Affinage

KANSL3

KAT8 regulatory NSL complex subunit 3 · UniProt Q9P2N6

Length
904 aa
Mass
96.0 kDa
Annotated
2026-06-10
23 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KANSL3 is a core subunit of the evolutionarily conserved NSL histone acetyltransferase complex that associates with the acetyltransferase MOF and other NSL members to activate transcription genome-wide (PMID:20620954). At target promoters—predominantly TATA-less, housekeeping-gene promoters bound in a sequence-dependent manner—the complex maintains nucleosome-depleted regions and ensures accurate transcription start-site selection by recruiting the NURF chromatin remodeler, and is required for efficient assembly of the RNA Polymerase II pre-initiation complex (TBP, TFIIB) coincident with active chromatin marks including H4K16ac, H3K4me2/3, and H3K9ac (PMID:22723752, PMID:30819819). KANSL3 carries out a moonlighting structural role outside chromatin: during mitosis it relocalizes to the spindle in a RanGTP-dependent manner, where it binds and stabilizes microtubule minus ends to enable spindle assembly and chromosome segregation (PMID:26243146). KANSL3 also partitions to mitochondria, where it is required for MOF binding to mtDNA and the consequent expression of respiratory genes (PMID:27768893). Its abundance and activity are post-translationally controlled: OGT1-mediated O-GlcNAcylation at Thr755 stabilizes KANSL3 and sustains NSL complex integrity and H4K5/K8/K16 acetylation, opposing UBE2S-driven ubiquitin-proteasomal degradation, with OGT1 and UBE2S competing for binding (PMID:28450392, PMID:31881804), while TRAP1 binding restrains KANSL3 acetylation to preserve mitophagy under metabolic stress (PMID:41039555). Through these transcriptional and structural roles, KANSL3 loss in vivo produces tissue-specific pathology—peri-implantation lethality with reduced inner cell mass (PMID:38769918), neurovascular breakdown via LCFA-driven TLR4-NFκB signaling (PMID:32541879), kidney dysfunction through disrupted intraciliary-transport gene programs and microtubule dynamics (PMID:37624894), and liver disease through defective hepatocyte differentiation and lipid metabolism (PMID:41044006).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2010 High

    Established that KANSL3 is a bona fide subunit of the MOF-associated NSL complex and a positive regulator of genome-wide transcription, answering whether KANSL3 functions in chromatin-based gene activation.

    Evidence Biochemical purification, ChIP-Seq, RNAi depletion, and heterologous promoter tethering in Drosophila and mammals

    PMID:20620954

    Open questions at the time
    • Did not define which promoter features dictate NSL targeting
    • Direct enzymatic contribution of KANSL3 to acetylation not isolated from MOF
  2. 2012 High

    Showed the NSL complex acts at the pre-initiation step by promoting RNA Pol II, TBP, and TFIIB recruitment at housekeeping-gene promoters, defining the transcriptional mechanism.

    Evidence ChIP-seq of NSL subunits and Pol II in NSL3-depleted Drosophila cells with RNAi knockdown

    PMID:22723752

    Open questions at the time
    • Mechanism of PIC stabilization not resolved
    • Did not address non-chromatin roles
  3. 2015 High

    Revealed a non-transcriptional structural function: KANSL3 relocalizes to the mitotic spindle and acts as a microtubule minus-end-binding stabilizer essential for chromosome segregation.

    Evidence Live-cell imaging, immunofluorescence, RanGTP-dependent spindle assembly assay, and loss-of-function mitotic readouts

    PMID:26243146

    Open questions at the time
    • Structural basis of minus-end binding not defined
    • Relationship between chromatin and spindle pools unclear
  4. 2016 High

    Demonstrated a mitochondrial pool of KANSL3 required for MOF–mtDNA association and respiratory gene expression, extending NSL function to oxidative phosphorylation.

    Evidence Subcellular fractionation, mtDNA ChIP, and conditional cardiac knockout mouse

    PMID:27768893

    Open questions at the time
    • Direct mtDNA-binding activity of KANSL3 itself not shown
    • How nuclear vs mitochondrial partitioning is controlled is unknown
  5. 2017 High

    Identified OGT1-mediated O-GlcNAcylation as a stabilizing modification of KANSL3 that boosts NSL acetyltransferase output on H4K5/K8/K16.

