Affinage

FTSJ3

pre-rRNA 2'-O-ribose RNA methyltransferase FTSJ3 · UniProt Q8IY81

Length
847 aa
Mass
96.6 kDa
Annotated
2026-06-09
19 papers in source corpus 10 papers cited in narrative 10 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

FTSJ3 is a nucleolar RNA 2'-O-methyltransferase that functions both in ribosome biogenesis and as a sequence-targeted RNA modifier across viral, telomeric, and messenger RNA substrates (PMID:22195017, PMID:30626973, PMID:42236690). In its canonical role, FTSJ3 associates with the ribosome biogenesis factor NIP7, localizes to the nucleolus, and is required for pre-rRNA processing at sites A0, 1, and 2 in the pathway producing 18S rRNA, placing it in 40S ribosomal subunit biogenesis; its C-terminal Spb1_C domain mediates incorporation into preribosomal complexes containing both small- and large-subunit ribosomal proteins and synthesis factors (PMID:22195017, PMID:22540864). FTSJ3 is also recruited in a DICER-independent complex with TRBP to HIV-1 genomic RNA, where it installs 2'-O-methylations that shield the viral genome from MDA5-mediated type I interferon sensing and from ISG20 exonuclease degradation—ISG20 stalling sterically at the 2'-O-methyl group—while paradoxically impeding reverse transcriptase translocation, and FTSJ3 thereby also promotes HIV-1 latency by restraining Pol II-mediated viral transcription (PMID:30626973, PMID:36354007, PMID:38015463, PMID:33270809). The same 2'-O-methyltransferase activity suppresses dsRNA-triggered type I IFN signaling to enable hepatocellular carcinoma immune evasion (PMID:37963197). Beyond viral RNA, FTSJ3 methylates telomeric TERRA RNA to stabilize it and drive a SUV39H1/H3K9me3/HP1α heterochromatin cascade at telomeres in hTERT-positive cancer cells, and it regulates R-loop homeostasis to protect genomic integrity (PMID:42236690, PMID:40517939). Guided by the snoRNA SNORD46, FTSJ3 methylates FOXO4 mRNA to downregulate it and de-repress lipogenic genes in glioma (PMID:40681010).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2011 High

    Established FTSJ3's first cellular function by linking it physically and functionally to ribosome biogenesis, answering where this putative methyltransferase acts.

    Evidence Yeast two-hybrid, reciprocal Co-IP and colocalization with NIP7, plus conditional knockdown with Northern analysis of pre-rRNA intermediates

    PMID:22195017

    Open questions at the time
    • Did not demonstrate direct 2'-O-methylation of rRNA by FTSJ3
    • Catalytic requirement for the processing phenotype not tested
  2. 2012 Medium

    Mapped the structural determinant of FTSJ3's ribosomal engagement, showing the C-terminal Spb1_C domain mediates preribosomal complex assembly.

    Evidence FLAG Co-IP/mass spectrometry interactome with domain-deletion mapping of the Spb1_C domain

    PMID:22540864

    Open questions at the time
    • Interactome from a single lab without orthogonal validation
    • Functional consequence of Spb1_C-mediated binding not assayed
  3. 2019 High

    Revealed an unexpected antiviral-evasion role: FTSJ3 in a TRBP complex methylates HIV-1 RNA to hide it from innate immune sensing, expanding its substrate range beyond rRNA.

    Evidence TRBP complex purification with MS, in vitro/ex vivo 2'O-MTase assays, RiboMethSeq site mapping, knockdown with IFN induction readout in dendritic cells

    PMID:30626973

    Open questions at the time
    • Precise recognition determinants of viral target sites unresolved
    • Whether host mRNAs are similarly methylated not addressed here
  4. 2020 Medium

    Connected FTSJ3 to control of viral gene expression by identifying it as a host factor promoting HIV-1 latency through restraint of Pol II transcription.

    Evidence Genome-wide CRISPRi screen and shRNA validation in primary CD4+ T cells with HIV expression and Pol II transcription analysis

    PMID:33270809

    Open questions at the time
    • Mechanistic link between methyltransferase activity and transcriptional repression unclear
    • Direct chromatin or RNA substrate at the latent provirus not defined
  5. 2023 High

    Defined a biochemical basis for viral RNA protection, showing FTSJ3-installed 2'-O-methyl groups block the antiviral exonuclease ISG20 by steric clash.

