Affinage

FTSJ3

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

Round 2 corrected
Length
847 aa
Mass
96.6 kDa
Annotated
2026-04-28
44 papers in source corpus 7 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FTSJ3 is a 2'-O-ribose RNA methyltransferase that functions in ribosome biogenesis and innate immune evasion by modifying diverse RNA substrates. In ribosome assembly, FTSJ3 interacts with NIP7 and preribosomal complexes via its Spb1_C domain, and its yeast ortholog Spb1 methylates 25S rRNA G2922 to establish a GTPase checkpoint controlling 60S subunit maturation (PMID:22195017, PMID:22540864, PMID:36864048). FTSJ3 also 2'-O-methylates HIV-1 genomic RNA (recruited via TRBP) and cellular double-stranded RNA species, and loss of this modification triggers MDA5-dependent type I interferon responses; accordingly, FTSJ3 deletion activates innate immune signaling and suppresses tumor growth in an IFNAR-dependent manner (PMID:30626973, PMID:37963197). FTSJ3 is additionally recruited to R-loop structures, where it prevents R-loop-dependent DNA damage (PMID:40517939).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2011 High

    Establishing FTSJ3 as a ribosome biogenesis factor: its interaction with NIP7 and requirement for pre-rRNA processing at sites A0/1/2 placed human FTSJ3 in the 18S rRNA maturation pathway, analogous to yeast Spb1.

    Evidence Yeast two-hybrid, reciprocal Co-IP, conditional siRNA knockdown with Northern blot analysis of pre-rRNA intermediates in human cells

    PMID:22195017

    Open questions at the time
    • Direct enzymatic activity of human FTSJ3 on rRNA was not demonstrated
    • Target nucleotide(s) on human pre-rRNA not identified
    • Whether processing defects are a direct consequence of lost methylation was unknown
  2. 2012 Medium

    Proteomic dissection of FTSJ3 complexes revealed association with both small and large ribosomal subunit proteins and biogenesis factors, and mapped the preribosome-binding interface to the Spb1_C domain.

    Evidence FLAG-affinity purification coupled to mass spectrometry with domain-specific Co-IP

    PMID:22540864

    Open questions at the time
    • Single AP-MS study; stoichiometry and stability of these interactions not determined
    • Whether Spb1_C domain is sufficient for nucleolar localization was not tested
  3. 2019 High

    Demonstration that FTSJ3 is an active 2'-O-methyltransferase that modifies HIV-1 RNA — recruited via TRBP in a DICER-independent complex — revealed a non-ribosomal substrate and established that FTSJ3-mediated methylation shields viral RNA from MDA5-dependent innate immune sensing.

    Evidence In vitro and ex vivo 2'-O-MTase assays, RiboMethSeq site mapping, FTSJ3 knockdown with IFN-α/β induction in primary dendritic cells

    PMID:30626973

    Open questions at the time
    • Whether FTSJ3 methylates endogenous cellular mRNAs or other non-coding RNAs beyond rRNA and viral RNA was unknown
    • Structural basis for TRBP-mediated recruitment not resolved
  4. 2023 High

    Structural and genetic analysis in yeast showed that Spb1-catalyzed 2'-O-methylation of G2922 in the A-loop acts as a kinetic checkpoint: unmethylated G2922 prematurely activates the GTPase Nog2, disrupting 60S subunit assembly.

    Evidence Cryo-EM of 60S intermediates with catalytically dead spb1-D52A, genetic suppressor screen, in vivo fluorescence imaging in yeast

    PMID:36864048

    Open questions at the time
    • Whether human FTSJ3 methylates the equivalent position in 28S rRNA has not been directly shown
    • Whether the Nog2 checkpoint mechanism is conserved in human ribosome biogenesis is inferred but not demonstrated
  5. 2024 High

    Genetic epistasis experiments established that FTSJ3's tumor-promoting role depends on suppressing dsRNA-triggered type I IFN signaling: FTSJ3 deletion activated MDA5/RIG-I pathways and suppressed HCC growth in an IFNAR-dependent manner in vivo.

    Evidence CRISPR knockout of FTSJ3 and RNA sensors in HCC cells, IFNAR-KO mouse model, anti-PD-1 combination therapy

    PMID:37963197

    Open questions at the time
    • Identity of endogenous dsRNA substrates methylated by FTSJ3 that trigger innate immunity upon loss was not defined
    • Whether the immune-evasion function is independent of the ribosome biogenesis role was not formally separated
  6. 2025 Medium

    FTSJ3 was found to localize to R-loop structures and suppress R-loop-dependent DNA damage, providing a mechanistic basis for its role in genome integrity and cisplatin sensitivity in lung cancer.

