Affinage

NVL

Nuclear valosin-containing protein-like · UniProt O15381

Length
856 aa
Mass
95.1 kDa
Annotated
2026-06-10
17 papers in source corpus 12 papers cited in narrative 13 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

NVL encodes a nuclear AAA-ATPase whose major isoform, NVL2, is targeted to the nucleolus and operates as an energy-dependent remodeling factor in ribosome biogenesis (PMID:9286697, PMID:15469983). NVL2 associates with pre-ribosomal particles and engages the ribosomal protein L5 and the DExD/H-box helicase MTR4/DOB1 through its ATP-binding modules; ATPase activity drives the controlled release of processing factors from these particles, and ATPase-deficient mutants cause aberrant retention of MTR4 and defective maturation of 28S and 5.8S rRNAs (PMID:15469983, PMID:16782053, PMID:26166824). Acting on the MTR4-nuclear exosome complex, NVL2 stimulates ATP hydrolysis-dependent dissociation of a WDR74 module (WDR74-RPF1-MAK16-RRP1) and of the splicing factor SPF30, thereby controlling early ITS1 cleavage and licensing recruitment of the adaptor PICT1 for 5.8S 3'-end maturation during 60S subunit assembly (PMID:26456651, PMID:29107693, PMID:33422691, PMID:39706051). A structurally distinct N-terminal winged-helix domain anchors NVL2 to the nucleolus by binding nucleolin-RNA complexes via an RRKR loop, and NVL2 additionally associates with hTERT to support telomerase holoenzyme assembly and activity (PMID:21474449, PMID:22226966). Small-molecule inhibition of the NVL hexamer arrests nucleolar 60S biogenesis and triggers MDM2/p53-dependent and p53-independent cell-cycle arrest or apoptosis (PMID:40766499).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1997 Medium

    Established the gene product's basic identity—an unknown nuclear protein was defined as a two-domain AAA-ATPase, framing all subsequent mechanistic work around ATP-driven remodeling.

    Evidence Degenerate PCR cloning, cDNA sequencing and nuclear localization by protein characterization

    PMID:9286697

    Open questions at the time
    • No substrate or pathway assigned
    • No subnuclear resolution beyond bulk nuclear localization
  2. 2004 High

    Resolved why NVL has two functional forms and connected it to ribosome production—NVL2's N-terminal extension carries a nucleolar localization signal and mediates ATP-dependent binding to ribosomal protein L5, with a dominant-negative mutant blocking ribosome biosynthesis.

    Evidence Mutational analysis, subcellular fractionation, fluorescence microscopy, yeast two-hybrid and Co-IP with dominant-negative ribosome readout

    PMID:15469983

    Open questions at the time
    • Step of ribosome biogenesis affected not defined
    • Biochemical role of ATP hydrolysis vs binding unresolved
  3. 2006 High

    Identified the first direct enzymatic substrate-like partner—NVL2 binds MTR4/DOB1 via its first ATP module, and a second-module mutant traps DOB1 on pre-ribosomal particles, establishing NVL2 as a regulator of factor association/dissociation.

    Evidence Yeast two-hybrid, reciprocal Co-IP, ATPase domain mutagenesis, dominant-negative overexpression

    PMID:16782053

    Open questions at the time
    • Direct ATP-driven remodeling not reconstituted in vitro
    • Distinct roles of the two ATP modules not fully separated
  4. 2011 High

    Defined the structural basis of nucleolar targeting and revealed a second functional axis—an NMR structure showed a unique winged-helix N-terminal domain whose RRKR loop binds nucleolin-RNA complexes, while a separate study linked NVL2 to hTERT and telomerase assembly.

    Evidence NMR structure determination, RRKR mutagenesis, HeLa extract binding assays; Co-IP, siRNA knockdown and TRAP telomerase activity assay

    PMID:21474449 PMID:22226966

    Open questions at the time
    • Mechanistic link between nucleolin binding and ribosome remodeling unclear
    • How NVL2 promotes hTERT stability/telomerase assembly mechanistically undefined
  5. 2015 High

    Placed NVL2 within the nuclear exosome machinery and tied its ATPase to rRNA maturation—NVL2 joins the MTR4-exosome (RRP6, MPP6) and, via ATP hydrolysis, drives dissociation of the 60S factor WDR74, with ATPase mutants causing 28S/5.8S processing defects.

