Affinage

NUFIP2

FMR1-interacting protein NUFIP2 · UniProt Q7Z417

Length
695 aa
Mass
76.1 kDa
Annotated
2026-06-10
26 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUFIP2 is a multifunctional RNA-binding protein cofactor that operates at the interface of post-transcriptional regulation, stress-responsive ribonucleoprotein condensates, and lysosomal stress signaling (PMID:12837692, PMID:29352114, PMID:36394332). It was first defined as an FMRP-interacting protein (82-FIP) associated with polyribosomes within FMRP-containing mRNP complexes (PMID:12837692), with structural work localizing the interaction to the second, flexible Tudor repeat of FMRP's N-terminal domain, whose fold also encodes a nucleolar localization signal that allosterically couples FMRP localization to its protein interactions (PMID:16407062). As a cofactor of Roquin-1/Roquin-2-induced mRNA decay, NUFIP2 binds Roquin directly and with high affinity and the two cooperatively recognize non-canonical stem-loop structures in target 3'-UTRs such as those of ICOS and Ox40 to drive post-transcriptional repression, with Roquin reciprocally stabilizing NUFIP2 in cells (PMID:29352114). NUFIP2 interacts RNA-independently with the helicase DDX6 and relocalizes to stress granules upon cellular stress, consistent with a role in translational repression (PMID:26184334); its incorporation into stress-granule condensates is promoted by O-GlcNAcylation during stress recovery (PMID:40307207). Distinct from its condensate function, NUFIP2 is recruited to damaged lysosomes through direct binding to GABARAP-family mATG8 proteins in an Atg8ylation-dependent manner, where it cooperates with galectin-8 to inactivate MTOR via the Ragulator-Rag complex (PMID:36394332). NUFIP2 is the primary interactor of ATXN2L and is depleted in ATXN2L-null cells, and it is captured into pathological aggregates with ATXN2 and with cytoplasmically mislocalized TDP-43 in neurodegeneration contexts (PMID:40220918).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 High

    Establishing what NUFIP2 does began with identifying its physical partner, defining it as an FMRP-associated, polyribosome-bound mRNP component rather than an orphan protein.

    Evidence Co-IP, yeast two-hybrid, subcellular fractionation, and immunofluorescence in cultured cells and neurons

    PMID:12837692

    Open questions at the time
    • RNA targets bound by NUFIP2 not defined
    • functional consequence of the FMRP association on translation not established
  2. 2006 High

    Structural definition of the FMRP N-terminal domain pinpointed the second Tudor repeat as the NUFIP2 contact and linked fold stability to FMRP localization, providing a molecular basis for the interaction.

    Evidence NMR structure determination with mutagenesis and localization assays

    PMID:16407062

    Open questions at the time
    • NUFIP2 region engaging the Tudor repeat not mapped
    • functional output of the regulated interaction not resolved
  3. 2015 Medium

    Linking NUFIP2 to a translational-repression machinery showed it binds DDX6 RNA-independently and partitions into stress granules, not P-bodies, under stress.

    Evidence RNA-independent Co-IP with mass spectrometry and immunofluorescence

    PMID:26184334

    Open questions at the time
    • functional role of the DDX6 interaction in repression not directly tested
    • single-lab finding
  4. 2018 High

    An unbiased screen assigned NUFIP2 a defined post-transcriptional function as a Roquin cofactor that cooperatively recognizes non-canonical 3'-UTR stem-loops to drive mRNA decay.

    Evidence siRNA screen, direct binding and RNA EMSA, Co-IP, and reporter decay assays for ICOS/Ox40 elements

    PMID:29352114

    Open questions at the time
    • full set of NUFIP2-dependent Roquin targets unknown
    • structural basis of cooperative RNA recognition not solved
  5. 2018 Low

    Co-IP placed NUFIP2 within a broader stress-granule protein network including ATXN2/ATXN2L and FAM98A.