    Evidence FTSJ3 depletion, S9.6-based R-loop detection, γH2AX DNA damage assays, cisplatin sensitivity in vitro and in xenograft models

    PMID:40517939

    Open questions at the time
    • Whether R-loop suppression requires FTSJ3 catalytic activity or a non-enzymatic function was not resolved
    • Direct substrates at R-loops (RNA or RNA:DNA hybrid methylation) were not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full repertoire of endogenous RNA substrates methylated by FTSJ3, the structural basis for substrate recognition by the human enzyme, and whether its ribosome biogenesis and innate immune suppression functions are mechanistically coupled or independent remain unresolved.
  • No structure of human FTSJ3 or its catalytic domain bound to substrate RNA
  • Endogenous cellular RNA targets beyond rRNA and TERRA not mapped by site-resolution approaches
  • Functional separation of ribosome biogenesis versus innate immune roles has not been achieved with separation-of-function mutants

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 6 GO:0003723 RNA binding 3 GO:0016740 transferase activity 3
Localization
GO:0005634 nucleus 3 GO:0005730 nucleolus 2
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
NIP7SUV39H1TRBP

Evidence

Reading pass · 8 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 is recruited to HIV-1 RNA through its interaction with TRBP (TAR RNA-binding protein) in a DICER-independent complex. In vitro and ex vivo experiments demonstrated FTSJ3 enzymatic activity, and RiboMethSeq analysis identified predominantly FTSJ3-dependent 2'-O-methylations at specific residues on the HIV-1 viral genome. HIV-1 produced in FTSJ3 knockdown cells showed reduced 2'-O-methylation and triggered type I interferon responses (IFN-α and IFN-β) in human dendritic cells via the RNA sensor MDA5, leading to reduced HIV expression. TRBP pulldown/purification, in vitro and ex vivo 2'O-MTase assays, RiboMethSeq, FTSJ3 knockdown, type I IFN induction assay in dendritic cells Nature High 30626973
2011 Human FTSJ3, a putative ortholog of yeast Spb1p, interacts with NIP7 and functions in pre-rRNA processing and ribosome biogenesis. Colocalization and co-immunoprecipitation confirmed the NIP7–FTSJ3 association. Conditional knockdown of FTSJ3 impaired cell proliferation and caused accumulation of the 34S pre-rRNA (spanning site A' to site 2b), indicating that processing at sites A0, 1, and 2 is slowed, implicating FTSJ3 in the pathway leading to 18S rRNA maturation. Yeast two-hybrid, co-immunoprecipitation, colocalization, conditional siRNA knockdown, pre-rRNA processing analysis (Northern blot) PloS one High 22195017
2012 Proteomic characterization of FLAG-tagged FTSJ3 complexes revealed that FTSJ3 co-immunoprecipitates both small (RPS) and large (RPL) ribosomal proteins, as well as ribosome synthesis factors. The Spb1_C (C-terminal) domain of FTSJ3 co-immunoprecipitates a similar set of proteins, indicating that interaction with preribosome complexes is mediated through the Spb1_C domain. FTSJ3 complexes overlap significantly with those of RPS19, Par14, nucleolin, NOP56, NIP7, and other ribosome biogenesis factors. FLAG-affinity purification, mass spectrometry, domain-specific co-immunoprecipitation Journal of proteome research Medium 22540864
2023 The yeast ortholog of FTSJ3, Spb1, methylates the A-loop nucleotide G2922 of 25S rRNA. Cryo-EM structures revealed that unmethylated G2922 leads to premature activation of the GTPase Nog2, capturing a Nog2-GDP-AlF4- transition state that implicates unmodified G2922 directly in Nog2 GTPase activation. Genetic suppressors and in vivo imaging showed that premature GTP hydrolysis prevents efficient binding of Nog2 to early nucleoplasmic 60S intermediates, establishing G2922 methylation by Spb1 as a kinetic checkpoint regulating 60S subunit production. Cryo-EM structure determination, catalytically deficient mutant (spb1D52A), genetic suppressor analysis, in vivo fluorescence imaging Nature communications High 36864048
2024 FTSJ3 suppresses double-stranded RNA (dsRNA)-induced IFNβ signaling in a 2'-O-methyltransferase-dependent manner in hepatocellular carcinoma (HCC) cells. Deletion of RNA sensors in HCC cells or systemic knockout of type I IFN receptor IFNAR in mice rescued the in vivo tumor growth defect caused by FTSJ3 deficiency, demonstrating that FTSJ3 deletion suppresses tumor growth by activating the RNA sensor-mediated type I IFN pathway. FTSJ3 deletion also enhanced the efficacy of anti-PD-1 immune checkpoint blockade. FTSJ3 deletion (CRISPR), RNA sensor knockout, IFNAR knockout mouse model, dsRNA-induced IFNβ reporter assay, in vivo tumor growth assay, anti-PD-1 combination treatment Cancer research High 37963197
2020 Loss-of-function analysis identified FTSJ3 as a candidate RNA methyltransferase with functional roles in promoting breast cancer cell growth and survival, consistent with its activity as a 2'-O-Me methyltransferase. Loss-of-function (knockdown/knockout) in breast cancer cell lines, cell viability and growth assays RNA biology Medium 31957540
2025 FTSJ3 methylates telomeric repeat-containing RNA (TERRA) via its 2'-O-methyltransferase activity, and this modification is essential for recruiting SUV39H1 to telomeric ends to mediate H3K9 trimethylation and establish stable heterochromatin. Loss of FTSJ3 disrupts H3K9me3, HP1-alpha recruitment, and telomeric heterochromatin maintenance specifically in hTERT-overexpressing cancer cells, revealing the FTSJ3/TERRA/SUV39H1 axis as a mechanism supporting telomeric heterochromatin stability. Genome-wide synthetic dosage lethality (SDL) screening, FTSJ3 knockdown/knockout, chromatin immunoprecipitation (H3K9me3, HP1-alpha), patient-derived organoids bioRxivpreprint Medium
2025 FTSJ3 is specifically recruited to R-loop structures, where it prevents DNA damage by suppressing excessive R-loop formation. FTSJ3 depletion increased R-loop-dependent DNA damage and sensitized lung cancer cells to cisplatin both in vitro and in vivo. FTSJ3 depletion, R-loop immunofluorescence/S9.6 antibody staining, DNA damage assays (γH2AX), cisplatin sensitivity assay in vitro and in xenograft models Cancer letters Medium 40517939