    Evidence In vitro RNA degradation assays, ISG20 R53/D90 mutagenesis, and FTSJ3-KO cells with T-cell reverse transcription assays

    PMID:36354007

    Open questions at the time
    • In vivo contribution to viral fitness versus latency not quantified
  6. 2024 High

    Uncovered a paradoxical cost of methylation, demonstrating FTSJ3 marks impede HIV-1 reverse transcriptase, with K70 enabling bypass.

    Evidence Endogenous and biochemical RT assays on methylated vs hypomethylated particles with RT K70 mutagenesis

    PMID:38015463

    Open questions at the time
    • How the virus balances immune shielding against impaired RT in vivo not resolved
  7. 2024 High

    Generalized the immune-evasion role to cancer, showing FTSJ3 methyltransferase activity suppresses RNA-sensor-driven type I IFN to promote tumor growth.

    Evidence FTSJ3 CRISPR KO in HCC cells, RNA sensor double KO, IFNAR systemic KO mice, and in vivo tumor assays

    PMID:37963197

    Open questions at the time
    • Specific endogenous RNA substrates whose methylation prevents sensing not identified
  8. 2025 High

    Established a chromatin-level function: FTSJ3 methylates TERRA to nucleate a SUV39H1/H3K9me3/HP1α heterochromatin cascade and maintain telomere stability selectively in hTERT-positive cells.

    Evidence Genome-wide CRISPR/shRNA screens, in vivo screens, depletion in isogenic hTERT+/- lines and organoids, TERRA stability assays, and ChIP for SUV39H1/H3K9me3/HP1α

    PMID:42236690

    Open questions at the time
    • Direct enzymatic methylation of TERRA in vitro and the exact methylated residues not shown
    • How TERRA methylation mechanistically recruits SUV39H1 unresolved
  9. 2025 Medium

    Linked FTSJ3 to genome protection through R-loop homeostasis, showing its loss drives R-loop-dependent DNA damage and chemosensitivity.

    Evidence Knockdown in lung cancer lines with R-loop detection, DNA damage markers, and in vitro/xenograft cisplatin sensitivity

    PMID:40517939

    Open questions at the time
    • Whether R-loop control requires methyltransferase activity not established
    • Direct recruitment mechanism to R-loops undefined
  10. 2025 Medium

    Demonstrated snoRNA-guided mRNA targeting, with SNORD46 directing FTSJ3 to methylate FOXO4 mRNA and reprogram lipid metabolism in glioma.

    Evidence SRSF10/SNORD46/FTSJ3 knockdown in glioma cells with FOXO4 methylation detection, proliferation/lipid assays, and FOXO4 promoter-binding on ACLY/FASN

