Affinage

RPS3A

Small ribosomal subunit protein eS1 · UniProt P61247

Length
264 aa
Mass
29.9 kDa
Annotated
2026-06-10
35 papers in source corpus 19 papers cited in narrative 19 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

RPS3A is a structural protein of the 40S small ribosomal subunit that participates directly in translation by contacting Met-tRNA(f) within the 43S initiation complex and occupying the A-site codon of the assembled 80S ribosome, where it forms part of the A-site architecture independently of tRNA or eRF1 (PMID:925037, PMID:6910637, PMID:15697241). It is surface-exposed on the 40S subunit and cytoplasmically associated with the ribosome, and its loss is incompatible with normal development, abolishing oogenesis in Drosophila (PMID:6196023, PMID:9393444). Beyond translation, RPS3A acts extraribosomally as a chaperone: its N-terminal 50 amino acids are required to solubilize the aggregation-prone HBx protein and to suppress alpha-synuclein aggregation and toxicity, with RPS3A-dependent solubilization of HBx enhancing NF-kB (p65) nuclear translocation (PMID:21857917, PMID:23924367). RPS3A engages multiple regulatory partners that link it to apoptosis, transcription, and inflammatory signaling, including CHOP/GADD153, where it modulates erythroid differentiation (PMID:10713066), the automodification domain of PARP, where together with Bcl-2 it inhibits PARP enzymatic activity (PMID:11790116), and the transcription factor E4F1, through which it activates CSF1 transcription to drive tumor-associated macrophage recruitment (PMID:39560749). RPS3A also localizes to mitochondria to maintain brown adipocyte mitochondrial function (PMID:30131868), binds PIP3 selectively in the nucleus (PMID:19003108), and is a required component of LPS-triggered pro-inflammatory cytokine signaling (PMID:29169044). The human gene additionally hosts an intron-encoded C/D box snoRNA, U73 (PMID:9573378).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1977 High

    Established RPS3A as a discrete, purifiable polypeptide of the 40S small ribosomal subunit, defining it as a ribosomal protein.

    Evidence Ion exchange chromatography and SDS-PAGE/amino acid composition of rat liver 40S subunits

    PMID:925037

    Open questions at the time
    • No functional role within the ribosome defined
    • No sequence determined at this stage
  2. 1981 High

    Placed RPS3A at the decoding/initiation machinery by showing it physically contacts initiator Met-tRNA(f) and 18S rRNA in the 43S complex.

    Evidence Two independent cross-linking chemistries plus UV photocross-linking in reconstituted initiation complexes

    PMID:6910637

    Open questions at the time
    • Cross-links localize contacts but not the structural mechanism
    • Functional consequence of the tRNA contact not tested
  3. 1983 Medium

    Mapped RPS3A to the solvent-exposed surface of the 40S subunit, consistent with accessibility for both ribosomal and extraribosomal interactions.

    Evidence Antibody labeling and electron microscopy of 40S subunits

    PMID:6196023

    Open questions at the time
    • Epitope mapping is low resolution
    • Single lab
  4. 1992 High

    Defined the human RPS3A primary structure, confirming the 263-residue ribosomal protein across cDNA and protein-level evidence.

    Evidence cDNA cloning, nucleotide sequencing, and Edman degradation of purified protein

    PMID:1398113

    Open questions at the time
    • No structural fold determined
    • No domain function assigned
  5. 1997 High

    Demonstrated that RPS3A function is essential in vivo, with loss-of-function abolishing oogenesis and follicular cell viability.

    Evidence Cell fractionation, immunocytochemistry, and antisense transgenic analysis in Drosophila

    PMID:9393444

    Open questions at the time
    • Phenotype could reflect general ribosome loss rather than a specific RPS3A function
    • Does not separate ribosomal from extraribosomal roles
  6. 1998 Medium

    Revealed that the RPS3A gene hosts an intron-encoded C/D box snoRNA (U73) with antisense complementarity to 28S rRNA, linking the locus to rRNA modification.

