{"gene":"RPS3","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2004,"finding":"RPS3 induces apoptosis as a third function independent of its DNA repair and ribosomal roles. GFP-rpS3 relocalizes to the nuclear membrane during rpS3-induced apoptosis in lymphocytic cells, and transient expression activates caspase-8/caspase-3 and sensitizes cells to cytokine-induced apoptosis. Deletion analysis showed DNA repair and apoptosis functions use independent domains.","method":"GFP fusion live imaging, transient overexpression, caspase activity assays, deletion analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2/3 / Moderate — multiple functional readouts (localization, caspase activation, cytokine sensitization, domain mapping) in a single lab study","pmids":["14988002"],"is_preprint":false},{"year":2011,"finding":"IKKβ phosphorylates RPS3 at Ser209, which is required for nuclear translocation of RPS3 and its function as a subunit of NF-κB that directs specific gene transcription. E. coli O157:H7 virulence protein NleH1 specifically inhibits this IKKβ-mediated Ser209 phosphorylation, blocking RPS3 nuclear translocation and NF-κB target gene expression.","method":"Phospho-specific mutagenesis, kinase assays, nuclear fractionation, NleH1 bacterial infection model (gnotobiotic piglet), reporter assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct kinase assay identifying phosphorylation site, mutagenesis, fractionation, and in vivo animal model; published in high-quality journal with multiple orthogonal methods","pmids":["21399639"],"is_preprint":false},{"year":2008,"finding":"PKCδ phosphorylates RPS3, causing its mobilization from the ribosome to the nucleus for DNA repair. Phosphorylated rpS3 is found only in the non-ribosomal fraction, and its endonuclease activity is increased upon phosphorylation. Knockdown of rpS3 increases sensitivity to genotoxic stress, which is rescued by wild-type but not phosphorylation-defective rpS3.","method":"Kinase assay, subcellular fractionation, siRNA knockdown, endonuclease activity assay, rescue experiment with phospho-dead mutant","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase assay, fractionation, functional rescue with mutant; single lab, multiple orthogonal methods","pmids":["19059439"],"is_preprint":false},{"year":2013,"finding":"When ROS levels increase, rpS3 accumulates in mitochondria to repair damaged mitochondrial DNA. Nuclear import into mitochondria is regulated by interaction with HSP90 and HSP70 via TOM70. Geldanamycin (HSP90 inhibitor) decreases rpS3–HSP90 interaction and stimulates mitochondrial accumulation of rpS3, which reduces cellular ROS and rescues mtDNA damage.","method":"Co-immunoprecipitation, subcellular fractionation, pharmacological inhibition (geldanamycin), mtDNA damage assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP for binding partners, fractionation with functional consequence, pharmacological perturbation; single lab","pmids":["23911537"],"is_preprint":false},{"year":2005,"finding":"Mammalian rpS3 functions as a broad-specificity base-damage endonuclease, cleaving DNA containing AP sites, thymine glycols, pyrimidine dimers, and other UV-damaged lesions. It lacks glycosylase activity but has endonuclease activity on multiple DNA lesions. Its activity is inhibited by MgCl2 on AP DNA but not on UV-irradiated DNA.","method":"In vitro endonuclease assay on defined DNA substrates, supercoiled vs. relaxed DNA substrates, MgCl2 inhibition experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro biochemical assay with multiple substrates, single lab, no mutagenesis or structural validation","pmids":["15707971"],"is_preprint":false},{"year":2012,"finding":"The ankyrin repeat protein Yar1 (yeast) directly interacts with ribosomal protein Rps3, accompanies newly synthesized Rps3 from cytoplasm to nucleus where it assembles into pre-ribosomal subunits, and protects Rps3 from aggregation in vitro and increases its solubility in vivo. Yar1 acts as a specific chaperone for Rps3.","method":"Co-immunoprecipitation, in vitro aggregation assay, yeast genetics (deletion strains, suppression