    Evidence Co-IP with knockdowns of MTR4/RRP6/MPP6, ATPase domain mutagenesis, northern blotting, proteomic screen and ribosome profiling

    PMID:26166824 PMID:26456651

    Open questions at the time
    • Order of WDR74 release relative to other steps not defined
    • In vitro reconstitution of ATP-driven dissociation absent
  6. 2017 High

    Provided spatiotemporal mechanism—NVL2 ATPase activity controls where and when WDR74 detaches from the MTR4-exosome, with ATPase-deficient NVL2 redistributing WDR74 to the nucleoplasm and blocking ITS1 cleavage, an early 60S step.

    Evidence siRNA knockdown, dominant-negative NVL2, northern blotting, in situ proximity ligation assay, immunofluorescence

    PMID:29107693

    Open questions at the time
    • Downstream consequences of mislocalized WDR74 on later maturation not traced
    • Coupling between cleavage and factor release mechanistically incomplete
  7. 2021 Medium

    Generalized the remodeling model to additional clients—SPF30 was shown to be an MTR4-exosome-associated factor whose release is NVL2 ATPase-regulated like WDR74, with knockdown delaying 12S-to-5.8S processing.

    Evidence Co-IP, shotgun proteomics, siRNA knockdown, rRNA processing assay

    PMID:33422691

    Open questions at the time
    • Functional significance of subtle processing delay unclear
    • Direct ATP-dependence of SPF30 release not shown by mutant in this study
  8. 2024 High

    Defined the substrate as a multiprotein module and its downstream coupling—WDR74 acts within a WDR74-RPF1-MAK16-RRP1 subcomplex, and NVL2 ATPase failure blocks module release and prevents MTR4 from recruiting the PICT1 adaptor needed for 5.8S 3'-end maturation.

    Evidence Co-IP/mass spectrometry, individual siRNA knockdowns, pre-rRNA processing assays

    PMID:39706051

    Open questions at the time
    • Structural basis of module recognition by NVL2 unknown
    • Whether NVL2 directly contacts PICT1 unresolved
  9. 2025 High

    Delivered structural and therapeutic validation—a cryo-EM structure of the NVL hexamer bound to inhibitor MM17 (confirmed by resistance mutations) showed that blocking NVL arrests nucleolar 60S biogenesis and induces MDM2/p53-dependent and -independent death, with an analog suppressing tumors in vivo; CWF19L2 was identified as a new NVL2 partner linking it to lariat RNA debranching.

    Evidence Cryo-EM, forward-genetics resistance mutations, cellular and mouse tumor models, p53 pathway analysis (preprint); Co-IP, RNA debranching assays, super-resolution imaging

    PMID:40766499 PMID:41422678

    Open questions at the time
    • MM17/MM927 results are from a preprint pending peer review
    • Mechanistic role of CWF19L2-NVL2 association in debranching vs ribosome biogenesis not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NVL2 ATP hydrolysis is mechanically coupled to client release on pre-ribosomal particles, and whether its ribosome-biogenesis and telomerase roles are mechanistically linked, remain open.
  • No in vitro reconstitution of ATP-driven factor dissociation
  • Structural basis for substrate engagement by the hexamer incompletely defined
  • Relationship between nucleolin/hTERT binding and 60S remodeling unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 6 GO:0140096 catalytic activity, acting on a protein 3 GO:0003723 RNA binding 1
Localization
GO:0005730 nucleolus 6 GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CWF19L2HTERTMPP6MTR4RPL5RRP6SPF30WDR74
Complex memberships
MTR4-nuclear exosome complexWDR74 module (WDR74-RPF1-MAK16-RRP1)telomerase holoenzyme

