosis in resistant cells), and its expression is upregulated by EGF via PI3K/Akt signaling. siRNA knockdown, migration/invasion assays, EMT marker analysis, oxaliplatin resistance assays, ROS measurement, apoptosis assay, PI3K/Akt pathway inhibitor experiments Cell death & disease Medium 30787271
2022 HDAC3 interacts with ATXN2L (confirmed by co-immunoprecipitation and LC-MS/MS) and antagonizes the NRG1-ErbB2-PI3K-AKT signaling axis through this interaction to regulate Schwann cell myelination in diabetic peripheral neuropathy. Co-immunoprecipitation, liquid chromatography-mass spectrometry (LC-MS/MS), in vivo mouse model (db/db) Phytotherapy research : PTR Medium 36218239
2025 ATXN2L primarily interacts with a set of RNA-binding proteins including NUFIP2, PABPN1, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL (stronger than established interactors ATXN2, PABPC1, LSM12, and G3BP2), as well as actin complex components SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. Oxidative stress increases HNRNPK but decreases SYNE2 association with ATXN2L. ATXN2L-null fibroblasts show depletion of NUFIP2 and SYNE2 at the proteome level. In the SCA2 mouse model, NUFIP2 and SYNE1 accumulate during ATXN2 aggregation. Co-immunoprecipitation in wild-type and ATXN2L-null fibroblasts, mass spectrometry proteome profiling, SCA2 KnockIn mouse model tissue analysis Neurobiology of disease High 40220918
2025 Conditional deletion of ATXN2L LsmAD and PAM2 domains (exons 10-17) in CamK2a+ frontal cortex neurons reduces spontaneous horizontal movement and causes proteome dysregulations enriched in the alternative splicing pathway, suggesting that the Lsm/LsmAD domains of ATXN2L serve a role in splice regulation despite the protein's perinuclear localization. Conditional CamK2a-CreERT2 knockout mouse, tamoxifen induction, behavioral locomotion assay, global proteome profiling of frontal cortex Cells Medium 41090760
2025 ATXN2L undergoes liquid-liquid phase separation (LLPS) to form granules that recruit eukaryotic initiation factors (eIFs) and promote mRNA translation of downstream targets such as ADAM9; co-localization with stress granules further enhances ADAM9 translation. Knockdown or knockout of ATXN2L suppresses HCC progression. LLPS assays, ATXN2L knockdown/knockout (HCC cells and mice), eIF co-localization, ADAM9 translation assays, stress granule co-localization imaging Cell reports Medium 41273724
2025 FOXL1 (delivered via BMSC exosomes) acts as an RNA-binding protein that stabilizes METTL3, which in turn increases ATXN2L mRNA expression through m6A methylation, thereby protecting retinal microvascular endothelial cells against high glucose-induced inflammation, apoptosis, and oxidative stress. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), siRNA/overexpression, Western blotting, ELISA, flow cytometry Diabetology & metabolic syndrome Low 40533826
2025 Cytoplasmic HSATIII RNA-translated MEWNG-rich proteins form complexes with stress granule proteins including ATXN2L, as detected during thermal stress recovery. Immunofluorescence co-localization, co-immunoprecipitation (inferred from abstract description of complex formation) bioRxivpreprint Low bio_10.1101_2025.11.12.688122

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 ATXN2L upregulated by epidermal growth factor promotes gastric cancer cell invasiveness and oxaliplatin resistance. Cell death & disease 61 30787271
2020 Mid-Gestation lethality of Atxn2l-Ablated Mice. International journal of molecular sciences 23 32698485
2017 Fusion of the genes ataxin 2 like, ATXN2L, and Janus kinase 2, JAK2, in cutaneous CD4 positive T-cell lymphoma. Oncotarget 22 29262599
2015 PRMT1-mediated arginine methylation controls ATXN2L localization. Experimental cell research 17 25748791
2022 Jatrorrhizine ameliorates Schwann cell myelination via inhibiting HDAC3 ability to recruit Atxn2l for regulating the NRG1-ErbB2-PI3K-AKT pathway in diabetic peripheral neuropathy mice. Phytotherapy research : PTR 14 36218239
2025 ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation. Neurobiology of disease 8 40220918
2022 From the comparative study of a circRNA originating from an mammalian ATXN2L intron to understanding the genesis of intron lariat-derived circRNAs. Biochimica et biophysica acta. Gene regulatory mechanisms 7 35513260
2025 Exosomal FOXL1 from bone marrow mesenchymal stem cells activates the METTL3/ATXN2L pathway to ameliorate high glucose-induced human retinal microvascular endothelial cell injury. Diabetology & metabolic syndrome 5 40533826
2025 Conditional ATXN2L-Null in Adult Frontal Cortex CamK2a+ Neurons Does Not Cause Cell Death but Restricts Spontaneous Mobility and Affects the Alternative Splicing Pathway. Cells 3 41090760
2025 Liquid-liquid phase separation of ATXN2L enhances mRNA translation in hepatocellular carcinoma. Cell reports 1 41273724
2026 Complete remission of relapsed ATXN2L::JAK2 fusion positive anaplastic large cell lymphoma following ruxolitinib monotherapy in a child. NPJ precision oncology 0 41688673
2025 Circ-NMNAT1 Drives Tumor Progression in Bladder Cancer by Modulating the miR-370-3p/ATXN2L Axis. Applied biochemistry and biotechnology 0 39820928

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