    Evidence Gene cloning and sequence analysis identifying C/D box snoRNA features and rRNA complementarity in human and mouse

    PMID:9573378

    Open questions at the time
    • 2'-O-methylation guidance inferred from complementarity, not directly assayed
    • Functional dependence of host gene and snoRNA not tested
  7. 2000 High

    Identified the first extraribosomal regulatory partners (CHOP/GADD153 and Bcl-2), tying RPS3A to differentiation control and apoptosis-related machinery.

    Evidence Reciprocal co-IP, in vitro translation, and overexpression/antisense rescue in erythroleukemia cells (CHOP); Bcl-2 co-IP and cell-cycle/chemosensitivity assays in AML cells

    PMID:10648421 PMID:10713066

    Open questions at the time
    • Mechanism linking interactions to differentiation/apoptosis not fully resolved
    • Bcl-2 interaction is Medium confidence and single-lab
  8. 2002 High

    Defined a biochemical function for the RPS3A-Bcl-2 axis by showing RPS3A is a required co-factor for Bcl-2-mediated inhibition of PARP enzymatic activity, and showed compartment-specific PIP3 binding by nuclear RPS3A.

    Evidence Yeast two-hybrid, GST pulldown, co-IP, and PARP activity assays with Bcl-2-alone negative control; PIP3 analogue bead pulldown with recombinant protein and subcellular fractionation

    PMID:11790116 PMID:19003108

    Open questions at the time
    • Physiological context of PARP inhibition not established
    • Functional consequence of nuclear PIP3 binding not characterized
  9. 2005 High

    Refined RPS3A's translational role by placing it at the A-site codon of the 80S ribosome in a tRNA/eRF1-independent manner, and connected it to viral oncoprotein biology via EBNA-5.

    Evidence 4-thiouridine mRNA UV photocross-linking with primer extension in 80S complexes; co-IP and colocalization of EBNA-5 with Fte-1/S3a

    PMID:15572026 PMID:15697241

    Open questions at the time
    • Structural basis of A-site contact not resolved
    • Consequence of EBNA-5 binding (Medium confidence) on RPS3A function unknown
  10. 2011 High

    Established a defined extraribosomal mechanism: an N-terminal (aa 1-50) chaperone activity that solubilizes aggregation-prone clients, demonstrated for HBx and coupled to enhanced NF-kB signaling.

    Evidence Co-IP, HBx solubility assay, siRNA knockdown with NF-kB nuclear translocation readout, and domain deletion mutagenesis

    PMID:21857917

    Open questions at the time
    • Whether chaperone activity is intrinsic or requires partners not resolved
    • Link between solubilization and NF-kB activation mechanistically incomplete
  11. 2013 Medium

    Generalized the N-terminal chaperone activity to a second aggregation-prone client by showing mammalian RPS3A suppresses alpha-synuclein aggregation and toxicity, with the activity specific to the mammalian protein.

    Evidence Yeast overexpression, growth and GFP-inclusion imaging assays, N-terminal truncation, and yeast-homologue negative control

    PMID:23924367

    Open questions at the time
    • Tested in a heterologous yeast system
    • No mammalian neuronal validation
    • Single lab
  12. 2018 Medium

    Extended RPS3A localization and function to mitochondria, where it maintains brown adipocyte mitochondrial function with consequences for adipose browning and vascular inflammation.

    Evidence Subcellular fractionation, siRNA knockdown, adipocyte differentiation and mitochondrial assays, and in vivo periaortic adipose knockdown

    PMID:30131868

    Open questions at the time
    • Molecular mechanism of mitochondrial action unknown
    • Import/targeting pathway not defined
    • Single lab
  13. 2024 Medium

    Connected RPS3A to inflammatory and tumor signaling networks through new partners and pathways: a drug target in LPS signaling, a BTN3A3 partner modulating OCR/ROS and MAPK, and an E4F1-CSF1 transcriptional axis driving macrophage recruitment.

