Affinage

NUFIP1

FMR1-interacting protein NUFIP1 · UniProt Q9UHK0

Length
495 aa
Mass
56.3 kDa
Annotated
2026-04-29
19 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUFIP1 is a nucleocytoplasmic shuttling protein that functions as a selective autophagy (ribophagy) receptor, a scaffold for box C/D snoRNP assembly, and a participant in transcription and the DNA damage response. Upon mTORC1 inhibition or nutrient stress, NUFIP1 redistributes from the nucleus to autophagosomes, directly binds ribosomes and LC3B, and delivers ribosomes for lysosomal degradation, promoting cell survival and supplying nucleosides to neighboring cells (PMID:29700228, PMID:35982178). NUFIP1 bridges the 15.5K/Snu13p snoRNP core protein and the R2TP chaperone via a structurally characterized interface stabilized by ZNHIT3, preventing premature snoRNP activity during assembly (PMID:24234454, PMID:25170085). Phosphorylated NUFIP1 also binds RPA32 to recruit ATR-ATRIP, activating the DNA damage response under amino acid deficiency; loss of this function causes necroptosis-driven spontaneous enteritis in mice (PMID:39753713).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 High

    Establishing that NUFIP1 is not a purely nuclear protein but a CRM1-dependent nucleocytoplasmic shuttle associated with ribosomes in both the cytoplasm and synaptoneurosomes provided the first framework for understanding its dual nuclear and cytoplasmic roles.

    Evidence Subcellular fractionation, immunofluorescence, nuclear export signal mutagenesis, and leptomycin B treatment in neuronal and non-neuronal cells

    PMID:12941608

    Open questions at the time
    • Direct RNA or ribosome-binding domains were not mapped
    • Functional consequence of ribosome association in the cytoplasm was not tested
  2. 2004 High

    Demonstrating that NUFIP1 associates with BRCA1 and P-TEFb (Cyclin T1) and stimulates RNA Pol II transcription in a zinc-finger-dependent manner revealed an unexpected transcriptional co-activator function.

    Evidence Yeast two-hybrid, Co-IP, in vitro transcription with immunodepletion/rescue, zinc-finger mutagenesis

    PMID:15107825

    Open questions at the time
    • Endogenous target genes regulated by NUFIP1's transcriptional activity were not identified
    • Relationship between transcriptional and snoRNP/ribophagy functions was not addressed
  3. 2013 High

    Solving the NMR structure of the NUFIP1/Rsa1p–15.5K/Snu13p interface and showing mutual exclusivity with active snoRNP assembly established NUFIP1 as a quality-control scaffold that prevents premature snoRNP function.

    Evidence NMR structure determination, mutagenesis of interface residues, yeast genetics assessing snoRNP formation

    PMID:24234454

    Open questions at the time
    • Mechanism by which NUFIP1 is released upon completed snoRNP assembly was not defined
    • Whether NUFIP1 scaffolding extends to box H/ACA snoRNPs was not tested
  4. 2014 High

    Identifying ZNHIT3/Hit1p as a stabilizer of NUFIP1/Rsa1p and reconstituting a Snu13p–Rsa1p–Hit1p heterotrimer that binds C/D snoRNAs and Nop58 clarified the minimal assembly platform for snoRNP biogenesis.

    Evidence NMR structure of Rsa1p–Hit1p complex, biochemical reconstitution, protein stability assays across yeast and human

    PMID:25170085

    Open questions at the time
    • How the heterotrimer hands off the snoRNA to the mature snoRNP particle was not resolved
    • In vivo stoichiometry and dynamics of the complex were not measured
  5. 2018 High

    The key conceptual advance was identifying NUFIP1 as a selective autophagy receptor for ribosomes: upon mTORC1 inhibition it relocates to autophagosomes, directly binds both ribosomes and LC3B, and promotes ribophagy-dependent cell survival.

    Evidence Quantitative lysosome proteomics, subcellular fractionation, Co-IP, direct binding assays, and loss-of-function survival assays in mammalian cells

    PMID:29700228

    Open questions at the time
    • Structural basis for NUFIP1–ribosome recognition was not determined
    • Whether NUFIP1 distinguishes 40S from 60S subunits or targets specific ribosome populations was unclear
  6. 2019 Medium

    Observation that mechanical stress triggers NUFIP1 translocation to lysosomes and its interaction with nuclear LC3 in trabecular meshwork cells extended the autophagy receptor concept beyond nutrient deprivation, although the cargo in this context was not identified.

    Evidence Co-IP, live imaging of GFP-LC3, biochemical fractionation under cyclic mechanical stress

    PMID:31476975

    Open questions at the time
    • The specific autophagy cargo targeted by NUFIP1 under mechanical stress was not identified
    • Whether ribosome degradation occurs in this context was not tested
  7. 2022 Medium

    Showing that NUFIP1-dependent ribophagy in cancer-associated fibroblasts supplies nucleosides that fuel pancreatic tumor growth connected the ribophagy receptor function to a tumor-promoting metabolic pathway in vivo.