    Evidence Co-immunoprecipitation (NUFIP2 a secondary finding)

    PMID:29992460

    Open questions at the time
    • single Co-IP without reciprocal validation
    • direct versus indirect associations not distinguished
  6. 2020 Medium

    Quantitative interactome mapping confirmed NUFIP2 as an N-terminal FMRP interactor embedded in RNA-metabolism and stress-granule networks.

    Evidence Affinity pull-down with quantitative LC-MS/MS and domain mapping

    PMID:32525608

    Open questions at the time
    • functional consequence of network membership not tested
    • single-lab dataset
  7. 2022 High

    A new, condensate-independent role emerged: NUFIP2 is recruited to damaged lysosomes via direct GABARAP binding and contributes to MTOR inactivation through the Ragulator-Rag complex.

    Evidence LysoIP, proximity proteomics, Co-IP, and MTOR activity assays with Atg8ylation-dependence

    PMID:36394332

    Open questions at the time
    • how NUFIP2 mechanistically promotes MTOR inactivation at the lysosome unresolved
    • relationship between RNA-binding activity and lysosomal function unclear
  8. 2025 Medium

    NUFIP2 was defined as the primary ATXN2L interactor whose levels depend on ATXN2L and which is sequestered as homodimers during pathological ATXN2 aggregation, connecting it to neurodegeneration.

    Evidence Reciprocal Co-IP in ATXN2L-null cells, proteome profiling, and SCA2 mouse spinal cord analysis

    PMID:40220918

    Open questions at the time
    • functional consequence of NUFIP2 sequestration on neuronal physiology not established
    • single-lab
  9. 2025 Medium

    Context-dependent proximity labeling identified NUFIP2 as a TDP-43 interactor that sequesters mislocalized TDP-43 into cytoplasmic aggregates seen in ALS/FTLD tissue.

    Evidence APEX2 proximity labeling, mass spectrometry, functional screen, and patient-tissue immunofluorescence (preprint)

    PMID:40291645

    Open questions at the time
    • not yet peer-reviewed
    • directness of NUFIP2-TDP-43 interaction not established
  10. 2025 Medium

    A post-translational regulatory layer was added by showing O-GlcNAcylation of NUFIP2 promotes its incorporation into stress-granule biocondensates during stress recovery.

    Evidence Chemoproteomics, site mutagenesis, OGT inhibition, and fluorescence microscopy

    PMID:40307207

    Open questions at the time
    • modified residues' impact on RNA binding and Roquin/DDX6 functions not tested
    • single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NUFIP2's distinct activities — Roquin-dependent mRNA decay, stress-granule condensation, and lysosomal MTOR control — are integrated or switched within a cell remains unresolved.
  • no unifying structural or regulatory model linking the functions
  • intrinsic RNA-binding specificity of NUFIP2 alone not defined
  • in vivo physiological role in immunity versus neurodegeneration not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 1 GO:0005764 lysosome 1 GO:0005829 cytosol 1 GO:0005840 ribosome 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-162582 Signal Transduction 1 R-HSA-168256 Immune System 1 R-HSA-8953854 Metabolism of RNA 1
Partners
ATXN2ATXN2LDDX6FAM98AFMRPGABARAPRC3H1TARDBP
Complex memberships
stress granule