    Evidence Co-IP, in vitro O-GlcNAc transferase assay, WGA affinity purification, and OGT1 catalytic mutant in cells

    PMID:28450392

    Open questions at the time
    • Modified residue not yet mapped at this stage
    • In vivo physiological trigger of O-GlcNAcylation unknown
  6. 2019 High

    Mapped the stabilizing O-GlcNAc site to Thr755 and showed OGT1 and UBE2S compete to set KANSL3 stability and NSL holoenzyme integrity, defining the degradation control axis.

    Evidence In vitro transferase assay with mass spectrometry, T755A mutagenesis, Co-IP, and ubiquitination assay

    PMID:31881804

    Open questions at the time
    • UBE2S substrate-recognition determinants not defined
    • Upstream signals shifting the OGT1/UBE2S balance unknown
  7. 2019 High

    Defined how NSL achieves nucleosome-free promoters and accurate TSS selection: KANSL3 binds TATA-less promoters sequence-dependently and recruits NURF to maintain nucleosome-depleted regions.

    Evidence ChIP-seq, nucleosome positioning after NSL1 depletion, and biochemical NSL–NURF interaction

    PMID:30819819

    Open questions at the time
    • Sequence motif recognized by KANSL3 not specified
    • Domain mediating NURF contact not mapped
  8. 2019 Medium

    Indicated that mitotic defects after KANSL3-ortholog loss in Drosophila arise largely from transcriptional downregulation of centromere/kinetochore and centriole genes, linking transcriptional and mitotic phenotypes.

    Evidence RNAi depletion of Rcd1, immunofluorescence, GFP localization, and RT-qPCR in S2 cells

    PMID:31527906

    Open questions at the time
    • Single study; transcriptional vs direct spindle contributions not fully separated
    • Centrosome/midbody localization function not mechanistically dissected
  9. 2020 High

    Connected KANSL3-dependent epigenetic regulation to organ physiology by showing neural loss causes LCFA accumulation that drives TLR4-NFκB pericyte activation and neurovascular breakdown.

    Evidence Neural-specific conditional KO mice, metabolomics, TLR4 inhibitor rescue, and pericyte marker immunofluorescence

    PMID:32541879

    Open questions at the time
    • Direct transcriptional targets governing LCFA metabolism not enumerated
    • Cell-autonomous vs paracrine steps only partly separated
  10. 2022 Medium

    Identified YY1 as a key downstream transcriptional target in human cells, with KANSL3-driven clonogenicity rescued by YY1, placing YY1 epistatically below KANSL3.

    Evidence CRISPR/Cas9 KO, ChIP-seq, siRNA, overexpression, and colony formation in 293T/HepG2 cells

    PMID:35409160

    Open questions at the time
    • Single-lab study
    • Generalizability of YY1 axis to other cell types untested
  11. 2022 Medium

    Showed KANSL3 loss promotes mesenchymal/invasive phenotypes, implicating NSL transcriptional regulation in epithelial cell identity.

    Evidence CRISPR/Cas9 KO, Transwell invasion assay, immunostaining, and ChIP-seq

    PMID:35416545

    Open questions at the time
    • Direct vs indirect control of mesenchymal markers unresolved
    • Phosphoinositide-signaling link only correlative
  12. 2023 Medium

    Extended NSL transcriptional function to small-RNA biology, showing KANSL3 promotes transcription of piRNA precursors and restrains transposons in the Drosophila germline.

    Evidence Germline-specific RNAi, small RNA sequencing, and ChIP-seq

    PMID:37399316

    Open questions at the time
    • Single study with effect described alongside other NSL subunits
    • Conservation of piRNA role in mammals untested
  13. 2023 High

    Established the NSL complex as a master regulator of intraciliary-transport genes and microtubule dynamics in both dividing and postmitotic cells, explaining kidney pathology on KANSL3 loss.

    Evidence Kidney-specific conditional KO, single-cell RNA-seq, cilia immunofluorescence, and microtubule dynamics assays

    PMID:37624894

    Open questions at the time
    • Whether ciliary defect is purely transcriptional or also reflects direct microtubule role not fully separated
    • Specific IFT target genes driving phenotype not pinpointed
  14. 2024 Medium

    Defined the earliest developmental requirement, showing Kansl3 is essential at peri-implantation with selective reduction of inner cell mass lineages.

    Evidence Homozygous KO mice, in vitro zona pellucida removal, and lineage-marker immunofluorescence

    PMID:38769918

    Open questions at the time
    • Molecular targets underlying ICM-specific defect not identified
    • Single study
  15. 2025 Medium

    Identified TRAP1 as a direct KANSL3 partner that restrains its acetylation to preserve mitophagy, adding an acetylation-based control layer relevant to metabolic stress.