by RPS3 overexpression), 20S pre-rRNA accumulation and 40S export assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated, in vitro aggregation protection, genetic epistasis (suppression), multiple orthogonal methods","pmids":["22570489"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of yeast rpS3 in complex with its chaperone Yar1 resolved at 2.8 Å. The structure explains how Yar1 protects rpS3 from aggregation while facilitating nuclear import, and suggests a stepwise exchange of molecular partners during ribosome assembly.","method":"X-ray crystallography at 2.8 Å resolution","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional interpretation; single study but highest-quality method","pmids":["24021814"],"is_preprint":false},{"year":2016,"finding":"Newly synthesized Rps3 forms a dimer associated with one Yar1 chaperone molecule. Nuclear import of Rps3 proceeds via the classical importin α/β (Kap60/Kap95) pathway, which recognizes an N-terminal NLS in Rps3 directly adjacent to the Yar1-binding site. Kap60 binding to the Rps3 NLS displaces Yar1 in vitro, yet a trimeric Rps3/Yar1/Kap60 complex can be reconstituted in vitro and is detected in vivo.","method":"In vitro reconstitution of protein complexes, pull-down assays, affinity purifications, NLS mapping by mutagenesis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution of trimeric complex, mutagenesis of NLS, multiple orthogonal binding assays","pmids":["27819319"],"is_preprint":false},{"year":2004,"finding":"Yar1 (yeast) physically interacts with Rps3 and with Ltv1 (a pre-40S particle component). Genetic and biochemical evidence shows Yar1 and Ltv1 function in 40S subunit production. Overexpression of RPS3 suppresses stress sensitivity and ribosome biogenesis defects of Δyar1 but not Δltv1 mutants, placing Yar1 upstream of/at Rps3 in the assembly pathway.","method":"Co-immunoprecipitation, yeast genetic epistasis (suppression by RPS3 overexpression), polysome profiling","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, genetic suppression, polysome profiling; single lab with multiple methods","pmids":["15611164"],"is_preprint":false},{"year":2017,"finding":"Rps3/uS3 resides in the mRNA entry channel of the 40S subunit and contacts mRNA via conserved residues Arg116 and Arg117. Substitutions at these residues reduce bulk translation initiation, diminish near-cognate UUG start codon selection, and increase discrimination against AUG in poor Kozak context. In vitro reconstitution showed these residues stabilize TC binding to 48S PICs with UUG codons (closed PIN state), and Arg116/117 are crucial for PIC-mRNA contacts at the entry channel.","method":"In vitro reconstitution of 48S PICs, yeast genetics (UUG selection assays), mutagenesis of conserved residues, translation initiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined mutants, multiple genetic readouts, mechanistic link to specific residues","pmids":["28223523"],"is_preprint":false},{"year":2017,"finding":"RPS3 is the major TISU-element binding protein at the A site of the 48S ribosomal complex. Upon 80S complex formation, RPS3 interaction weakens and binding switches to RPS10e. TISU-directed translation initiation is particularly dependent on eIF1A, which interacts with both RPS3 and RPS10e.","method":"Site-specific UV cross-linking of ribosomal complexes assembled on TISU mRNA, comprehensive mutagenesis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — UV cross-linking directly identifies RPS3 as A-site contact protein, single lab","pmids":["28584194"],"is_preprint":false},{"year":2018,"finding":"Rps3/uS3 acts with Mbf1 and Asc1/RACK1 to prevent +1 frameshifting at inhibitory CGA-CGA codon pairs in yeast. Mutations in RPS3 near the mRNA entry site allow frameshifting. Mbf1 and Rps3 cooperate to maintain reading frame of stalled ribosomes. Frameshifting involves competition between codons entering the A site when the P-site CGA codon destabilizes elongation.","method":"Yeast genetic analysis, frameshifting reporter assays, double mutant analysis (epistasis)","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple mutants, functional reporter assays; single lab","pmids":["30465652"],"is_preprint":false},{"year":2019,"finding":"Sequential ubiquitination of uS3/Rps3 at lysine 212 is required for 18S non-functional rRNA decay (NRD). Mag2-mediated monoubiquitination followed by Hel2- and Rsp5-mediated K63-linked polyubiquitination triggers dissociation of the non-functional 80S ribosome into subunits, which requires the ATPase activity of Slh1 (Rqt2), as well as Asc1 and Dom34.","method":"Yeast genetics, sucrose gradient fractionation, ubiquitination site mapping (K212), E3 ligase deletion mutants, ATPase mutant analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific ubiquitination site identified, multiple E3 ligase mutants tested, functional dissociation assay, replicated with multiple genetic perturbations","pmids":["30893611"],"is_preprint":false},{"year":2017,"finding":"The balance of Rps3 mono-ubiquitination is controlled by reciprocal action of Hel2 E3 ligase (ubiquitination) and Ubp3 deubiquitinase (deubiquitination) in yeast, and their mammalian counterparts RNF123 and USP10 in mammalian cells. Rps3 mono-ubiquitination is coupled to ribosome quality control and autophagy.","method":"Co-immunoprecipitation, yeast genetic analysis, ubiquitination assays, autophagosome localization","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, genetic analysis, and localization; single lab with multiple approaches","pmids":["29147007"],"is_preprint":false},{"year":2017,"finding":"Asc1/RACK1 and Rps3 are factors in 18S nonfunctional rRNA decay (NRD) in yeast. A small region of the Rps3 C-terminal tail subject to post-translational modification is crucial for 18S NRD. Complete stabilization of mutant 18S rRNA occurs in dom34Δ;asc1Δ double mutants, indicating two genetically separable NRD pathways.","method":"Yeast genetic analysis, Northern blot for mutant 18S rRNA levels, epistasis in double mutants","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis, direct measurement of rRNA stability, C-terminal tail PTM mapping; single lab","pmids":["28956756"],"is_preprint":false},{"year":2018,"finding":"Residues of Rps3 at the mRNA entry tunnel of the ribosomal small subunit are important for No-Go Decay (NGD). Mutations in these entry-channel contact residues significantly reduce accumulation of NGD cleavage products, render cells sensitive to NGD-triggering agents, and are distinct from effects on ribosome ubiquitination, suggesting Rps3 plays a role in the endonucleolytic cleavage step of NGD independent of upstream RQC events.","method":"Yeast genetics with site-directed mutagenesis of mRNA-contact residues, NGD reporter assay, cleavage product Northern blot, sensitivity assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided mutagenesis, functional NGD reporter, multiple genetic backgrounds tested; single lab","pmids":["30475795"],"is_preprint":false},{"year":2019,"finding":"RPS3 functions as an RNA-binding protein that stabilizes SIRT1 mRNA post-transcriptionally by binding to AUUUA motifs in the 3' UTR (positions 3448-3530) of SIRT1 mRNA, thereby promoting HCC tumorigenesis.","method":"RNA-seq, RIP (RNA immunoprecipitation), gain/loss-of-function assays, 3' UTR binding site mapping","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RIP demonstrating binding, specific binding site mapping, functional consequence via gain/loss of function; single lab","pmids":["30517713"],"is_preprint":false},{"year":2015,"finding":"NleC metalloprotease of A/E pathogens cleaves p65, generating a p65(1-38) fragment that interferes with the interaction between p65 and RPS3, disrupting RPS3's role as a 'specifier' subunit of NF-κB for proinflammatory gene transcription. This amplifies the effect of cleaving a small percentage of p65.","method":"Co-immunoprecipitation, cleavage assays, mouse infection model (C. rodentium), NF-κB reporter assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating p65–RPS3 interaction disruption, in vivo mouse infection model, mechanistic cleavage assays; single lab","pmids":["25756944"],"is_preprint":false},{"year":2013,"finding":"E. coli NleH1 virulence