Affinage

U2AF1L4

IGF-like family receptor 1 · UniProt Q9H665

Length
355 aa
Mass
37.9 kDa
Annotated
2026-06-10
17 papers in source corpus 7 papers cited in narrative 7 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

U2AF1L4 (U2AF26) is a small U2AF subunit paralog that acts as a splicing regulator and, through alternative splicing of its own transcript, a multifunctional switch coupling pre-mRNA processing to cytoplasmic and physiological outputs (PMID:11739736, PMID:24837677). It associates with U2AF65 and can functionally substitute for U2AF35, enhancing U2AF65 binding to weak 3' splice sites to support constitutive and enhancer-dependent splicing, with both zinc fingers required for splicing activity and ZnF2 mediating the U2AF65 interaction and controlling protein stability (PMID:11739736, PMID:32116123). Nuclear import of full-length U2AF26 depends on a C-terminal NLS in exons 7–8 and on interaction with P32, whereas a splice variant lacking exon 7/ZnF2 accumulates in the cytoplasm; this cytoplasmic isoform is induced upon T cell activation and activates translation when tethered to a 5'UTR, partially via ZnF1 (PMID:18460468, PMID:32116123). In T cells U2AF26 promotes CD45RO formation by driving exon exclusion, an activity antagonized by direct interaction with the transcription factor Gfi1, so that the U2AF26:Gfi1 ratio sets CD45 isoform balance (PMID:16819553). In circadian biology, light-induced alternative splicing shifts the reading frame to create a TIMELESS-homology C-terminus that destabilizes PERIOD1; U2af26-deficient mice show arrhythmic PERIOD1 and circadian mRNA defects, and this rhythmic splicing switch is driven by SRSF2 and SRSF7 acting on defined enhancer elements under temperature-regulated SR-protein phosphorylation (PMID:24837677, PMID:30200840).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2002 High

    Established that U2AF26 is a functional small U2AF subunit by showing it can replace U2AF35 in splicing, defining its core biochemical role.

    Evidence In vitro splicing reconstitution, functional complementation, and binding assays

    PMID:11739736

    Open questions at the time
    • Did not define which native transcripts depend on U2AF26 in cells
    • RS domain dispensability for enhancer function not extended to all splicing contexts
  2. 2006 High

    Connected U2AF26 to immune signaling by showing it controls CD45 isoform choice and is counter-regulated by a direct Gfi1 interaction, revealing a regulatable splicing switch.

    Evidence Co-IP, splicing reporter assays, Gfi1-deficient mice, retroviral overexpression

    PMID:16819553

    Open questions at the time
    • Mechanism by which Gfi1 antagonizes exon exclusion not resolved at the spliceosome level
    • Physiological consequences for TCR signaling strength not directly measured here
  3. 2006 Low

    Reported a distinct U2AF1L4 splice isoform with tissue-enriched expression, hinting at isoform-specific regulation before function was known.

    Evidence RT-PCR, cloning and sequencing

    PMID:17312947

    Open questions at the time
    • No functional assay for the cloned isoform
    • Expression pattern descriptive only, no mechanistic link
  4. 2008 High

    Defined how U2AF26 localization is controlled, showing that an exon 7/8 NLS and P32 interaction govern nuclear import, while an exon-7-lacking variant is cytoplasmic.

    Evidence Subcellular fractionation, heterokaryon shuttling, Co-IP, NLS mutagenesis

    PMID:18460468

    Open questions at the time
    • Functional role of cytoplasmic variant not yet established
    • How P32 binding is regulated to gate import unknown
  5. 2014 High

    Revealed a non-splicing physiological output, showing light-induced frame-shifting alternative splicing generates a TIMELESS-homology variant that destabilizes PERIOD1 to buffer the circadian clock.

