Affinage

ATXN2L

Ataxin-2-like protein · UniProt Q8WWM7

Round 2 corrected
Length
1075 aa
Mass
113.4 kDa
Annotated
2026-04-28
42 papers in source corpus 8 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATXN2L is a perinuclear RNA-binding protein containing Lsm, LsmAD, and PAM2 domains that is essential for mammalian embryonic development, with homozygous loss causing mid-gestational lethality with brain lamination defects (PMID:32698485). ATXN2L undergoes liquid–liquid phase separation to form cytoplasmic granules that recruit eukaryotic initiation factors and promote mRNA translation, and it participates in alternative splicing regulation through its Lsm/LsmAD domains (PMID:41273724, PMID:41090760). Its primary physical interactor is NUFIP2, and it associates with a broad network of RNA-binding proteins and actin complex components; oxidative stress dynamically remodels these interactions as ATXN2L relocalizes to stress granules (PMID:40220918). ATXN2L is asymmetrically dimethylated by PRMT1, which controls its nuclear but not stress-granule localization, and its expression is upregulated by EGF/PI3K/Akt signaling to promote cancer cell invasiveness and chemoresistance (PMID:25748791, PMID:30787271).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2015 Medium

    The first post-translational regulatory mechanism for ATXN2L was defined: PRMT1-mediated asymmetric arginine dimethylation controls ATXN2L nuclear localization but is dispensable for its recruitment to stress granules, establishing that distinct signals govern ATXN2L's dual compartmentalization.

    Evidence Co-IP, methylation inhibition, RG-motif mutagenesis, and immunofluorescence in cultured cells

    PMID:25748791

    Open questions at the time
    • Nuclear functions of ATXN2L remain undefined
    • Whether other PRMTs modify ATXN2L is untested
    • Single-lab observation without independent replication
  2. 2017 Medium

    Discovery of an ATXN2L–JAK2 fusion transcript in cutaneous T-cell lymphoma demonstrated that ATXN2L can serve as a 5′ partner in oncogenic chromosomal rearrangements, analogous to other JAK2 fusions that constitutively activate JAK-STAT signaling.

    Evidence RNA-seq, RT-PCR, and Sanger sequencing of a t(9;13;16) translocation in a single patient

    PMID:29262599

    Open questions at the time
    • Constitutive kinase activity of the fusion was inferred by analogy, not directly demonstrated
    • Single case report; frequency of ATXN2L–JAK2 fusions unknown
    • Mechanism by which ATXN2L domains contribute to oncogenic activity is uncharacterized
  3. 2019 Medium

    ATXN2L was placed in the EGF/PI3K/Akt signaling axis as a downstream effector that promotes epithelial–mesenchymal transition, cell invasion, and chemoresistance in gastric cancer, revealing a cancer-relevant function beyond its RNA-binding roles.

    Evidence siRNA knockdown, invasion/migration assays, ROS and apoptosis measurement, oxaliplatin-resistant cell generation, PI3K/Akt inhibition in gastric cancer cell lines

    PMID:30787271

    Open questions at the time
    • Direct transcriptional or post-transcriptional targets mediating chemoresistance are not identified
    • In vivo validation in tumor models was not performed
    • Mechanism linking stress granule assembly to oxaliplatin resistance is unclear
  4. 2020 High

    Genetic ablation of Atxn2l in mice established its essentiality for embryonic development, with homozygous loss causing mid-gestational lethality, brain lamination defects, and increased multinucleated cell formation, distinguishing it functionally from its paralog ATXN2.

    Evidence CRISPR/Cas9 whole-body knockout mice, embryo histology across developmental stages, MEF culture, western blotting

    PMID:32698485

    Open questions at the time
    • Molecular pathways driving embryonic lethality are not delineated
    • Cell-type-specific requirements during development are unknown
    • Cause of multinucleated cell phenotype (cytokinesis failure vs. cell fusion) is unresolved
  5. 2022 Medium

    The HDAC3–ATXN2L interaction was identified as a negative regulator of NRG1-ErbB2-PI3K-AKT myelination signaling in Schwann cells, placing ATXN2L in a chromatin-associated regulatory complex relevant to peripheral neuropathy.