    PMID:40681010

    Open questions at the time
    • Mechanism inferred from knockdown cascade without in vitro reconstitution of guided methylation
    • Direct FTSJ3-SNORD46 binding not biochemically demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single nucleolar 2'-O-methyltransferase is targeted to such diverse substrates (rRNA, viral RNA, TERRA, specific mRNAs) and what governs guide/cofactor selection across these contexts remains unresolved.
  • No unifying model for substrate selection across TRBP, snoRNA, and telomere contexts
  • Structural basis of FTSJ3 catalysis on non-rRNA substrates not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0003723 RNA binding 3 GO:0016740 transferase activity 2
Localization
GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-8953854 Metabolism of RNA 2
Partners
NIP7SNORD46TRBP
Complex memberships
TRBP-FTSJ3 complexpreribosomal complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 FTSJ3 is a 2'-O-methyltransferase (2'O-MTase) that forms a DICER-independent complex with TRBP (TAR RNA-binding protein). This complex is recruited to HIV-1 RNA via TRBP, where FTSJ3 installs 2'-O-methylations at specific residues on the viral genome. Hypomethylated HIV-1 produced in FTSJ3 knockdown cells triggers MDA5-mediated type I interferon (IFN-α and IFN-β) responses in human dendritic cells, demonstrating that FTSJ3-mediated 2'-O-methylation shields HIV-1 RNA from innate immune sensing. TRBP complex purification and mass spectrometry; in vitro and ex vivo 2'O-MTase activity assays; RiboMethSeq mapping of methylation sites; shRNA knockdown; IFN induction assays in human dendritic cells Nature High 30626973
2011 FTSJ3 physically associates with human NIP7 (a ribosome biogenesis factor) and localizes to the nucleolus. Conditional knockdown of FTSJ3 causes accumulation of the 34S pre-rRNA (spanning site A' to site 2b), indicating that FTSJ3 is required for efficient processing at sites A0, 1, and 2 in the pathway leading to 18S rRNA maturation, implicating FTSJ3 in 40S ribosomal subunit biogenesis. Yeast two-hybrid; coimmunoprecipitation; colocalization (immunofluorescence); conditional shRNA knockdown; Northern blot analysis of pre-rRNA processing intermediates PloS one High 22195017
2012 FLAG-tagged FTSJ3 coimmunoprecipitates both small (RPS) and large (RPL) ribosomal proteins as well as ribosome synthesis factors in preribosomal complexes. The C-terminal Spb1_C domain of FTSJ3 mediates its interaction with preribosomal complexes, as a similar set of co-purifying proteins is recovered with the Spb1_C domain alone. FTSJ3 complexes share ~50% of components with complexes described for RPS19, Par14, nucleolin, and NOP56. FLAG-tag coimmunoprecipitation followed by mass spectrometry (proteomics); domain-deletion co-IP with Spb1_C domain Journal of proteome research Medium 22540864
2023 FTSJ3-mediated 2'-O-methylation of HIV-1 genomic RNA protects the virus from degradation by the antiviral exonuclease ISG20. Biochemical experiments showed that ISG20-mediated RNA degradation pauses two nucleotides upstream of and at 2'-O-methylated residues; structure-function analysis identified a steric clash between ISG20 residues R53 and D90 and the 2'-O-methyl group. HIV-1 produced in FTSJ3-KO cells (hypomethylated) is more susceptible to ISG20-mediated degradation in vitro and shows impaired reverse transcription in T cells in the presence of IFN-induced ISG20. In vitro RNA degradation assays; structure-function mutagenesis of ISG20 (R53, D90); FTSJ3-KO cell line; reverse transcription assays in primary T cells Nucleic acids research High 36354007
2024 2'-O-methylation installed by FTSJ3 on the HIV-1 genome negatively affects HIV-1 reverse transcriptase (RT) activity. Endogenous reverse transcription assays on methylated vs. hypomethylated HIV-1 particles show that methylation impedes RT, especially at low dNTP concentrations (mimicking quiescent cells), by reducing nucleotide incorporation efficiency and impairing translocation. Mutagenesis identified K70 of reverse transcriptase as a critical residue for RT to bypass 2'-O-methylated sites. Endogenous reverse transcription assays on FTSJ3-methylated vs. FTSJ3-KO hypomethylated particles; biochemical RT assays; site-directed mutagenesis of RT (K70) Nucleic acids research High 38015463
2024 FTSJ3 suppresses double-stranded RNA (dsRNA)-induced IFNβ signaling in hepatocellular carcinoma (HCC) cells in a 2'-O-methyltransferase-dependent manner. Deletion of RNA sensors in HCC cells or systemic knockout of type I IFN receptor IFNAR in mice rescued tumor growth defects caused by FTSJ3 deficiency, establishing that FTSJ3 promotes HCC immune evasion by suppressing the RNA sensor-mediated type I IFN pathway. FTSJ3 CRISPR knockout in HCC cells; RNA sensor double knockout; IFNAR systemic knockout mouse model; IFNβ signaling assays; in vivo tumor growth assays Cancer research High 37963197
2020 CRISPRi screening identified FTSJ3 as a host factor that promotes HIV-1 latency. shRNA knockdown of FTSJ3 in primary CD4+ T cells significantly enhances HIV expression. Mechanistically, downregulation of FTSJ3 stimulates RNA Polymerase II-mediated transcription of HIV-1. Genome-wide CRISPRi screen (REACT strategy); shRNA knockdown in primary CD4+ T cells; HIV expression assays; Pol II transcription analysis PLoS pathogens Medium 33270809
2025 FTSJ3 is recruited to R-loop structures and prevents excessive R-loop formation. Depletion of FTSJ3 in lung cancer cells increases R-loop-dependent DNA damage and sensitizes cells to cisplatin both in vitro and in vivo, identifying FTSJ3 as a regulator of R-loop homeostasis and genomic stability. FTSJ3 knockdown/depletion in lung cancer cell lines; R-loop detection assays; DNA damage markers; in vitro and in vivo (xenograft) cisplatin sensitivity assays Cancer letters Medium 40517939
2025 FTSJ3 installs 2'-O-methylation on telomeric repeat-containing RNA (TERRA). This modification is required for recruitment of the histone methyltransferase SUV39H1 to telomeric ends, leading to H3K9 trimethylation and HP1α assembly at sub-telomeric regions. Loss of FTSJ3 destabilizes TERRA, disrupts the SUV39H1/H3K9me3/HP1 cascade, impairs heterochromatin maintenance, and causes genome instability and apoptosis selectively in hTERT-positive cancer cells. Genome-wide CRISPR/Cas9 and shRNA screens; arrayed in vitro CRISPR screen; pooled in vivo CRISPR screen; FTSJ3 depletion in isogenic hTERT+/− cell lines and patient-derived organoids; TERRA stability assays; ChIP for SUV39H1, H3K9me3, HP1α Signal transduction and targeted therapy High 42236690
2025 SNORD46 guides FTSJ3 to install 2'-O-methylation on FOXO4 mRNA in glioma cells, leading to downregulation of FOXO4 expression. Loss of FOXO4 de-represses the lipogenic genes ACLY and FASN, promoting lipid metabolism and cell proliferation in glioma. The upstream regulator SRSF10 stabilizes SNORD46 by direct binding. SRSF10/SNORD46/FTSJ3 knockdown in glioma cell lines; 2'-O-methylation detection on FOXO4 mRNA; proliferation and lipid metabolism assays; promoter-binding assay for FOXO4 on ACLY/FASN Cellular signalling Medium 40681010