    Evidence Affinity pulldown/SPR and cytokine ELISA with knockdown (EsA/LPS); co-IP/MS with OCR and ROS assays (BTN3A3); co-IP plus ChIP with xenograft validation (E4F1-CSF1)

    PMID:29169044 PMID:37806541 PMID:39560749

    Open questions at the time
    • Each axis characterized in a distinct cell context
    • Direct vs indirect nature of some interactions not fully resolved
    • Single-lab studies
  14. 2025 Low

    Identified an upstream regulator of RPS3A protein stability, the micropeptide IADMP, linking RPS3A abundance to lung cancer phenotypes.

    Evidence Co-IP, proliferation/migration assays, and protein stability assay

    PMID:41444079

    Open questions at the time
    • Single co-IP interaction without reciprocal validation
    • Mechanism of stabilization not defined
    • Limited mechanistic detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RPS3A's structural role on the ribosome is mechanistically coupled to its extraribosomal chaperone, mitochondrial, and signaling functions, and what governs its partitioning among cytosol, nucleus, and mitochondria.
  • No structural model integrating ribosomal and extraribosomal functions
  • Regulation of subcellular partitioning unknown
  • No unifying mechanism linking the diverse partner interactions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0003723 RNA binding 2 GO:0044183 protein folding chaperone 2 GO:0008289 lipid binding 1
Localization
GO:0005840 ribosome 5 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2
Partners
BCL2BTN3A3CHOPE4F1EBNA-5HBXPARP1
Complex memberships
40S ribosomal small subunit