    Evidence LC-MS/MS proteomics, Co-IP, in vivo db/db diabetic mouse model with nerve histopathology and conduction velocity

    PMID:36218239

    Open questions at the time
    • Whether ATXN2L acts as an HDAC3 co-repressor or scaffold is not determined
    • Direct gene targets of the HDAC3–ATXN2L complex are uncharacterized
    • Single-lab finding without independent confirmation
  6. 2025 High

    Systematic interactome mapping identified NUFIP2 as ATXN2L's primary binding partner and revealed a broad network of RNA-binding proteins and actin complex components; stress-dependent remodeling of these interactions linked ATXN2L to stress granule biology and, in an SCA2 mouse model, suggested that ATXN2 aggregation sequesters ATXN2L-associated factors.

    Evidence Co-IP/MS in WT and ATXN2L-null MEFs, SCA2 Atxn2-CAG100-KnockIn mouse spinal cord proteomics

    PMID:40220918

    Open questions at the time
    • Direct RNA targets bound by ATXN2L are not defined
    • Whether ATXN2L sequestration causally contributes to SCA2 pathogenesis is unproven
    • Structural basis of the ATXN2L–NUFIP2 interaction is unknown
  7. 2025 Medium

    Conditional deletion of ATXN2L's Lsm/LsmAD/PAM2 domains in cortical neurons demonstrated a requirement for these domains in normal locomotor behavior and implicated ATXN2L in alternative splicing regulation based on proteome-level changes.

    Evidence CamK2a-CreERT2 conditional KO mice, open-field locomotor testing, global proteome profiling by MS

    PMID:41090760

    Open questions at the time
    • Specific splice targets are not identified
    • Contribution of individual domains (Lsm vs. PAM2) was not dissected
    • Only proteome-level enrichment inferred; direct splicing assays were not performed
  8. 2025 Medium

    ATXN2L was shown to undergo liquid–liquid phase separation forming cytoplasmic granules that recruit eIF complexes to promote mRNA translation of specific targets such as ADAM9, directly linking ATXN2L's condensation behavior to translational control and hepatocellular carcinoma progression.

    Evidence LLPS assays, granule imaging with eIF co-localization, ADAM9 translation assays, ATXN2L KO in mice with in vivo HCC models

    PMID:41273724

    Open questions at the time
    • Transcriptome-wide identification of ATXN2L-granule-regulated mRNAs is lacking
    • Biophysical determinants of phase separation (IDRs, multivalency) not fully mapped
    • Whether LLPS is required for all ATXN2L translational functions or specific subsets is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full repertoire of direct RNA targets, the structural basis of ATXN2L phase separation and NUFIP2 binding, the mechanism by which ATXN2L loss causes embryonic lethality, and whether ATXN2L sequestration is a causal contributor to SCA2 neurodegeneration.
  • No CLIP-seq or equivalent data defining direct RNA targets
  • No high-resolution structure of ATXN2L or its complexes
  • Causal role of ATXN2L in SCA2 pathogenesis untested by genetic rescue