effector prevents nuclear translocation of RPS3 to inhibit NF-κB by binding to CRKL, which interacts with IKKβ. NleH1 kinase activity is required to phosphorylate CRKL, and CRKL knockdown prevents NleH1 from inhibiting RPS3 nuclear translocation. Neither RPS3 nor IKKβ is a direct NleH1 kinase substrate.","method":"Large-scale kinase substrate screen (~9,000 proteins), co-immunoprecipitation, siRNA knockdown, nuclear fractionation, mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate screen, co-IP, knockdown rescue, mutagenesis; single lab, multiple orthogonal methods","pmids":["24145029"],"is_preprint":false},{"year":2018,"finding":"RNF138 E3 ubiquitin ligase ubiquitinates nuclear rpS3 in irradiated GBM cells, leading to ubiquitin-dependent degradation of rpS3 and consequent radioresistance. In ΔRNF138 cells, nuclear rpS3 accumulates and interacts with DDIT3, leading to DDIT3-induced apoptosis.","method":"Co-immunoprecipitation, interactome analysis, RNF138 knockout, in vivo xenograft model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, KO with defined phenotype, in vivo validation; single lab","pmids":["29371697"],"is_preprint":false},{"year":2022,"finding":"The E2-E3 ubiquitin complex UBE2J1-TRIM25 physically interacts with RPS3 and targets it for poly-ubiquitination and degradation at the K214 residue, leading to reduced RPS3 levels, restraint of NF-κB nuclear translocation, and inactivation of NF-κB signaling in colorectal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K214), overexpression/knockdown with NF-κB pathway readout","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination site identification (K214), co-IP of E2-E3-substrate complex, functional NF-κB readout; single lab","pmids":["36567344"],"is_preprint":false},{"year":2021,"finding":"circPLCE1-encoded protein circPLCE1-411 promotes ubiquitin-dependent degradation of RPS3 by binding to the HSP90α/RPS3 complex and facilitating dissociation of RPS3 from HSP90α, thereby reducing NF-κB nuclear translocation in colorectal cancer cells.","method":"Co-immunoprecipitation, LC-MS protein identification, gain/loss of function assays, in vivo xenograft model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP showing complex disruption, LC-MS identification, functional in vivo validation; single lab","pmids":["34412652"],"is_preprint":false},{"year":2020,"finding":"Latexin (LXN) forms a functional complex with HECTD1 (E3 ubiquitin ligase) and Rps3. LXN deficiency enhances the HECTD1–Rps3 interaction, promoting ubiquitination and degradation of IκBα (a HECTD1 substrate), thereby enhancing NF-κB inflammatory responses. Ectopic LXN expression leads to IκBα accumulation.","method":"Proteomics, co-immunoprecipitation, IκBα ubiquitination assay, LXN knockout mouse model (DSS-colitis)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — proteomics-identified complex, co-IP, ubiquitination assay, in vivo colitis model; single lab","pmids":["32555320"],"is_preprint":false},{"year":2015,"finding":"RPS3 physically interacts with MIF (macrophage migration inhibitory factor) under unirradiated conditions. Ionizing radiation induces dissociation of the MIF-rpS3 complex, activating NF-κB and its target genes. MIF-rpS3 dissociation also modulates epithelial-mesenchymal transition marker expression and pro-inflammatory cytokine secretion.","method":"Co-immunoprecipitation, xenograft tumor model, NF-κB reporter assays","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP demonstrating complex and its IR-induced disruption, limited mechanistic follow-up on how dissociation activates NF-κB","pmids":["25900216"],"is_preprint":false},{"year":2019,"finding":"LCN2 promotes NF-κB activation by binding to RPS3 and enhancing the interaction between RPS3 and p65 in oral squamous cell carcinoma cells.","method":"Co-immunoprecipitation, LCN2 overexpression/knockdown, NF-κB activity assay","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP, single lab, limited mechanistic detail on how LCN2-RPS3 interaction enhances p65 binding","pmids":["31819048"],"is_preprint":false},{"year":2019,"finding":"Cancer-associated