    Evidence Co-IP, LC-MS/MS, TRAP1 overexpression and KANSL3 knockdown, mKeima mitophagy flux, and TEM

    PMID:41039555

    Open questions at the time
    • Acetyltransferase responsible for KANSL3 acetylation not identified
    • Single-lab study; in vivo relevance untested
  16. 2025 High

    Demonstrated that KANSL3 governs hepatocyte differentiation and lipid/steroid metabolic transcription, with loss causing biliary hyperplasia and fibrosis.

    Evidence Hepatocyte-specific conditional KO, single-cell RNA-seq, organoid differentiation, and histone acetylation analysis

    PMID:41044006

    Open questions at the time
    • Key direct target genes of hepatocyte program not isolated
    • Whether metabolic phenotype is cell-autonomous to hepatocytes not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KANSL3 dynamically partitions among nuclear chromatin, mitotic spindle, and mitochondria, and what governs its tissue-specific target gene selection, remain open.
  • No structural model of KANSL3 domains for DNA, microtubule, and partner binding
  • Mechanism of context-dependent localization switching unknown
  • Sequence determinants of promoter targeting unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0003677 DNA binding 1 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 1 R-HSA-4839726 Chromatin organization 1
Partners
KAT8NURFOGT1TRAP1UBE2S
Complex memberships
NSL (KANSL/MOF) histone acetyltransferase complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 KANSL3 (NSL3) is a subunit of the NSL complex (NSL1, NSL2, NSL3, MCRS2, MBD-R2, WDS) that associates with the histone acetyltransferase MOF in both Drosophila and mammals. Depletion of NSL3 severely affects gene expression genome-wide. Tethering of NSL3 to a heterologous promoter leads to robust transcription activation dependent on NSL1, MCRS2, and MOF levels. NSL complex members bind target promoters independently of MOF, but depletion of MCRS2 affects MOF recruitment. Biochemical purification, ChIP-Seq, RNAi depletion, heterologous promoter tethering assay Molecular cell High 20620954
2012 NSL3 (KANSL3) binds promoters of housekeeping genes in Drosophila and is required for efficient recruitment of RNA Polymerase II to NSL target gene promoters. NSL3 depletion reduces TBP and TFIIB binding at target promoters, indicating the NSL complex is required for optimal pre-initiation complex recruitment. NSL-bound promoters are associated with H4K16ac, H3K4me2, H3K4me3, and H3K9ac histone modifications. ChIP-seq (NSL1, NSL3, MBD-R2, MCRS2), RNA Pol II ChIP-seq in NSL3-depleted cells, RNAi knockdown PLoS genetics High 22723752
2015 During mitosis, KANSL3 relocalizes from chromatin to the mitotic spindle in a RanGTP-dependent manner. KANSL3 is identified as a microtubule minus-end-binding protein that stabilizes microtubule minus ends, and is essential for spindle assembly and chromosome segregation. Live-cell imaging, immunofluorescence localization, RanGTP-dependent spindle assembly assay, loss-of-function with mitotic phenotype readout Nature communications High 26243146
2016 MOF and a subset of NSL complex partners, including KANSL3, reside in mitochondria. MOF binds mtDNA, and this binding is dependent on KANSL3. MOF regulates oxidative phosphorylation by controlling expression of respiratory genes from both nuclear and mtDNA. Subcellular fractionation, immunofluorescence, mtDNA ChIP, conditional knockout mouse model with cardiac phenotype Cell High 27768893
2017 OGT1 physically interacts with NSL3 (KANSL3) and O-GlcNAcylates it, stabilizing NSL3 protein. This stabilization promotes NSL complex histone acetyltransferase activity, leading to increased global acetylation of histone H4 at K5, K8, and K16. Knockdown or overexpression of OGT1 markedly affects these H4 acetylation levels. Co-immunoprecipitation, in vitro O-GlcNAc transferase assay, wheat germ agglutinin affinity purification, OGT1 catalytic mutant (C964A) co-transfection The Journal of biological chemistry High 28450392
2019 O-GlcNAcylation of KANSL3 at Thr755 by OGT1 is required for NSL complex integrity and holoenzyme activity. Mutation T755A promotes ubiquitin-mediated proteasomal degradation of NSL3. UBE2S (ubiquitin-conjugating enzyme E2 S) directly binds NSL3 and accelerates its degradation. OGT1 and UBE2S competitively bind to NSL3, coordinating its stability. In vitro O-GlcNAc transferase assay combined with mass spectrometry, site-directed mutagenesis (T755A), co-immunoprecipitation, ubiquitination assay International journal of molecular sciences High 31881804
2019 In Drosophila S2 cells, depletion of Rcd1 (KANSL3 ortholog) by RNAi leads to defects in chromosome segregation, reduced levels of centromere component Cid/CENP-A and kinetochore component Ndc80, and negatively affects centriole duplication. Rcd1-GFP accumulates at centrosomes and the telophase midbody during mitosis. RT-qPCR showed that transcription of centromere/kinetochore genes (cid, Mis12, Nnf1b) and centriole duplication genes is substantially reduced in Rcd1 RNAi cells, suggesting mitotic phenotypes are primarily due to transcriptional downregulation of these genes. RNAi depletion, immunofluorescence, GFP live-cell localization, RT-qPCR PLoS genetics Medium 31527906