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1977 RPS3A (S3a) was isolated as a component of the 40S ribosomal small subunit from rat liver ribosomes; its molecular weight and amino acid composition were determined by SDS-PAGE and biochemical analysis. Ion exchange chromatography, SDS-PAGE, amino acid composition analysis The Journal of biological chemistry High 925037
1981 RPS3A (S3a) directly contacts Met-tRNA(f) within the eukaryotic 43S initiation complex (eIF-2·GMPPCP·Met-tRNA(f)·40S subunit), as shown by cross-linking with both diepoxybutane and UV-activated methyl-rho-azido-benzoylaminoacetimidate; S3a is also covalently bound to 18S rRNA in this complex. Chemical cross-linking (bifunctional reagents diepoxybutane and methyl-rho-azido-benzoylaminoacetimidate) combined with UV photocross-linking in reconstituted initiation complexes Nucleic acids research High 6910637
1983 RPS3A (S3a) is surface-exposed on the 40S ribosomal subunit, with multiple antigenic determinants mapped to both the head and body regions of the subunit by antibody labeling and electron microscopy. Antibody labeling and electron microscopy of 40S ribosomal subunits Biomedica biochimica acta Medium 6196023
1992 Human RPS3A encodes a 263 amino acid protein (Mr ~29,813) and is a component of the 40S ribosomal subunit; the full primary structure was determined from cDNA sequencing confirmed by direct N-terminal sequencing of purified protein. cDNA cloning, nucleotide sequencing, direct Edman degradation of purified protein Gene High 1398113
1997 Drosophila RPS3A (C3) protein is localized to the cytoplasm and physically associated with the 40S ribosomal subunit; antisense suppression of RPS3A is essential for oogenesis, causing loss of follicular cells and failure of egg production. Cell fractionation, Western blot with specific antibody, immunocytochemistry, antisense transgenic analysis in Drosophila Molecular & general genetics : MGG High 9393444
1998 The human and mouse RPS3A genes each harbor an intron-encoded snoRNA designated U73, which contains C, D, and D' boxes and 12-nucleotide antisense complementarity to 28S rRNA, placing it in the family of antisense snoRNAs that guide 2'-O-ribose methylation of pre-rRNA at G1739. Gene cloning, sequence analysis, identification of C/D box snoRNA features and rRNA complementarity Gene Medium 9573378
2000 RPS3A (FTE/S3a) physically interacts with the transcription factor CHOP (GADD153); the interaction was demonstrated by co-immunoprecipitation of bacterially expressed His-CHOP with in vitro translated FTE/S3a, confirmed by reciprocal co-IP from cell lysates; overexpression of FTE/S3a inhibited erythroid differentiation, which was partially reversed by co-overexpression of CHOP or antisense fte/S3a. Co-immunoprecipitation (reciprocal, using anti-CHOP and anti-FTE/S3a antibodies), in vitro translation, Western blot, functional overexpression/antisense experiments in Rauscher murine erythroleukemia cells The Journal of biological chemistry High 10713066
2000 RPS3A co-precipitates with Bcl-2 from ATRA-treated AML cell extracts; increased RPS3A expression is associated with increased S-phase fraction, enhanced sensitivity to ara-C and doxorubicin, and ATRA-induced sensitization to chemotherapy. Immunoprecipitation of Bcl-2 from 32P-labeled cell extracts with identification of co-precipitated S3a; cell line genetic overexpression and disruption experiments with cell cycle analysis Blood Medium 10648421
2002 RPS3A directly interacts with the automodification domain of PARP (poly(ADP-ribose) polymerase) and, together with Bcl-2, significantly inhibits PARP enzymatic activity; Bcl-2 alone failed to inhibit PARP activity in the absence of S3a, establishing S3a as a required co-factor for Bcl-2-mediated PARP inhibition. Yeast two-hybrid screen, GST pulldown with nuclear extracts, co-immunoprecipitation, PARP activity assay Biochemistry High 11790116
2002 Nuclear RPS3A (but not cytosolic RPS3A) specifically binds PIP3 (phosphatidylinositol 3,4,5-trisphosphate), identified by affinity pulldown with PIP3 analogue beads and confirmed with recombinant S3a protein; S3a localizes to both cytosol and nucleus. PIP3 analogue bead affinity pulldown, mass spectrometry, recombinant protein binding assay, subcellular fractionation Cytotechnology Medium 19003108