eIF1A N-terminal tail mutations diminish eIF1A interaction with RPS3 and RPS10, retaining the ribosome in an open state that facilitates scanning of long 5' UTR-containing cell cycle genes.","method":"Co-immunoprecipitation, ribosome profiling, eIF1A knockdown/mutation, reporter assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP demonstrating eIF1A–RPS3 interaction, functional ribosome profiling, mutagenesis; single lab","pmids":["30420357"],"is_preprint":false}],"current_model":"RPS3 (uS3) is a multifunctional ribosomal protein of the 40S small subunit that contacts mRNA at the entry channel to stabilize preinitiation complexes and promote accurate start codon selection; outside the ribosome it acts as a DNA damage endonuclease (switched to this role by PKCδ-dependent phosphorylation), serves as a nuclear 'specifier' subunit of NF-κB whose nuclear translocation is gated by IKKβ-mediated phosphorylation at Ser209, participates in ribosome quality control through sequential ubiquitination (monoubiquitination by Hel2/RNF123 balanced by Ubp3/USP10 deubiquitinase, followed by K63-polyubiquitination to trigger 18S NRD subunit dissociation), is chaperoned from cytoplasm to nucleus by Yar1 (whose crystal structure with RPS3 has been solved), and undergoes ubiquitin-dependent degradation by UBE2J1-TRIM25 (at K214) or RNF138 to modulate NF-κB signaling and apoptosis."},"narrative":{"mechanistic_narrative":"RPS3 (uS3) is a multifunctional protein of the 40S small ribosomal subunit that contributes both to canonical translation and to a set of moonlighting roles in DNA repair, ribosome quality control, and NF-κB signaling [PMID:28223523, PMID:21399639, PMID:30893611]. Within the ribosome it occupies the mRNA entry channel, where conserved residues Arg116/Arg117 stabilize mRNA contacts and tune translation initiation: their substitution reduces bulk initiation, alters near-cognate UUG start codon selection, and shifts discrimination against poorly contexted AUG codons [PMID:28223523]. It also contacts mRNA at the A site of the 48S complex as the major TISU-element binding protein, an interaction coordinated with eIF1A and handed off to RPS10e upon 80S formation [PMID:28584194, PMID:30420357]. Through these entry-channel contacts RPS3 maintains translational fidelity, preventing +1 frameshifting at inhibitory codon pairs together with Mbf1 and Asc1/RACK1 [PMID:30465652] and participating in No-Go Decay endonucleolytic cleavage [PMID:30475795]. RPS3 is a target of ribosome quality control: sequential ubiquitination at lysine 212 — monoubiquitination followed by Hel2/Rsp5-mediated K63-linked polyubiquitination, balanced by the Ubp3/USP10 (mammalian RNF123/USP10) deubiquitinase axis — triggers dissociation of nonfunctional 80S ribosomes during 18S nonfunctional rRNA decay [PMID:30893611, PMID:29147007, PMID:28956756]. Biogenesis of RPS3 depends on the ankyrin-repeat chaperone Yar1, which binds nascent Rps3, prevents its aggregation, and accompanies it to the nucleus, with import proceeding via the importin α/β pathway recognizing an N-terminal NLS adjacent to the Yar1-binding site [PMID:22570489, PMID:24021814, PMID:27819319]. Outside the ribosome, RPS3 acts as a base-damage endonuclease cleaving AP sites, thymine glycols, and UV lesions [PMID:15707971], a role mobilized by PKCδ-dependent phosphorylation that relocalizes it from the ribosome to repair nuclear and (under ROS, via HSP90/HSP70/TOM70) mitochondrial DNA [PMID:19059439, PMID:23911537]. As a 'specifier' subunit of NF-κB, RPS3 directs p65 to specific proinflammatory target genes; its nuclear translocation requires IKKβ-mediated phosphorylation at Ser209, a step targeted by bacterial effectors NleH1 and NleC [PMID:21399639, PMID:25756944, PMID:24145029]. RPS3 abundance and signaling output are further controlled by ubiquitin-dependent degradation through UBE2J1-TRIM25 (at K214) and RNF138, modulating NF-κB activity and apoptosis [PMID:36567344, PMID:29371697].","teleology":[{"year":2004,"claim":"Established that RPS3 carries an apoptotic function genetically separable from its ribosomal and DNA-repair roles, first framing