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 FTSJ3 is an RNA 2'-O-methyltransferase recruited by HIV to avoid innate immune sensing. Nature 173 30626973
2011 The human nucleolar protein FTSJ3 associates with NIP7 and functions in pre-rRNA processing. PloS one 32 22195017
2020 Pan-cancer analysis of RNA methyltransferases identifies FTSJ3 as a potential regulator of breast cancer progression. RNA biology 31 31957540
2020 Identification of unrecognized host factors promoting HIV-1 latency. PLoS pathogens 29 33270809
2023 Internal RNA 2'O-methylation in the HIV-1 genome counteracts ISG20 nuclease-mediated antiviral effect. Nucleic acids research 24 36354007
2024 RNA Methyltransferase FTSJ3 Regulates the Type I Interferon Pathway to Promote Hepatocellular Carcinoma Immune Evasion. Cancer research 17 37963197
2012 Proteomic characterization of the human FTSJ3 preribosomal complexes. Journal of proteome research 17 22540864
2014 FTSJ2, a heat shock-inducible mitochondrial protein, suppresses cell invasion and migration. PloS one 14 24595062
2024 Unravelling novel and pleiotropic genes for cannon bone circumference and bone mineral density in Yorkshire pigs. Journal of animal science 9 38330300
2021 A host-based whole genome sequencing study reveals novel risk loci associated with severity of influenza A(H1N1)pdm09 infection. Emerging microbes & infections 8 33393450
2024 Internal RNA 2'-O-methylation on the HIV-1 genome impairs reverse transcription. Nucleic acids research 7 38015463
2020 Variants in FtsJ RNA 2'-O-Methyltransferase 3 and Growth Hormone 1 are associated with small body size and a dental anomaly in dogs. Proceedings of the National Academy of Sciences of the United States of America 5 32958658
2021 Establishment of a typing model for diffuse large B-cell lymphoma based on B-cell receptor repertoire sequencing. BMC cancer 4 33752626
2025 HIV-1 latency: From acquaintance to confidant. Journal of virus eradication 2 40497153
2025 Loss of FTSJ3 promotes R-loop-associated DNA damage and facilitates chemosensitivity in lung cancer cells. Cancer letters 1 40517939
2024 [How do 2'-O-methylations within Human Immunodeficiency Virus type 1 (HIV-1) genome regulate its replication?]. Medecine sciences : M/S 1 38819277
2026 FTSJ1-mediated IL1RN mRNA instability promotes inflammation-driven hepatocellular carcinoma. Journal of gastrointestinal oncology 0 41816574
2026 Epigenetic control of telomeric RNA maintains heterochromatin in telomerase-driven cancers. Signal transduction and targeted therapy 0 42236690
2025 SNORD46 stabilized by SRSF10 regulating lipid metabolism and cell proliferation of glioma cells via mediating FOXO4 2'-O-methylation. Cellular signalling 0 40681010

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