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 NUFIP2 (82-FIP) was identified as a novel FMRP-interacting protein. FMRP interacts with NUFIP2 through a novel interaction motif located in its N-terminal region. NUFIP2 is associated with polyribosomes as a component of mRNP complexes containing FMRP. Subcellular distribution of NUFIP2 is cell cycle-dependent in cultured cells, appearing in both nucleus and cytoplasm in some neurons and only cytoplasmic in others. Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation, immunofluorescence microscopy Human molecular genetics High 12837692
2006 The N-terminal domain of FMRP (NDF) adopts a composite fold comprising two Tudor motif repeats followed by a short alpha helix. The second, more flexible Tudor repeat is responsible for interacting with NUFIP2 (82-FIP). The NDF fold contains a 3D nucleolar localization signal, such that destabilization of the fold leads to altered nucleolar localization of FMRP, suggesting an allosteric mechanism regulates FMRP functions including its interaction with NUFIP2. NMR structure determination, mutagenesis, functional localization assays Structure High 16407062
2015 NUFIP2 interacts with the RNA helicase DDX6 in an RNA-independent manner. NUFIP2 is not a P-body component but re-localizes to stress granules upon cellular stress exposure, suggesting a function in translation repression during the stress response. Immunoprecipitation with nuclease digestion (RNA-independent pulldown), mass spectrometry, immunofluorescence microscopy Biomolecules Medium 26184334
2018 NUFIP2 was identified as a cofactor of Roquin-1/Roquin-2-induced mRNA decay. NUFIP2 binds directly and with high affinity to Roquin, and Roquin stabilizes NUFIP2 in cells. NUFIP2 and Roquin cooperatively bind non-canonical stem-loop structures in the ICOS 3'-UTR and in the Ox40 3'-UTR tandem loop element to mediate post-transcriptional repression of ICOS mRNA. Knockdown of NUFIP2 identified by siRNA screen (~1500 genes) impaired Roquin-induced mRNA decay. siRNA screen, direct binding assay (high-affinity interaction), co-immunoprecipitation, RNA electrophoretic mobility shift assay, reporter assays Nature communications High 29352114
2018 NUFIP2 associates with stress granule-localized proteins including DDX1, ATXN2, ATXN2L, and FAM98A, as shown by co-immunoprecipitation in the context of stress granule biology. Co-immunoprecipitation Molecular and cellular biochemistry Low 29992460
2020 NUFIP2 was identified as an FMRP-interacting protein by affinity pull-down and quantitative LC-MS/MS analysis. NUFIP2 interacts with the N-terminus of FMRP (among 28 proteins interacting with the N-terminal domain). FMRP interactome studies placed NUFIP2 within networks associated with RNA metabolism and ribonucleoprotein stress granule formation. Affinity pull-down, quantitative LC-MS/MS proteomics The FEBS journal Medium 32525608
2022 Upon lysosomal damage, NUFIP2 is recruited to damaged lysosomes together with G3BP1 and GABARAP-family mATG8 proteins. GABARAPs interact directly with NUFIP2, and Atg8ylation (membrane conjugation of mATG8s) is required for NUFIP2 recruitment to damaged lysosomes. At the lysosome, NUFIP2 contributes to MTOR inactivation together with LGALS8 (galectin-8) via the Ragulator-RRAGA-RRAGB complex. This function is separable from NUFIP2's role in stress granule formation and is governed by GABARAP and Atg8ylation. Lysosome immunopurification (LysoIP), proximity proteomics, co-immunoprecipitation, MTOR activity assays, genetic knockdown with functional readout Autophagy High 36394332
2025 NUFIP2 is the primary interactor of ATXN2L as identified by co-immunoprecipitation in wild-type murine embryonic fibroblasts. NUFIP2 protein levels are depleted in ATXN2L-null fibroblasts as shown by proteome profiling. In a SCA2 mouse model (Atxn2-CAG100-KnockIn), NUFIP2 homodimers accumulate in aged spinal cord tissues during ATXN2 aggregation, suggesting NUFIP2 is sequestered during pathological ATXN2 aggregation. Co-immunoprecipitation in wild-type and ATXN2L-null cells, mass spectrometry proteomics, SCA2 mouse model tissue analysis Neurobiology of disease Medium 40220918
2025 NUFIP2 was identified as a TDP-43 interactor specifically associated with TDP-43 cytoplasmic mislocalization conditions (not under normal nuclear conditions). NUFIP2 sequesters TDP-43 into cytoplasmic aggregates and co-localizes with TDP-43 pathology in ALS/FTLD patient tissue. APEX2-driven proximity labeling, mass spectrometry, functional screen, immunofluorescence in patient tissue bioRxivpreprint Medium 40291645
2025 O-GlcNAcylation of NUFIP2 regulates the formation of RNA-protein biocondensates (stress granules). Site mutagenesis and inhibition of O-GlcNAc transferase combined with fluorescence microscopy validated that O-GlcNAcylation promotes NUFIP2 condensate formation during stress recovery. Mass spectrometry-based chemoproteomics, site mutagenesis, O-GlcNAc transferase inhibition, fluorescence microscopy Nature communications Medium 40307207