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 NVL encodes an ~110-kDa nuclear protein with two highly similar ATP-binding domains, establishing it as a member of the AAA ATPase family localized to the nucleus. Degenerate PCR cloning, cDNA sequencing, nuclear localization confirmed by protein characterization Genomics Medium 9286697
2004 NVL2 (the major isoform with a longer N-terminal extension) localizes to the nucleolus, whereas NVL1 is nucleoplasmic. Mutational analysis identified two nuclear localization signals and a distinct nucleolar localization signal (NoLS) within NVL2's N-terminal extra region. Mutational analysis, subcellular fractionation, fluorescence microscopy Molecular biology of the cell High 15469983
2004 NVL2 interacts with ribosomal protein L5 through its nucleolar localization signal; this interaction is ATP-dependent and contributes to nucleolar translocation of NVL2. A dominant-negative NVL2 mutant inhibits ribosome biosynthesis. Yeast two-hybrid screening, co-immunoprecipitation, dominant-negative overexpression with ribosome biosynthesis readout Molecular biology of the cell High 15469983
2006 NVL2 is associated with pre-ribosomal particles in the nucleus and interacts with the DExD/H-box RNA helicase DOB1/MTR4. This interaction requires the first ATP-binding module of NVL2; a dominant-negative second-module mutant causes aberrant retention of DOB1 on pre-ribosomal particles, suggesting NVL2 regulates association/dissociation of DOB1 from these particles. Yeast two-hybrid, co-immunoprecipitation, ATPase domain mutagenesis, cellular overexpression of dominant-negative mutants Biochemical and biophysical research communications High 16782053
2011 The solution structure of the N-terminal unique domain of NVL2 (NVL2-UD) was determined by NMR and found to adopt a winged-helix-like fold distinct from VCP/p97. NVL2-UD binds nucleolin from HeLa extracts in an RNA-dependent manner, with RRKR basic residues in a characteristic loop being necessary and sufficient for nucleolin-RNA complex binding and nucleolar localization. NMR structure determination, binding assays with HeLa cell extracts, mutagenesis of RRKR residues The Journal of biological chemistry High 21474449
2011 NVL2 interacts with hTERT (human telomerase reverse transcriptase) in the nucleolus and is found in association with catalytically competent telomerase. Depletion of NVL2 by siRNA decreases hTERT protein levels (without affecting hTERT mRNA) and reduces telomerase activity. ATP-binding activity of NVL2 is required for hTERT binding and telomerase assembly. Co-immunoprecipitation, co-localization, siRNA knockdown, TRAP assay for telomerase activity, RT-qPCR Biochemical and biophysical research communications Medium 22226966
2015 NVL2 is associated with the nuclear exosome complex (including RRP6 as a nucleus-specific catalytic subunit). This interaction is mediated by MTR4 and RRP6, as depletion of either prevents NVL2-exosome association. MPP6 (another exosome cofactor) is also required, as its knockdown causes MTR4 to dissociate from the nuclear exosome. ATPase domain mutations in NVL2 cause defects in pre-rRNA processing into mature 28S and 5.8S rRNAs. Co-immunoprecipitation, siRNA knockdown, ATPase domain mutagenesis, northern blotting/rRNA processing assay Biochemical and biophysical research communications High 26166824
2015 NVL2 acts on the MTR4-exosome complex to stimulate ATP hydrolysis-dependent dissociation of WDR74 (a WD repeat protein with similarity to yeast Nsa1). Knockdown of WDR74 decreases 60S ribosome levels, and WDR74 co-localizes with NVL2 in the nucleolus. Proteomic screen, co-immunoprecipitation, ATPase-deficient NVL2 mutant, siRNA knockdown, ribosome profiling Biochemical and biophysical research communications High 26456651
2017 WDR74 knockdown causes defects in pre-rRNA cleavage within ITS1, an early step in the 60S processing pathway. Expression of ATPase-deficient NVL2 also causes the same ITS1 processing defect with partial redistribution of WDR74 from nucleolus to nucleoplasm, where increased WDR74-MTR4 interaction is detected. This establishes that NVL2 ATPase activity spatiotemporally regulates WDR74 dissociation from the MTR4-exosome complex for proper pre-60S maturation. siRNA knockdown, dominant-negative NVL2 overexpression, northern blotting for pre-rRNA processing, in situ proximity ligation assay, immunofluorescence Biochemical and biophysical research communications High 29107693
2021 SPF30 (a Tudor domain-containing pre-mRNA splicing factor) is an MTR4-interacting protein whose association with the MTR4-exosome complex is regulated by NVL2 ATPase activity, analogous to WDR74. The interaction between SPF30 and the exosome core is mediated by MTR4 and RRP6. Knockdown of SPF30 caused a subtle delay in 12S pre-rRNA processing to mature 5.8S rRNA. Co-immunoprecipitation, siRNA knockdown, shotgun proteomics (interactome), rRNA processing assay The international journal of biochemistry & cell biology Medium 33422691
2024 WDR74 functions as part of a pre-ribosomal subcomplex (the WDR74 module) consisting of WDR74, RPF1, MAK16, and RRP1. Each component is mutually required for the interaction of the others with MTR4. NVL2 dysfunction (ATP hydrolysis-deficient mutant) prevents MTR4 from recruiting PICT1 (an MTR4 adaptor required for 5.8S rRNA 3'-end maturation) by blocking release of the WDR74 module from the MTR4-exosome complex. Co-immunoprecipitation combined with mass spectrometry, siRNA knockdown, pre-rRNA processing assays Biochemical and biophysical research communications High 39706051
2025 A small molecule inhibitor MM17 (dibenzothiazepinone) binds NVL at two sites on the hexameric assembly as revealed by cryo-EM. Mutations in NVL at these sites confer resistance to MM17. NVL inhibition arrests 60S ribosome biogenesis in the nucleolus and induces cell cycle arrest or apoptosis via MDM2/p53-dependent and p53-independent pathways without causing DNA damage. A bioavailable analog MM927 suppresses tumor growth in mouse leukemia and colorectal cancer models. Forward genetics (resistance mutations), cryo-EM structure of NVL hexamer with inhibitor, in vitro and cellular inhibitor treatment, MDM2/p53 pathway analysis, mouse tumor models bioRxivpreprint High 40766499
2025 CWF19L2 is a novel NVL2-interacting protein that associates with intron lariat spliceosome (ILS) components, lariat RNA debranching enzyme DBR1, and the MTR4-RNA exosome complex. CWF19L2 is required for debranching of intron-derived lariat RNAs, functioning as potently as DBR1 itself. Co-immunoprecipitation, RNA debranching assay (minigene splicing reporter, RT-PCR for endogenous lariat RNA), super-resolution immunofluorescence Biochemical and biophysical research communications Medium 41422678