RPS3 as a multifunctional protein.","evidence":"GFP-fusion imaging, overexpression with caspase activity assays, and domain deletion mapping in lymphocytic cells","pmids":["14988002"],"confidence":"Medium","gaps":["Mechanism linking nuclear-membrane relocalization to caspase-8/3 activation not defined","Physiological trigger for the apoptotic function not identified"]},{"year":2005,"claim":"Demonstrated that RPS3 has intrinsic broad-specificity DNA endonuclease activity, providing the biochemical basis for its non-ribosomal DNA-repair role.","evidence":"In vitro endonuclease assays on defined AP, thymine glycol, and UV-damaged DNA substrates","pmids":["15707971"],"confidence":"Medium","gaps":["No catalytic residue identified by mutagenesis","No structural model of the active site","In vivo contribution to repair not established here"]},{"year":2008,"claim":"Showed that PKCδ phosphorylation switches RPS3 from a ribosomal to a DNA-repair function by mobilizing it to the nucleus and enhancing endonuclease activity.","evidence":"Kinase assay, subcellular fractionation, siRNA knockdown with phospho-dead mutant rescue against genotoxic stress","pmids":["19059439"],"confidence":"Medium","gaps":["Phosphosite not mapped","Quantitative partition between ribosomal and nuclear pools not defined"]},{"year":2013,"claim":"Extended the repair role to mitochondria, showing ROS-driven mitochondrial accumulation of RPS3 regulated by an HSP90/HSP70-TOM70 import axis.","evidence":"Co-IP, fractionation, geldanamycin inhibition, and mtDNA damage assays","pmids":["23911537"],"confidence":"Medium","gaps":["Direct mtDNA endonuclease activity in organello not shown","Relationship to nuclear repair pool unclear"]},{"year":2011,"claim":"Identified IKKβ phosphorylation of RPS3 at Ser209 as the gate for its nuclear translocation and function as an NF-κB specifier subunit directing gene-specific transcription.","evidence":"Phospho-specific mutagenesis, kinase assays, nuclear fractionation, gnotobiotic piglet infection with NleH1, reporter assays","pmids":["21399639"],"confidence":"High","gaps":["How RPS3 confers promoter specificity to NF-κB not mechanistically resolved","Generality across stimuli beyond infection not defined"]},{"year":2004,"claim":"Defined the chaperone Yar1 as a dedicated escort for Rps3 in 40S biogenesis, placing it in the ribosome assembly pathway alongside Ltv1.","evidence":"Reciprocal co-IP, genetic suppression by RPS3 overexpression, polysome profiling in yeast","pmids":["15611164"],"confidence":"Medium","gaps":["Order of Yar1 vs Ltv1 action only inferred genetically","Structural basis of binding not addressed here"]},{"year":2012,"claim":"Showed Yar1 directly binds Rps3, protects it from aggregation, and accompanies it from cytoplasm to nucleus, defining it as a specific Rps3 chaperone.","evidence":"Co-IP, in vitro aggregation assays, yeast deletion/suppression genetics, pre-rRNA and 40S export assays","pmids":["22570489"],"confidence":"High","gaps":["Hand-off from Yar1 to nuclear assembly factors not yet defined"]},{"year":2013,"claim":"Provided the structural basis for Yar1-mediated protection of Rps3 and stepwise partner exchange during assembly.","evidence":"X-ray crystallography of the yeast Rps3–Yar1 complex at 2.8 Å","pmids":["24021814"],"confidence":"High","gaps":["Structure of import-competent intermediates absent","No human RPS3 structure in this context"]},{"year":2016,"claim":"Resolved the import logic, showing the importin α/β pathway recognizes an Rps3 NLS adjacent to the Yar1 site, with Kap60 displacing Yar1 yet a trimeric complex being possible.","evidence":"In vitro reconstitution, pull-downs, affinity purification, and NLS mutagenesis","pmids":["27819319"],"confidence":"High","gaps":["In vivo sequence of Yar1 release versus import not directly timed","Dimerization functional significance unclear"]},{"year":2017,"claim":"Pinpointed Rps3 entry-channel residues Arg116/Arg117 as direct mRNA contacts that govern start codon selection accuracy and PIC stabilization.","evidence":"In vitro 48S PIC reconstitution, UUG-selection genetics, and conserved-residue