2005 RPS3A (S3a) directly contacts the first position of the A-site codon in the human 80S ribosome, as established by UV cross-linking of 4-thiouridine-containing mRNA analogues; S3a contacts were poorly dependent on the presence of tRNA or eRF1, indicating a structural role in A-site architecture. UV photocross-linking with 4-thiouridine-containing mRNA analogues in human 80S ribosome complexes, primer extension mapping Biochemistry High 15697241
2005 EBV-encoded EBNA-5 binds to RPS3A (Fte-1/S3a); in transfected cells, Fte-1/S3a and EBNA-5 colocalize in extranucleolar nuclear inclusions; EBV-induced B cell transformation leads to upregulation of Fte-1/S3a. Co-immunoprecipitation, fluorescence colocalization in transfected cells, Western blot Experimental cell research Medium 15572026
2011 RPS3A enhances HBx-induced NF-κB (p65) nuclear translocation via a novel extraribosomal chaperone activity: RPS3A significantly increases the solubility of the aggregation-prone HBx protein; the N-terminal domain (amino acids 1–50) of RPS3A is required for chaperoning and interaction with HBx; knockdown of RPS3A reduces NF-κB signaling. Co-immunoprecipitation, siRNA knockdown, NF-κB nuclear translocation assay, solubility assay for HBx, domain deletion mutagenesis PloS one High 21857917
2013 Mammalian RPS3A suppresses α-synuclein aggregation and toxicity in yeast; the N-terminal 50 amino acids are essential for this chaperone function; co-expression of RPS3A delayed formation of αSyn-GFP inclusions; yeast homologues of RPS3A were not effective, indicating the chaperone function is specific to mammalian RPS3A. Yeast overexpression screen, yeast growth assay, GFP inclusion imaging, N-terminal truncation analysis The Biochemical journal Medium 23924367
2017 RPS3A directly binds the small molecule esculentoside A (EsA); affinity resin pulldown identified RPS3A as the primary binding target in RAW264.7 macrophage lysates, confirmed by surface plasmon resonance; RPS3A knockdown suppressed TNF-α and IL-6 production and LPS-triggered signaling, establishing RPS3A as a required component of LPS-mediated pro-inflammatory signaling. Affinity resin pulldown, mass spectrometry, Western blot competition assay, surface plasmon resonance, lentivirus-mediated RNAi, cytokine ELISA International immunopharmacology High 29169044
2018 RPS3A migrates to mitochondria where it maintains brown adipocyte mitochondrial function; knockdown of RPS3A inhibited adipocyte differentiation, impaired mitochondrial function in mature adipocytes, and impaired browning of perivascular adipose tissue in vivo, accelerating vascular inflammation and atherosclerosis. Subcellular fractionation/mitochondrial localization, siRNA knockdown, adipocyte differentiation assay, mitochondrial function assays, in vivo mouse periaortic adipose tissue knockdown model Cell discovery Medium 30131868
2023 BTN3A3 directly binds RPS3A as demonstrated by co-immunoprecipitation followed by mass spectrometry; BTN3A3/RPS3A complex positively regulates cellular oxygen consumption rate (OCR) and ROS levels, and negatively regulates MAPK pathway activation in clear cell renal cell carcinoma. Co-immunoprecipitation followed by mass spectrometry, Western blot, oxygen consumption rate assay, ROS measurement, RNA-Seq, siRNA knockdown and overexpression Cellular signalling Medium 37806541
2024 RPS3A interacts with the transcription factor E4F1 (via Co-IP); E4F1 then binds the CSF1 promoter (via ChIP) to activate CSF1 transcription; this RPS3A–E4F1–CSF1 axis recruits tumor-associated macrophages and promotes their M2 polarization through autophagy, driving glioma progression. Co-immunoprecipitation (RPS3A–E4F1 interaction), ChIP (E4F1 binding to CSF1 promoter), shRNA knockdown, overexpression rescue, autophagy modulation with rapamycin, in vivo xenograft model Naunyn-Schmiedeberg's archives of pharmacology Medium 39560749
2025 The micropeptide IADMP physically interacts with RPS3A and enhances its protein stability, promoting lung cancer malignant phenotypes. Co-immunoprecipitation, functional cell-based assays (proliferation, migration), protein stability assay Biochemical and biophysical research communications Low 41444079