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 Nucleolar proteome dynamics. Nature 934 15635413
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2002 Functional proteomic analysis of human nucleolus. Molecular biology of the cell 391 12429849
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2011 Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 286 21903422
2006 Phosphoproteome analysis of the human mitotic spindle. Proceedings of the National Academy of Sciences of the United States of America 281 16565220
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2019 FTSJ3 is an RNA 2'-O-methyltransferase recruited by HIV to avoid innate immune sensing. Nature 173 30626973
2015 Purification and identification of Bacillus subtilis SPB1 lipopeptide biosurfactant exhibiting antifungal activity against Rhizoctonia bataticola and Rhizoctonia solani. Environmental science and pollution research international 48 26645234
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
2011 Phylogenetic lineage and pilus protein Spb1/SAN1518 affect opsonin-independent phagocytosis and intracellular survival of Group B Streptococcus. Microbes and infection 29 21238599
2011 The impact of the Bacillus subtilis SPB1 biosurfactant on the midgut histology of Spodoptera littoralis (Lepidoptera: Noctuidae) and determination of its putative receptor. Journal of invertebrate pathology 26 22079884
2015 Assessment of the antidiabetic and antilipidemic properties of Bacillus subtilis SPB1 biosurfactant in alloxan-induced diabetic rats. Biopolymers 24 26228442
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
2023 rRNA methylation by Spb1 regulates the GTPase activity of Nog2 during 60S ribosomal subunit assembly. Nature communications 11 36864048
2016 Evaluation of Bacillus subtilis SPB1 biosurfactant effects on hyperglycemia, angiotensin I-converting enzyme (ACE) activity and kidney function in rats fed on high-fat-high-fructose diet. Archives of physiology and biochemistry 9 28019119
2023 Enhanced biosurfactant production by Bacillus subtilis SPB1 using developed fed-batch fermentation: effects of glucose levels and feeding systems. Bioprocess and biosystems engineering 7 36645491
2001 A Saccharomyces servazzii clone homologous to Saccharomyces cerevisiae chromosome III spanning KAR4, ARS 304 and SPB1 lacks the recombination enhancer but contains an unknown ORF. Yeast (Chichester, England) 3 11427961
2025 Loss of FTSJ3 promotes R-loop-associated DNA damage and facilitates chemosensitivity in lung cancer cells. Cancer letters 1 40517939