    Evidence NUFIP1 knockdown in CAFs, orthotopic PDAC mouse model, metabolic profiling, co-culture assays

    PMID:35982178

    Open questions at the time
    • Whether tumor cells also utilize intrinsic NUFIP1-mediated ribophagy for survival was not distinguished
    • Specificity of nucleoside supply versus other autophagy-derived metabolites was not fully resolved
  8. 2025 High

    Two studies expanded NUFIP1's mechanistic repertoire: phospho-NUFIP1 recruits ATR-ATRIP via RPA32 to activate the DNA damage response under amino acid deficiency (with conditional knockout causing necroptosis-driven enteritis), and separately NUFIP1-mediated ribophagy alleviates sepsis-induced PANoptosis of CD4+ T cells via the cGAS-STING axis.

    Evidence Co-IP of phospho-NUFIP1 with RPA32/ATR-ATRIP, phospho-mutant rescue, conditional KO mouse enteritis model (DDR study); Co-IP of NUFIP1 with STING, CLP sepsis model, TMT proteomics (sepsis study)

    PMID:39753713 PMID:40995563

    Open questions at the time
    • The kinase responsible for NUFIP1 phosphorylation upstream of DDR activation was not identified
    • Whether the DDR and ribophagy functions of NUFIP1 are coordinated or mutually exclusive under nutrient stress was not resolved
    • The NUFIP1–STING interaction in sepsis was shown by single-lab Co-IP and awaits independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NUFIP1 toggles between its distinct roles — snoRNP assembly scaffold, ribophagy receptor, transcriptional co-activator, and DDR adaptor — depending on cellular context remains an open question; the regulatory switches (post-translational modifications, competitive binding) that partition NUFIP1 among these functions are not understood.
  • No integrated model explains how NUFIP1 is partitioned among its four known functions
  • Structural basis for NUFIP1–ribosome and NUFIP1–LC3B interaction has not been determined
  • Whether loss of NUFIP1 in humans causes a Mendelian phenotype is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005764 lysosome 2 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-73894 DNA Repair 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
BRCA1CCNT1MAP1LC3BNHPXRPA2STING1ZNHIT3
Complex memberships
Snu13/15.5K-NUFIP1-ZNHIT3 snoRNP assembly platform

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 NUFIP1 acts as a selective autophagy receptor (ribophagy receptor) that, upon mTORC1 inhibition/starvation, redistributes from the nucleus to autophagosomes and lysosomes, directly binds ribosomes, and delivers them to autophagosomes by directly binding LC3B; this ribophagy depends on NUFIP1's capacity to bind LC3B and promotes cell survival. Quantitative lysosome proteomics, subcellular fractionation, Co-IP, loss-of-function with cell survival readout, direct binding assays Science High 29700228
2003 NUFIP1 is a nucleocytoplasmic shuttling protein that localizes to the nuclear matrix in RNA-containing structures, is present in the cytoplasm associated with ribosomes, and contains a functional CRM1-dependent nuclear export signal; in neurons it is detected in functional synaptoneurosomes co-localizing with ribosomes, suggesting a role in mRNA export/localization and local synaptic protein synthesis in association with FMRP. Subcellular fractionation, immunofluorescence, nuclear export signal mutagenesis, leptomycin B treatment, synaptoneurosomes isolation Experimental cell research High 12941608
2004 NUFIP interacts with BRCA1 and associates with the positive transcription elongation factor P-TEFb through its Cyclin T1 subunit; NUFIP stimulates activator-independent RNA polymerase II transcription in vitro and in vivo, is associated with preinitiation, open, and elongation complexes, and facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes; mutation of its zinc-finger domain abolishes transcriptional activation. Yeast two-hybrid, immunodepletion, in vitro transcription assay, co-immunoprecipitation, zinc-finger domain mutagenesis Oncogene High 15107825
2013 NUFIP (human homolog of yeast Rsa1p) acts as an assembly scaffold for box C/D snoRNPs by binding the 15.5K protein (human homolog of yeast Snu13p); NMR structure and mutagenesis identified specific electrostatic and hydrophobic interface residues (R249, R246, K250 in Rsa1p; E72, D73 in Snu13p; W253 of Rsa1p inserted in hydrophobic cavity); this interaction is predicted to be mutually exclusive with active snoRNP assembly, suggesting NUFIP prevents premature snoRNP activity. NMR structure determination, mutagenesis, biophysical binding assays, yeast genetics (growth and snoRNP formation) Nucleic acids research High 24234454
2014 The human ZNHIT3 (TRIP3) protein, showing sequence homology with yeast Hit1p, regulates the abundance of NUFIP1 (the human Rsa1p homolog); Hit1p/ZNHIT3 is required to maintain steady-state levels of Rsa1p/NUFIP1, and the Snu13p-Rsa1p-Hit1p heterotrimer can interact with C/D snoRNAs and the core protein Nop58. Proteomics, NMR structure of Rsa1p-Hit1p complex, biochemical reconstitution of heterotrimer, protein stability assays Nucleic acids research High 25170085
2019 Under cyclic mechanical stress in trabecular meshwork cells, NUFIP1 translocates from the nucleus to LAMP2-positive lysosomal organelles and co-immunoprecipitates with nuclear LC3, suggesting a selective autophagy receptor role for a target other than ribosomes in this context; nuclear LC3 localizes to the nucleolus and interacts with NUFIP1 under mechanical stress. Biochemical fractionation, co-immunoprecipitation, live imaging (GFP-LC3/tfLC3), leptomycin B treatment, immunofluorescence Autophagy Medium 31476975
2022 In cancer-associated fibroblasts (CAFs), NUFIP1-dependent autophagy mediates secretion of nucleosides that support pancreatic tumor growth under glutamine deprivation; inhibiting NUFIP1 in the stroma reduced tumor weight in an orthotopic mouse model. NUFIP1 knockdown/loss-of-function, orthotopic mouse model, metabolic profiling, CAF-PDAC co-culture Nature cancer Medium 35982178
2025 Phosphorylated NUFIP1 binds replication protein A2 (RPA32) to recruit the ATR-ATRIP complex, thereby triggering the DNA damage response (DDR); loss of NUFIP1 or its non-phosphorylatable mutant impairs the DDR under amino acid deficiency and induces necroptosis-related spontaneous enteritis in mice. Co-IP (phospho-NUFIP1 with RPA32/ATR-ATRIP), conditional knockout mouse model, phospho-mutant rescue experiments, in vitro DDR assays Nature metabolism High 39753713
2025 Sepsis-induced ribosome collision activates the cGAS-STING signaling axis, which recruits NUFIP1 to STING protein complexes; NUFIP1-mediated ribophagy alleviates PANoptosis of CD4+ T lymphocytes via this cGAS-STING pathway, preserving immune function. NUFIP1 knockdown, CLP sepsis model, TMT proteomics, Co-IP (NUFIP1 with STING), cytokine assays, T cell proliferation Research (Washington, D.C.) Medium 40995563