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1977 Isolation of eukaryotic ribosomal proteins. Purification and characterization of the 40 S ribosomal subunit proteins Sa, Sc, S3a, S3b, S5', S9, S10, S11, S12, S14, S15, S15', S16, S17, S18, S19, S20, S21, S26, S27', and S29. The Journal of biological chemistry 60 925037
1981 Cross-linking of Met-tRNAf to eIF-2 beta and to the ribosomal proteins S3a and S6 within the eukaryotic inhibition complex, eIF-2 .GMPPCP.Met-tRNAf.small ribosomal subunit. Nucleic acids research 54 6910637
2011 Sequence variants of the Phytophthora sojae RXLR effector Avr3a/5 are differentially recognized by Rps3a and Rps5 in soybean. PloS one 52 21779316
2021 Narrow Leaf21, encoding ribosomal protein RPS3A, controls leaf development in rice. Plant physiology 50 33591317
2011 RPS3a over-expressed in HBV-associated hepatocellular carcinoma enhances the HBx-induced NF-κB signaling via its novel chaperoning function. PloS one 48 21857917
2001 Dual role of the Leishmania major ribosomal protein S3a homologue in regulation of T- and B-cell activation. Infection and immunity 44 11598026
2000 Novel interaction between the transcription factor CHOP (GADD153) and the ribosomal protein FTE/S3a modulates erythropoiesis. The Journal of biological chemistry 44 10713066
2017 Potato spindle tuber viroid infection triggers degradation of chloride channel protein CLC-b-like and Ribosomal protein S3a-like mRNAs in tomato plants. Scientific reports 37 28827569
2002 Inhibition of poly(ADP-ribose) polymerase activity by Bcl-2 in association with the ribosomal protein S3a. Biochemistry 36 11790116
2005 The first position of a codon placed in the A site of the human 80S ribosome contacts nucleotide C1696 of the 18S rRNA as well as proteins S2, S3, S3a, S30, and S15. Biochemistry 35 15697241
2018 RPS3A positively regulates the mitochondrial function of human periaortic adipose tissue and is associated with coronary artery diseases. Cell discovery 34 30131868
1992 Human ribosomal protein S3a: cloning of the cDNA and primary structure of the protein. Gene 28 1398113
2000 Regulation of drug sensitivity by ribosomal protein S3a. Blood 27 10648421
2009 RNA interference directed against ribosomal protein S3a suggests a link between this gene and arrested ovarian development during adult diapause in Culex pipiens. Insect molecular biology 25 19863669
1997 Antisense suppression of the putative ribosomal protein S3A gene disrupts ovarian development in Drosophila melanogaster. Molecular & general genetics : MGG 23 9393444
2005 Epstein-Barr virus-encoded EBNA-5 binds to Epstein-Barr virus-induced Fte1/S3a protein. Experimental cell research 22 15572026
1983 Electron microscopic investigations on the location of rat liver ribosomal proteins S3a, S5, S6, S7 and S9 by means of antibody labeling. Biomedica biochimica acta 21 6196023
2005 [The NOLA2 and RPS3A genes as highly informative markers for human squamous cell lung cancer]. Bioorganicheskaia khimiia 16 15889794
1997 The S3a ribosomal protein gene is identical to the Fte-1 (v-fos transformation effector) gene and the TNF-alpha-induced TU-11 gene, and its transcript level is altered in transformed and tumor cells. Gene 16 9074506
1996 The primary structures of rat ribosomal proteins S3a (the V-Fos transformation effector) and of S3b. Biochemical and biophysical research communications 15 8912649
2000 Down-regulated RPS3a/nbl expression during retinoid-induced differentiation of HL-60 cells: a close association with diminished susceptibility to actinomycin D-stimulated apoptosis. Cell structure and function 13 10885580
1998 Eimeria tenella: cloning and characterization of cDNA encoding a S3a ribosomal protein. Gene 13 9931469
1998 A novel snoRNA (U73) is encoded within the introns of the human and mouse ribosomal protein S3a genes. Gene 12 9573378
2013 Mammalian ribosomal and chaperone protein RPS3A counteracts α-synuclein aggregation and toxicity in a yeast model system. The Biochemical journal 11 23924367
1998 Drosophila RpS3a, a novel Minute gene situated between the segment polarity genescubitus interruptus and dTCF. Nucleic acids research 11 9742251
1999 Cloning of a Leishmania major gene encoding for an antigen with extensive homology to ribosomal protein S3a. Gene 10 10564812
1996 The human S3a ribosomal protein: sequence, location and cell-free transcription of the functional gene. Gene 10 8647443
2023 BTN3A3 inhibits clear cell renal cell carcinoma progression by regulating the ROS/MAPK pathway via interacting with RPS3A. Cellular signalling 7 37806541
2017 Esculentoside A specifically binds to ribosomal protein S3a and impairs LPS-induced signaling in macrophages. International immunopharmacology 6 29169044
2024 Ribosomal protein S3A (RPS3A), as a transcription regulator of colony-stimulating factor 1 (CSF1), promotes glioma progression through regulating the recruitment and autophagy-mediated M2 polarization of tumor-associated macrophages. Naunyn-Schmiedeberg's archives of pharmacology 5 39560749
2000 Isolation and characterization of medaka ribosomal protein S3a (fte-1) cDNA and gene. Gene 5 10854794
2021 Mutations in the Promoter and Coding Regions of Avr3a Cause Gain of Virulence of Phytophthora sojae to Rps3a in Soybean. Frontiers in microbiology 3 34858371
2002 Identification of ribosomal protein S3a as a candidate for a novel PI 3-kinase target in the nucleus. Cytotechnology 2 19003108
2025 The oncomicropeptide IADMP promotes lung cancer progression by stablilized RPS3A expression. Biochemical and biophysical research communications 1 41444079
2016 Molecular cloning and expression analyses of RPS3a gene from mulberry under abiotic stresses and among different mulberry varieties. Genetics and molecular research : GMR 1 27173298

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