2019 NSL3 (KANSL3) binds to TATA-less promoters in a sequence-dependent manner. The NSL complex interacts with the NURF chromatin remodeling complex and is necessary and sufficient to recruit NURF to target promoters, thereby maintaining nucleosome-depleted regions at transcription start sites and enabling accurate TSS selection. ChIP-seq, NSL1 depletion with nucleosome positioning analysis, biochemical interaction with NURF complex Genes & development High 30819819
2020 Neural-specific depletion of Kansl3 (along with Mof or Kansl2) causes widespread metabolic defects including accumulation of free long-chain fatty acids (LCFAs). LCFAs trigger TLR4-NFκB-dependent pro-inflammatory signaling in neighboring vascular pericytes, leading to pericyte activation and vascular breakdown. This establishes KANSL3 as part of a pathway linking epigenetic regulation to neurovascular homeostasis via metabolic intermediates. Conditional neural-specific knockout in mice, metabolomics, TLR4 inhibitor rescue, immunofluorescence of pericyte markers Nature cell biology High 32541879
2022 NSL3 (KANSL3) knockout in human 293T cells, identified by CRISPR/Cas9 and ChIP-seq, reveals over 100 transcriptional targets including YY1. MOF and NSL3 co-localize with H4K16ac, H3K4me2, and H3K4me3 at the YY1 TSS. NSL3 silencing reduces YY1 expression; NSL3 knockout suppresses CDC6 (a YY1 target) expression. NSL3 regulates clonogenic ability of HepG2 cells, which is rescued by YY1 overexpression, placing YY1 downstream of KANSL3. CRISPR/Cas9 NSL3-KO, ChIP-seq, siRNA knockdown, overexpression, colony formation assay International journal of molecular sciences Medium 35409160
2022 NSL3 (KANSL3) knockout promotes cell invasion in cancer cells and positively correlates with mesenchymal biomarkers (N-cadherin, vimentin, snail). NSL3-KO causes lumen-like cell morphology. ChIP-seq indicates NSL complex may be involved in phosphoinositide-mediated signaling pathways. Unlike MSL1, NSL3 does not bind the E-box-containing Snail promoter. CRISPR/Cas9 KO, Transwell invasion assay, immunostaining, ChIP-seq Cellular and molecular life sciences : CMLS Medium 35416545
2023 Germline-specific knockdown of NSL3 (KANSL3) in Drosophila results in reduced piRNA production from a subset of bidirectional piRNA clusters, with widespread transposon derepression. This establishes a role for the NSL complex in promoting transcription of piRNA precursors from telomeric piRNA clusters. RNAi germline-specific knockdown, small RNA sequencing, ChIP-seq Life science alliance Medium 37399316
2023 Deletion of KANSL3 in postmitotic podocytes leads to catastrophic kidney dysfunction. KANSL3 ablation disrupts microtubule dynamics and podocyte functions in nonciliated cells, while in ciliated fibroblasts it leads to loss of cilia and impaired sonic hedgehog pathway. The NSL complex is a master regulator of intraciliary transport genes in both dividing and nondividing cells. Kidney-specific conditional knockout, single-cell RNA sequencing, cilia immunofluorescence, microtubule dynamics assay Science advances High 37624894
2024 Homozygous knockout of Kansl3 in mice leads to embryonic lethality at peri-implantation stages; embryos fail to hatch from the zona pellucida. Kansl3-null embryos have a significantly reduced inner cell mass (ICM) cell number with normal trophectoderm cell numbers, and both epiblast and primitive endoderm lineages show reduced cell numbers. Conditional/homozygous KO mouse, zona pellucida removal in vitro, immunofluorescence lineage marker analysis Molecular reproduction and development Medium 38769918
2025 TRAP1 (molecular chaperone) directly interacts with KANSL3, as demonstrated by co-immunoprecipitation and LC-MS/MS. Under diabetic/high glucose-palmitate conditions, TRAP1-KANSL3 interaction decreases, and KANSL3 acetylation increases. TRAP1 inhibits KANSL3 acetylation under normal conditions to preserve mitophagy; loss of TRAP1 under diabetic conditions impairs mitophagy and mitochondrial function. Co-immunoprecipitation, LC-MS/MS, lentiviral TRAP1 overexpression and KANSL3 knockdown, mitophagy flux assay (mKeima), transmission electron microscopy Cell communication and signaling : CCS Medium 41039555
2025 Hepatocyte-specific deletion of KANSL3 in mice results in early-onset liver disease marked by biliary hyperplasia and hepatic fibrosis. KANSL3 regulates hepatocyte transcriptional networks for hepatic steroid and lipid metabolism through histone acetylation. Loss of KANSL3 disrupts hepatocyte differentiation in vivo and impairs transcriptional programs for hepatocyte differentiation in ductal and fetal liver organoids. Hepatocyte-specific conditional KO, single-cell RNA sequencing, organoid differentiation assay, histone acetylation analysis Life science alliance High 41044006