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The structure of the N-terminal domain of the fragile X mental retardation protein: a platform for protein-protein interaction. Structure (London, England : 1993) 91 16407062
2003 82-FIP, a novel FMRP (fragile X mental retardation protein) interacting protein, shows a cell cycle-dependent intracellular localization. Human molecular genetics 61 12837692
2015 Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 45 25681562
2020 Novel FMRP interaction networks linked to cellular stress. The FEBS journal 40 32525608
2021 Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis. Arthritis research & therapy 34 33482886
2018 Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. Nature communications 33 29352114
2015 Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins. Biomolecules 28 26184334
2008 Characterization of a 7.6-Mb germline deletion encompassing the NF1 locus and about a hundred genes in an NF1 contiguous gene syndrome patient. European journal of human genetics : EJHG 28 18648396
2022 Membrane Atg8ylation, stress granule formation, and MTOR regulation during lysosomal damage. Autophagy 23 36394332
2018 FAM98A is localized to stress granules and associates with multiple stress granule-localized proteins. Molecular and cellular biochemistry 17 29992460
2016 A novel de novo microdeletion at 17q11.2 adjacent to NF1 gene associated with developmental delay, short stature, microcephaly and dysmorphic features. Molecular cytogenetics 17 27247625
2017 Visualization and Analysis of MicroRNAs within KEGG Pathways using VANESA. Journal of integrative bioinformatics 16 28609293
2006 Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation. Human genetics 15 16395596
2012 Personality assessment and its association with genetic factors in captive Asian and African elephants. Zoo biology 12 22996044
2018 Visualization and Analysis of miRNAs Implicated in Amyotrophic Lateral Sclerosis Within Gene Regulatory Pathways. Studies in health technology and informatics 10 30147069
2025 O-GlcNAcylation reduces proteome solubility and regulates the formation of biomolecular condensates in human cells. Nature communications 9 40307207
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
2025 Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD. bioRxiv : the preprint server for biology 8 40291645
2024 The identification of key molecules and pathways in the crosstalk of calcium oxalate-treated TCMK-1 cells and macrophage via exosomes. Scientific reports 4 39251681
2025 Identification of Common miRNAs Differentially Expressed in Periodontitis and Pancreatic Cancer. In vivo (Athens, Greece) 3 40294979
2023 DHT inhibits REDOX damage and neuroinflammation to reduce PND occurrence in aged mice via mmu_circ_0001442/miR-125a-3p/NUFIP2 axis. Brain and behavior 3 37550899
2021 Predicted SARS-CoV-2 miRNAs Associated with Epigenetic Viral Pathogenesis and the Detection of New Possible Drugs for Covid-19. Current drug delivery 3 33645482
2015 Establishment of a recessive mutant small-eye rat with lens involution and retinal detachment associated with partial deletion and rearrangement of the Cryba1 gene. The Biochemical journal 2 26303524
2024 Identifying feature genes of chickens with different feather pecking tendencies based on three machine learning algorithms and WGCNA. Frontiers in veterinary science 1 39679174
2026 Distinct Serum MicroRNA Signatures and mRNA Decay Pathway Dysregulation in NSAID-Exacerbated Chronic Urticaria. International journal of molecular sciences 0 41596550
2022 Network architecture of non-coding RNAs provides insights into the pathogenesis of upper tract urothelial carcinoma. Urologic oncology 0 35659483

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