    Evidence Alternative splicing analysis, U2af26 KO mice, PERIOD1 Western blot, behavioral circadian assays, mRNA profiling

    PMID:24837677

    Open questions at the time
    • Molecular mechanism of PERIOD1 destabilization not defined
    • Direct biochemical interaction with PERIOD1 not shown
  6. 2018 High

    Dissected the cis/trans logic of the circadian splicing switch, mapping enhancer elements and identifying SRSF2/SRSF7 and temperature-regulated SR phosphorylation as drivers of rhythmic splicing.

    Evidence Minigene assays, siRNA screen, iCLIP, RNA-Seq, cis-element mutagenesis

    PMID:30200840

    Open questions at the time
    • Kinase responsible for temperature-regulated SR phosphorylation not identified
    • How light input feeds into the SR-protein circuit unresolved
  7. 2020 High

    Assigned domain-specific functions and a cytoplasmic translational role, showing both ZnFs are needed for splicing while a ZnF2-lacking, T-cell-activation-induced cytoplasmic isoform promotes translation.

    Evidence ZnF mutagenesis, splicing reporters, Ribo-Seq, MS2 tethering, U2AF65 Co-IP, subcellular fractionation

    PMID:32116123

    Open questions at the time
    • Endogenous mRNA targets of cytoplasmic translation activation not defined
    • Mechanism of translational activation via ZnF1 not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How U2AF26's nuclear splicing, cytoplasmic translational, and isoform-switching activities are integrated across tissues and physiological contexts remains open.
  • No structural model of the U2AF26–U2AF65 heterodimer on RNA
  • Genome-wide endogenous splicing targets of U2AF26 uncharacterized
  • Unified model linking circadian, immune, and translational roles absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0045182 translation regulator activity 1 GO:0140098 catalytic activity, acting on RNA 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-168256 Immune System 1 R-HSA-9909396 Circadian clock 1
Partners
GFI1P32U2AF65

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 U2AF26 (U2AF1L4) associates with U2AF65 and can functionally substitute for U2AF35 in both constitutive and enhancer-dependent splicing. The RS domain of the small U2AF subunit is not required for splicing enhancer function. U2AF26 functions by enhancing the binding of U2AF65 to weak 3' splice sites. In vitro splicing assays, protein-protein interaction assays, functional complementation of U2AF35 Molecular and cellular biology High 11739736
2006 U2AF26 promotes formation of the CD45RO isoform by facilitating exon exclusion in CD45 alternative splicing. The transcription factor Gfi1 directly interacts with U2AF26 and antagonizes this exon exclusion, thereby promoting CD45RB formation. The relative abundance of U2AF26 and Gfi1 determines the ratio of CD45 isoforms. Co-immunoprecipitation, splicing reporter assays, Gfi1-deficient mice, retroviral overexpression Nature immunology High 16819553
2008 U2AF26 (full-length) is nuclear and displays active nucleo-cytoplasmic shuttling, whereas the splice variant lacking exon 7 (U2AF26ΔE7) is localized in the cytoplasm. A nuclear localization sequence (NLS) in the C-terminal exons 7 and 8 is required for nuclear import. The protein P32 interacts with U2AF26 through this C-terminal domain, and this interaction is required for nuclear translocation of U2AF26. Subcellular fractionation, fluorescence microscopy, heterokaryon shuttling assay, co-immunoprecipitation, deletion/mutagenesis of NLS The Journal of biological chemistry High 18460468
2014 Light-inducible alternative splicing of U2af26 shifts the reading frame to generate a C-terminal domain with homology to Drosophila TIMELESS. This new U2AF26 variant destabilizes PERIOD1 protein. U2AF26-deficient mice show nearly arrhythmic PERIOD1 protein levels and broad defects in circadian mRNA expression in peripheral clocks, and display increased phase advance adaptation following jet lag. Alternative splicing analysis, RT-PCR, U2AF26 knockout mice, Western blot for PERIOD1 stability, behavioral circadian assays, mRNA expression profiling Molecular cell High 24837677
2018 Oscillating alternative splicing of U2af26 is controlled by a complex network of cis-regulatory sequences, including two enhancer elements whose combined activity is necessary for rhythmic splicing. SRSF2 (binding within exon 6, mapped to single-nucleotide resolution) and SRSF7 cooperate to drive oscillating U2af26 alternative splicing. Temperature-regulated SR protein phosphorylation controls this rhythmic AS. Minigene splicing assays, siRNA screen, iCLIP, RNA-Seq, site-directed mutagenesis of cis elements RNA biology High 30200840
2020 Both zinc finger (ZnF) domains of U2AF26 are required for splicing regulation. ZnF2, but not ZnF1, controls U2AF26 protein stability and contributes to interaction with U2AF65. A naturally occurring splice variant of U2AF26 lacking ZnF2 is strongly induced upon primary mouse T cell activation, localizes to the cytoplasm, and participates in activating translation. An MS2 tethering assay shows that cytoplasmic U2AF26 increases translation when localized to the 5'UTR of a model mRNA, partially dependent on ZnF1. Splicing reporter assays, mutagenesis of ZnF domains, Ribo-Seq, MS2 tethering assay, co-immunoprecipitation with U2AF65, subcellular fractionation, T cell activation experiments RNA biology High 32116123
2006 A splice variant of U2AF1L3 (alias for U2AF1L4) was cloned; RT-PCR shows this isoform has a different expression pattern from the full-length gene and is highly expressed in heart, brain, and lung. RT-PCR, cloning and sequencing DNA sequence : the journal of DNA sequencing and mapping Low 17312947