mutagenesis","pmids":["28223523"],"confidence":"High","gaps":["Contribution to scanning dynamics in vivo not fully quantified"]},{"year":2017,"claim":"Identified RPS3 as the major TISU-element A-site contact protein, coordinated with eIF1A and exchanged for RPS10e upon 80S assembly.","evidence":"Site-specific UV cross-linking of complexes on TISU mRNA and mutagenesis","pmids":["28584194"],"confidence":"Medium","gaps":["Structural basis of the RPS3→RPS10e switch unresolved"]},{"year":2019,"claim":"Showed that eIF1A's interaction with RPS3 (and RPS10) sets the ribosome's open/closed conformational state, with cancer eIF1A mutations weakening this contact to favor scanning of long 5' UTRs.","evidence":"Co-IP, ribosome profiling, eIF1A mutation/knockdown, reporter assays","pmids":["30420357"],"confidence":"Medium","gaps":["Direct conformational measurement of RPS3 contact not performed"]},{"year":2018,"claim":"Demonstrated that entry-tunnel Rps3 residues mediate the endonucleolytic cleavage step of No-Go Decay, separable from ribosome ubiquitination.","evidence":"Structure-guided mutagenesis, NGD reporter, cleavage-product Northern blot, sensitivity assays in yeast","pmids":["30475795"],"confidence":"Medium","gaps":["Whether Rps3 itself catalyzes cleavage or recruits a nuclease unresolved"]},{"year":2018,"claim":"Established that Rps3 maintains reading frame at inhibitory codon pairs, acting with Mbf1 and Asc1/RACK1 to suppress +1 frameshifting.","evidence":"Yeast genetics, frameshifting reporters, double-mutant epistasis","pmids":["30465652"],"confidence":"Medium","gaps":["Molecular basis of frame maintenance at the entry site not structurally defined"]},{"year":2017,"claim":"Connected Rps3 ubiquitination to quality control, defining a Hel2/RNF123 (ubiquitination) versus Ubp3/USP10 (deubiquitination) balance coupled to RQC and autophagy.","evidence":"Co-IP, yeast genetics, ubiquitination assays, autophagosome localization across yeast and mammalian cells","pmids":["29147007"],"confidence":"Medium","gaps":["Functional outcome of the autophagy link not fully defined"]},{"year":2017,"claim":"Placed Rps3 within the 18S nonfunctional rRNA decay machinery via its modified C-terminal tail, alongside Asc1/RACK1 in genetically separable NRD pathways.","evidence":"Yeast genetics, Northern blot of mutant 18S rRNA, double-mutant epistasis","pmids":["28956756"],"confidence":"Medium","gaps":["Identity of the C-terminal modification not determined here"]},{"year":2019,"claim":"Defined the molecular trigger of 18S NRD: sequential ubiquitination of Rps3 at K212 drives ATPase-dependent dissociation of nonfunctional ribosomes.","evidence":"Yeast genetics, sucrose gradient fractionation, K212 site mapping, E3-ligase and Slh1 ATPase mutants","pmids":["30893611"],"confidence":"High","gaps":["Structural basis of how K212 ubiquitin signals subunit splitting unresolved"]},{"year":2019,"claim":"Revealed a non-ribosomal RNA-binding role: RPS3 stabilizes SIRT1 mRNA via 3' UTR AUUUA motifs to promote hepatocellular carcinoma.","evidence":"RNA-seq, RIP, binding-site mapping, gain/loss-of-function assays","pmids":["30517713"],"confidence":"Medium","gaps":["Breadth of RPS3-stabilized mRNA targets not defined","Link to ribosomal pool unclear"]},{"year":2015,"claim":"Showed bacterial NleC indirectly disrupts RPS3's NF-κB specifier function by cleaving p65 to a fragment that blocks the p65–RPS3 interaction.","evidence":"Co-IP, cleavage assays, C. rodentium mouse infection, NF-κB reporters","pmids":["25756944"],"confidence":"Medium","gaps":["Stoichiometric basis of amplification not quantified"]},{"year":2013,"claim":"Defined how NleH1 inhibits RPS3 nuclear translocation by acting through CRKL–IKKβ rather than directly phosphorylating RPS3 or IKKβ.","evidence":"Large-scale kinase substrate screen, co-IP, siRNA rescue, fractionation, mutagenesis","pmids":["24145029"],"confidence":"Medium","gaps":["How CRKL phosphorylation feeds into IKKβ activity not fully resolved"]},{"year":2015,"claim":"Suggested an MIF–RPS3 complex sequesters RPS3, with ionizing radiation triggering dissociation to activate NF-κB.","evidence":"Co-IP, xenograft