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science (New York, N.Y.) 290 29700228
2022 Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth. Nature cancer 75 35982178
2019 The autophagic protein LC3 translocates to the nucleus and localizes in the nucleolus associated to NUFIP1 in response to cyclic mechanical stress. Autophagy 56 31476975
2003 NUFIP1 (nuclear FMRP interacting protein 1) is a nucleocytoplasmic shuttling protein associated with active synaptoneurosomes. Experimental cell research 46 12941608
2014 Protein Hit1, a novel box C/D snoRNP assembly factor, controls cellular concentration of the scaffolding protein Rsa1 by direct interaction. Nucleic acids research 44 25170085
2013 Characterization of the interaction between protein Snu13p/15.5K and the Rsa1p/NUFIP factor and demonstration of its functional importance for snoRNP assembly. Nucleic acids research 33 24234454
1985 Rsa1 polymorphism at the insulin receptor locus (INSR) on chromosome 19. Nucleic acids research 33 3001646
2019 Thrombolytic Potential of Novel Thiol-Dependent Fibrinolytic Protease from Bacillus cereus RSA1. Biomolecules 27 31861284
2004 BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II. Oncogene 26 15107825
1982 Purification of rabbit sperm autoantigens by preparative SDS gel electrophoresis: amino acid and carbohydrate content of RSA-1. Biology of reproduction 26 7139016
2021 Computational-approach understanding the structure-function prophecy of Fibrinolytic Protease RFEA1 from Bacillus cereus RSA1. PeerJ 14 34141495
2025 NUFIP1 integrates amino acid sensing and DNA damage response to maintain the intestinal homeostasis. Nature metabolism 13 39753713
2025 NUFIP1-Mediated Ribophagy Alleviates PANoptosis of CD4+ T Lymphocytes in Sepsis via the cGAS-STING Pathway. Research (Washington, D.C.) 9 40995563
2024 NUFIP1-engineered exosomes derived from hUMSCs regulate apoptosis and neurological injury induced by propofol in newborn rats. Neurotoxicology 5 38599287
2021 Targeting NUFIP1 Suppresses Growth and Induces Senescence of Colorectal Cancer Cells. Frontiers in oncology 4 34367967
2021 High Resolution Structure of the Mature Capsid of Ralstonia solanacearum Bacteriophage ϕRSA1 by Cryo-Electron Microscopy. International journal of molecular sciences 3 34681713
2026 Erratum to "NUFIP1-Mediated Ribophagy Alleviates PANoptosis of CD4+ T Lymphocytes in Sepsis via the cGAS-STING Pathway". Research (Washington, D.C.) 0 41783044
2026 NUFIP1-engineered exosomes modulate propofol-induced neurotoxicity in neonatal rats via the ERS apoptotic pathway. Apoptosis : an international journal on programmed cell death 0 41942784
2025 NUFIP1 at the crossroads of ribophagy and disease: unveiling therapeutic implications. Journal of translational medicine 0 41366789