Affinage

NAP1L4

Nucleosome assembly protein 1-like 4 · UniProt Q99733

Length
375 aa
Mass
42.8 kDa
Annotated
2026-06-10
10 papers in source corpus 5 papers cited in narrative 6 extracted findings
Cross-family judge faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NAP1L4 is a histone chaperone that binds both core and linker histones and transfers them onto naked DNA, an activity requiring both its N- and C-terminal domains (PMID:9325046), and it shuttles between cytoplasm and nucleus consistent with delivering histones into the nucleus (PMID:9325046). Beyond chromatin assembly, NAP1L4 regulates cell fate by controlling site-specific p53 acetylation: its loss raises Lys320 acetylation and the pro-arrest target p21 under normal conditions while lowering Lys382 acetylation and the proapoptotic factor Bax under genotoxic stress (PMID:31634504). NAP1L4 is also exploited or countered by viruses — it binds the phosphorylated hypervariable domain of Chikungunya virus nsP3 (a CK2-dependent interaction) to stimulate viral replication (PMID:34076483), and it directly binds the porcine circovirus 2 capsid protein through residues 124–279, restricting replication by suppressing a CCP5/CCP6–cGAS–IFN-β axis (PMID:32605741).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1997 High

    Established NAP1L4 as a bona fide histone chaperone by showing it both binds histones and deposits them onto DNA, and mapped this activity to two terminal domains.

    Evidence In vitro histone binding and transfer assays with recombinant protein plus deletion mutagenesis

    PMID:9325046

    Open questions at the time
    • No structural model of the histone-binding interface
    • In vitro deposition does not establish which histones are physiological substrates in cells
    • No identification of partner assembly factors in vivo
  2. 1997 Medium

    Addressed where NAP1L4 acts by showing it shuttles between cytoplasm and nucleus, supporting a histone-delivery role.

    Evidence Subcellular fractionation/imaging of recombinant protein

    PMID:9325046

    Open questions at the time
    • Shuttling signals/receptors not identified
    • Functional coupling of shuttling to histone delivery inferred, not demonstrated
    • No regulation of localization characterized
  3. 2019 Medium

    Linked NAP1L4 to cell fate control by showing it modulates p53 acetylation in a residue-specific manner, biasing cells toward arrest versus apoptosis.

    Evidence siRNA knockdown with western blots for K320/K382 acetylation and p21/Bax readouts in mammalian cells

    PMID:31634504

    Open questions at the time
    • Mechanism of how a histone chaperone alters site-specific p53 acetylation unknown
    • Direct interaction with p53 or acetyltransferases/deacetylases not shown
    • Single knockdown method without rescue
  4. 2020 Medium

    Identified NAP1L4 as a restriction factor against PCV2, binding capsid protein and dampening a cGAS-driven IFN-β response that the virus exploits.

    Evidence Co-IP domain mapping, CRISPR/Cas9 knockout and overexpression in PK15 cells, viral titer and IFN-β readouts

    PMID:32605741

    Open questions at the time
    • Mechanistic link from NAP1L4 to CCP5/CCP6 expression unresolved
    • Whether capsid binding or chaperone activity drives restriction unclear
    • Single lab/system
  5. 2021 Medium

    Showed NAP1L4 is a proviral host factor for CHIKV, binding the phospho-nsP3 hypervariable domain in a CK2-dependent manner to stimulate replication.

    Evidence Co-IP and binding assays with CK2 inhibition/mutation and viral replication assays

    PMID:34076483

    Open questions at the time
    • Functional role of the bound NAP1L4 in the replication complex undefined
    • Whether chaperone activity is required for the proviral effect unknown
    • No structural detail of the HVD-binding motifs
  6. 2024 Low

    Reported NAP1L4 as a prenylated protein whose lipidation governs cardiomyocyte mitosis and centrosome homeostasis, implying a non-chromatin role in cell division.

    Evidence Prenyl probe labeling/MS and chemical/genetic prenylation perturbation in hPSC-derived cardiomyocytes (preprint)

    PMID:bio_10.1101_2024.07.01.601625

    Open questions at the time
    • Preprint, not peer reviewed; prenylation site not defined
    • Mechanistic connection between prenylation and centrosome/mitosis control unknown
    • Relationship to histone chaperone function unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NAP1L4's chromatin chaperone activity mechanistically intersects with its p53 regulation, viral interactions, and prenylation-dependent mitotic roles remains unresolved.
  • No unifying mechanism connecting histone chaperone activity to p53 and centrosome functions
  • No structural data on any complex
  • Physiological substrate and partner landscape in cells unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 1
Partners
CAPNAP1L1NSP3TP53