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Rhythmic U2af26 alternative splicing controls PERIOD1 stability and the circadian clock in mice. Molecular cell 61 24837677
2006 Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing. Nature immunology 41 16819553
2002 Characterization of U2AF(6), a splicing factor related to U2AF(35). Molecular and cellular biology 33 11739736
2018 Characterization of cis-acting elements that control oscillating alternative splicing. RNA biology 18 30200840
2022 LncRNA Pnky Positively Regulates Neural Stem Cell Migration by Modulating mRNA Splicing and Export of Target Genes. Cellular and molecular neurobiology 15 35748966
2008 Differential isoform expression and interaction with the P32 regulatory protein controls the subcellular localization of the splicing factor U2AF26. The Journal of biological chemistry 13 18460468
2012 Human PSENEN and U2AF1L4 genes are concertedly regulated by a genuine bidirectional promoter. Gene 10 23246698
2017 The role of human chorionic gonadotropin in regulation of naïve and memory T cells activity in vitro. International immunopharmacology 7 29100035
2020 The zinc finger domains in U2AF26 and U2AF35 have diverse functionalities including a role in controlling translation. RNA biology 6 32116123
2023 The diagnostic significance of the ZNF gene family in pancreatic cancer: a bioinformatics and experimental study. Frontiers in genetics 5 37396042
2016 [Cytokine-mediated regulation of expression of Gfi1 and U2afll4 genes activated by T-cells with different differentiation status in vitro]. Biomeditsinskaia khimiia 1 27143377
2006 Cloning and characterization of a novel splice variant of human U2AF1L3 gene. DNA sequence : the journal of DNA sequencing and mapping 1 17312947
2026 Causal splicing variants revealed by deep-learning integration of single-cell sQTL mapping under influenza infection. Research square 0 41542048
2025 Extracellular proteins from Perkinsus olseni: LC-MS/MS-based proteomic profiling and functional insights into host-parasite interactions. Fish & shellfish immunology 0 40782844
2024 [Multi-omics genetic association analysis identifies susceptibility risk gene of acute viral respiratory infections in multi-ancestry populations and screening of potential traditional Chinese medicines]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 0 39701775
2015 Effects of Immunoregulatory Cytokines (IL-2, IL-7, and IL-15) on Expression of Gfi1 and U2afll4 Genes in T Cells at Different Stages of Differentiation. Bulletin of experimental biology and medicine 0 26085358
2011 Functional dissection of an enhancer-like element located within the second intron of the human U2AF1L4 gene. Biochemistry. Biokhimiia 0 22022969

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