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 NVL2 is a nucleolar AAA-ATPase that interacts with ribosomal protein L5 through its nucleolar localization sequence. Molecular biology of the cell 45 15469983
2021 Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? Translational oncology 44 34365220
2024 NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations. Cancer discovery 41 39269178
2006 The AAA-ATPase NVL2 is a component of pre-ribosomal particles that interacts with the DExD/H-box RNA helicase DOB1. Biochemical and biophysical research communications 33 16782053
2011 The AAA-ATPase NVL2 is a telomerase component essential for holoenzyme assembly. Biochemical and biophysical research communications 29 22226966
1997 NVL: a new member of the AAA family of ATPases localized to the nucleus. Genomics 28 9286697
2015 NVL2, a nucleolar AAA-ATPase, is associated with the nuclear exosome and is involved in pre-rRNA processing. Biochemical and biophysical research communications 27 26166824
2017 WDR74 participates in an early cleavage of the pre-rRNA processing pathway in cooperation with the nucleolar AAA-ATPase NVL2. Biochemical and biophysical research communications 26 29107693
2015 AAA-ATPase NVL2 acts on MTR4-exosome complex to dissociate the nucleolar protein WDR74. Biochemical and biophysical research communications 20 26456651
2011 Structure and function of the N-terminal nucleolin binding domain of nuclear valosin-containing protein-like 2 (NVL2) harboring a nucleolar localization signal. The Journal of biological chemistry 19 21474449
2015 The NVL gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population. Progress in neuro-psychopharmacology & biological psychiatry 16 25891250
2021 Interactome analysis of the Tudor domain-containing protein SPF30 which associates with the MTR4-exosome RNA-decay machinery under the regulation of AAA-ATPase NVL2. The international journal of biochemistry & cell biology 7 33422691
2024 Pre-ribosomal WDR74 module coordinates the early and late pre-rRNA processing stages for the NVL2-mediated regulation of 60S ribosome biogenesis. Biochemical and biophysical research communications 3 39706051
2025 Prediction of potential drug-resistant ALK mutations against fourth-generation inhibitors NVL-655 and TPX-0131. International journal of biological macromolecules 1 40714107
2025 Development of an enzyme-linked immunosorbent assay for the efficient detection of autoantibodies against nuclear valosin-containing protein-like protein (NVL) 2 using its manipulated cDNA. RMD open 1 40780730
2025 A small molecule inhibitor of NVL suppresses tumor growth by blocking ribosome biogenesis. bioRxiv : the preprint server for biology 0 40766499
2025 NVL2-interacting protein CWF19L2 is required for debranching of intron-derived lariat RNAs. Biochemical and biophysical research communications 0 41422678

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