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria. Cell 150 27768893
2010 The nonspecific lethal complex is a transcriptional regulator in Drosophila. Molecular cell 121 20620954
2012 The NSL complex regulates housekeeping genes in Drosophila. PLoS genetics 81 22723752
2015 An epigenetic regulator emerges as microtubule minus-end binding and stabilizing factor in mitosis. Nature communications 57 26243146
2020 Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature. Nature cell biology 30 32541879
2017 O-Linked N-acetylglucosamine transferase 1 regulates global histone H4 acetylation via stabilization of the nonspecific lethal protein NSL3. The Journal of biological chemistry 18 28450392
2022 EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities. Cell death & disease 14 35973998
2019 RNAi-mediated depletion of the NSL complex subunits leads to abnormal chromosome segregation and defective centrosome duplication in Drosophila mitosis. PLoS genetics 12 31527906
2019 The NSL complex-mediated nucleosome landscape is required to maintain transcription fidelity and suppression of transcription noise. Genes & development 11 30819819
2022 The Non-Specific Lethal (NSL) Histone Acetyltransferase Complex Transcriptionally Regulates Yin Yang 1-Mediated Cell Proliferation in Human Cells. International journal of molecular sciences 10 35409160
2022 Two distinct males absent on the first (MOF)-containing histone acetyltransferases are involved in the epithelial-mesenchymal transition in different ways in human cells. Cellular and molecular life sciences : CMLS 9 35416545
2021 Generation of locus-specific degradable tag knock-ins in mouse and human cell lines. STAR protocols 9 34151298
2019 O-GlcNAc-Modification of NSL3 at Thr755 Site Maintains the Holoenzyme Activity of MOF/NSL Histone Acetyltransfease Complex. International journal of molecular sciences 9 31881804
2014 Evidence of a MOF histone acetyltransferase-containing NSL complex in C. elegans. Worm 8 26430553
2014 SUMV-1 antagonizes the activity of synthetic multivulva genes in Caenorhabditis elegans. Developmental biology 6 24882710
2023 CRISPR-Cas9 knockout screen identifies novel treatment targets in childhood high-grade glioma. Clinical epigenetics 5 37161535
2023 Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells. Science advances 5 37624894
2022 Exploration of new therapeutic targets for viral hepatic fibrosis, alcoholic hepatic fibrosis, and non-alcoholic hepatic fibrosis. Annals of translational medicine 4 36111046
2025 TRAP1 inhibits KANSL3 acetylation to alleviate mitochondrial dysfunction by promoting mitophagy in cardiomyocytes under diabetic conditions. Cell communication and signaling : CCS 2 41039555
2024 Loss of KANSL3 leads to defective inner cell mass and early embryonic lethality. Molecular reproduction and development 2 38769918
2023 The NSL complex is required for piRNA production from telomeric clusters. Life science alliance 2 37399316
2026 Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and Parkinson's disease. medRxiv : the preprint server for health sciences 0 41867223
2025 KANSL3 directs transcriptional programs essential for hepatic metabolism and differentiation. Life science alliance 0 41044006

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