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Recombinant NAP1L4 (NAP-2) protein interacts with both core and linker histones and can transfer histones onto naked DNA templates in vitro, demonstrating histone chaperone activity. Deletion mutagenesis showed that both NH2- and COOH-terminal domains are required for this histone transfer activity. In vitro histone binding and transfer assays with recombinant protein purified from E. coli; deletion mutagenesis Genomics High 9325046
1997 NAP1L4 (NAP-2) shuttles between the cytoplasm and the nucleus, consistent with a role as a histone chaperone delivering histones to the nucleus. Subcellular localization studies (fractionation/imaging of recombinant NAP-2) Genomics Medium 9325046
2019 NAP1L4 knockdown increases Lys320 acetylation of p53 and enhances expression of the pro-arrest gene p21, thereby suppressing cell growth under normal conditions. Under genotoxic stress, NAP1L4 knockdown decreases Lys382 acetylation of p53 and attenuates proapoptotic Bax levels, suppressing apoptosis. These results indicate NAP1L4 modulates cell fate by controlling site-specific p53 acetylation. siRNA knockdown of NAP1L4 in mammalian cells, western blot for p53 acetylation at specific lysines (K320, K382), and measurement of p21 and Bax expression levels Biochimica et biophysica acta. Molecular cell research Medium 31634504
2021 NAP1L4 (and NAP1L1) binds to the hypervariable domain (HVD) of Chikungunya virus nsP3 at two motifs located upstream and downstream of the G3BP-binding motifs. This interaction requires CK2 kinase-mediated phosphorylation of the HVD and has a strong stimulatory effect on CHIKV replication in vertebrate cells. Co-immunoprecipitation, binding assays, phosphorylation-dependency experiments with CK2 kinase inhibition/mutation, viral replication assays Journal of virology Medium 34076483
2020 NAP1L4 directly interacts with porcine circovirus type 2 (PCV2) capsid protein (Cap) via NAP1L4 residues 124–279. Overexpression of NAP1L4 inhibits PCV2 Cap and Rep expression and reduces viral DNA copies and titers, while CRISPR/Cas9 knockout of NAP1L4 increases viral replication. Mechanistically, NAP1L4 depletion facilitates CCP5 and CCP6 expression, which activates cGAS to promote IFN-β production, and IFN-β stimulation promotes PCV2 replication. Co-IP to map interaction domain; NAP1L4 overexpression and CRISPR/Cas9 knockout in PK15 cells; qRT-PCR and western blot for viral and IFN-β markers; viral titer measurement Veterinary microbiology Medium 32605741
2024 NAP1L4 is a prenylated protein in human cardiac cells. Prenylation of NAP1L4 regulates cardiomyocyte mitosis and centrosome homeostasis, as shown by chemical and genetic perturbation of the mevalonate/prenylation pathway in human pluripotent stem cell-derived cardiomyocytes. Prenyl probe labeling and mass spectrometry identification; chemical inhibition and genetic perturbation of prenylation; cardiomyocyte proliferation and centrosome assays bioRxivpreprint Low bio_10.1101_2024.07.01.601625

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Functional characterization of human nucleosome assembly protein-2 (NAP1L4) suggests a role as a histone chaperone. Genomics 93 9325046
2020 A novel NAP1L4/NUTM1 fusion arising from translocation t(11;15)(p15;q12) in a myeloid neoplasm with eosinophilia and rearrangement of PDGFRA highlights an unusual clinical feature and therapeutic reaction. Annals of hematology 22 32451710
2021 NAP1L1 and NAP1L4 Binding to Hypervariable Domain of Chikungunya Virus nsP3 Protein Is Bivalent and Requires Phosphorylation. Journal of virology 19 34076483
2019 Nucleosome assembly proteins NAP1L1 and NAP1L4 modulate p53 acetylation to regulate cell fate. Biochimica et biophysica acta. Molecular cell research 17 31634504
2010 Telomeric NAP1L4 and OSBPL5 of the KCNQ1 cluster, and the DECORIN gene are not imprinted in human trophoblast stem cells. PloS one 11 20644730
2024 CircNAP1L4 regulates pulmonary artery smooth muscle cell proliferation via the NAP1L4-mediated super-enhancer-driven glycolysis gene hexokinase II (HK II) in pulmonary hypertension. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 39102213
2016 Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent. Molecular vision 9 27440996
2012 Characterization, tissue expression, and imprinting analysis of the porcine CDKN1C and NAP1L4 genes. Journal of biomedicine & biotechnology 8 22500112
2020 NAP1L4 inhibits porcine circovirus type 2 replication via IFN-β signaling pathway. Veterinary microbiology 7 32605741
2015 Biallelic expression of Tssc4, Nap1l4, Phlda2 and Osbpl5 in adult cattle. Journal of genetics 6 26440077

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