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0045182 translation regulator activity 1
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
GO:0003723 RNA binding 3 R-HSA-162582 Signal Transduction 2 R-HSA-8953854 Metabolism of RNA 2
Partners
FMR1HDAC3HNRNPKLARP1NUFIP2PABPN1PRMT1SYNE2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ATXN2L is asymmetrically dimethylated in vivo and associates with protein arginine-N-methyltransferase 1 (PRMT1). Inhibition of arginine methylation alters the nuclear localization of ATXN2L, but neither mutation of the arginine-glycine-rich motifs nor methylation inhibition affects ATXN2L localization to stress granules, indicating that arginine methylation by PRMT1 controls ATXN2L nuclear (but not stress granule) localization. Co-immunoprecipitation, methylation inhibition assays, site-directed mutagenesis of RG motifs, immunofluorescence localization Experimental cell research Medium 25748791
2017 A chromosomal translocation t(9;13;16) in cutaneous CD4+ T-cell lymphoma fuses ATXN2L (chromosome 16p11) to JAK2 (chromosome 9p24), producing an ATXN2L–JAK2 chimeric protein that retains all ATXN2L domains fused to the JAK2 catalytic tyrosine kinase domain, predicted to cause constitutive JAK-STAT pathway activation. RNA sequencing, RT-PCR, Sanger sequencing of fusion transcript Oncotarget Medium 29262599
2019 ATXN2L promotes gastric cancer cell migration and invasion via epithelial-to-mesenchymal transition and confers intrinsic and acquired resistance to oxaliplatin by reducing reactive oxygen species and apoptosis. EGF upregulates ATXN2L expression through PI3K/Akt signaling, and oxaliplatin treatment itself induces ATXN2L expression and stress granule assembly. siRNA knockdown, invasion/migration assays, ROS measurement, apoptosis assays, generation of oxaliplatin-resistant cell strains, pharmacological PI3K/Akt inhibition, EGFR blocking Cell death & disease Medium 30787271
2020 ATXN2L is essential for embryonic development: homozygous CRISPR/Cas9 deletion of Atxn2l exons 5–8 in mice causes mid-gestational lethality with brain lamination defects and apoptosis, while heterozygotes are phenotypically normal over 12 months. ATXN2L-null mouse embryonic fibroblasts show increased multinucleated giant cells. ATXN2L and its paralog ATXN2 do not regulate each other's expression levels. CRISPR/Cas9 knockout mice, embryo histology, MEF culture, western blotting, locomotor assessment of heterozygotes International journal of molecular sciences High 32698485
2022 HDAC3 interacts with ATXN2L and through this interaction antagonizes the NRG1-ErbB2-PI3K-AKT signaling axis in Schwann cells to suppress myelination. Inhibiting HDAC3's recruitment of ATXN2L (by jatrorrhizine treatment) restores myelination in diabetic peripheral neuropathy mice. LC-MS/MS proteomics, co-immunoprecipitation, in vivo db/db mouse model, nerve histopathology, nerve conduction velocity measurement Phytotherapy research Medium 36218239
2025 ATXN2L's primary interactor is NUFIP2, with additional strong associations to RNA-binding proteins (PABPN1, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, HNRNPDL) and actin complex components (SYNE2, LMOD1, ACTA2, FYB, GOLGA3). ATXN2L absence leads to depletion of NUFIP2 and SYNE2 in fibroblasts. Oxidative stress increases HNRNPK but decreases SYNE2 association with ATXN2L, reflecting stress granule relocalization. In an SCA2 mouse model (Atxn2-CAG100-KnockIn), NUFIP2 homodimers and SYNE1 accumulate during ATXN2 aggregation, suggesting ATXN2L sequestration contributes to disease. Co-immunoprecipitation in WT and ATXN2L-null MEFs, mass spectrometry proteome profiling, SCA2 knock-in mouse spinal cord analysis Neurobiology of disease High 40220918
2025 Conditional deletion of ATXN2L Lsm/LsmAD/PAM2 domains (exons 10–17) in CamK2a+ frontal cortex neurons reduces spontaneous horizontal movement without causing neuronal death, and proteome profiling reveals dysregulation enriched in the alternative splicing pathway, suggesting ATXN2L's Lsm/LsmAD domains contribute to splice regulation from a perinuclear location. Conditional CamK2a-CreERT2 × floxed ATXN2L mice, tamoxifen induction, open-field locomotor testing, global proteome profiling by mass spectrometry Cells Medium 41090760
2025 ATXN2L undergoes liquid-liquid phase separation (LLPS) to form cytoplasmic granules that recruit eukaryotic initiation factors (eIFs) and promote mRNA translation of targets such as ADAM9 (ADAM metallopeptidase domain 9), thereby driving hepatocellular carcinoma progression. Co-localization with stress granules further enhances ATXN2L granule-mediated ADAM9 translation. Knockout of Atxn2l in mice suppresses HCC progression. LLPS assay, granule imaging, eIF co-localization, ADAM9 translation assays, ATXN2L knockdown/knockout in cell lines and mice, in vivo HCC models Cell reports Medium 41273724
2025 ATXN2L-containing stress granule proteins (including ATXN2L itself) associate with MEWNG-rich proteins translated from cytoplasmic HSATIII lncRNAs during thermal stress recovery, placing ATXN2L in a cytoplasmic granule complex that also contains HSPA8 and ZC3HAV1. Proximity labeling, co-immunoprecipitation, fluorescence imaging, ribosome profiling (preprint) bioRxivpreprint Low

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature genetics 2251 20935630
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
1996 Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nature genetics 967 8896555
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
2013 GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science (New York, N.Y.) 503 23722424
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2009 Common variants at five new loci associated with early-onset inflammatory bowel disease. Nature genetics 394 19915574
2005 Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proceedings of the National Academy of Sciences of the United States of America 383 16009940
2004 Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nature methods 364 15782174
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
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 22 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 13 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 7 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 4 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 2 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