model, NF-κB reporters","pmids":["25900216"],"confidence":"Low","gaps":["Single co-IP without reciprocal validation of the dissociation mechanism","How dissociation mechanistically activates NF-κB unresolved"]},{"year":2019,"claim":"Suggested LCN2 enhances NF-κB by binding RPS3 and strengthening RPS3–p65 interaction in oral cancer cells.","evidence":"Co-IP, LCN2 overexpression/knockdown, NF-κB activity assay","pmids":["31819048"],"confidence":"Low","gaps":["Single co-IP with limited mechanistic detail on how binding enhances p65 association"]},{"year":2018,"claim":"Identified RNF138 as an E3 ligase that degrades nuclear rpS3 to confer radioresistance, with rpS3 otherwise driving DDIT3-dependent apoptosis.","evidence":"Co-IP, interactome analysis, RNF138 knockout, xenograft model in GBM","pmids":["29371697"],"confidence":"Medium","gaps":["Ubiquitination site on rpS3 not mapped here","Mechanism of rpS3–DDIT3 apoptosis not detailed"]},{"year":2020,"claim":"Placed Rps3 in a LXN–HECTD1 complex regulating IκBα turnover and thereby NF-κB inflammatory output.","evidence":"Proteomics, co-IP, IκBα ubiquitination assay, LXN-knockout colitis mouse model","pmids":["32555320"],"confidence":"Medium","gaps":["Direct role of Rps3 versus HECTD1 in IκBα ubiquitination not separated"]},{"year":2021,"claim":"Showed circPLCE1-411 promotes RPS3 degradation by displacing it from HSP90α, dampening NF-κB nuclear translocation in colorectal cancer.","evidence":"Co-IP, LC-MS identification, gain/loss-of-function, xenograft model","pmids":["34412652"],"confidence":"Medium","gaps":["E3 ligase mediating the degradation not identified here"]},{"year":2022,"claim":"Defined UBE2J1-TRIM25 as an E2-E3 pair that polyubiquitinates RPS3 at K214 for degradation, restraining NF-κB signaling in colorectal cancer.","evidence":"Co-IP, ubiquitination assay, K214 mutagenesis, NF-κB pathway readouts","pmids":["36567344"],"confidence":"Medium","gaps":["Relationship between K214 (degradation) and K212/K214 RQC ubiquitination not reconciled"]},{"year":null,"claim":"How RPS3's distinct functional pools — ribosomal, DNA-repair endonuclease, NF-κB specifier, and mRNA stabilizer — are quantitatively partitioned and coordinately regulated within a cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating phosphorylation, ubiquitination, and partner-binding switches","Catalytic residues of the DNA endonuclease activity not defined","Structural basis of the NF-κB specifier role missing"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,10,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[9,10]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[4,15]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,17]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[9,11]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[9,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,5,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[12,13,14,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,17,20]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,17,22]}],"complexes":["40S ribosomal small subunit","NF-κB (p65-RPS3 specifier complex)","RPS3-Yar1 chaperone complex","UBE2J1-TRIM25 E2-E3 complex"],"partners":["YAR1","RELA","IKBKB","EIF1AX","HSP90AA1","TRIM25","RNF138","HECTD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23396","full_name":"Small ribosomal subunit protein uS3","aliases":["40S ribosomal protein S3"],"length_aa":243,"mass_kda":26.7,"function":"Component of the small ribosomal subunit (PubMed:23636399, PubMed:8706699). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:8706699). Has endonuclease activity and plays a role in repair of damaged DNA (PubMed:7775413). Cleaves phosphodiester bonds of DNAs containing altered bases with broad specificity and cleaves supercoiled DNA more efficiently than relaxed DNA (PubMed:15707971). Displays high binding affinity for 7,8-dihydro-8-oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species (ROS) (PubMed:14706345). Has also been shown to bind with similar affinity to intact and damaged DNA (PubMed:18610840). Stimulates the N-glycosylase activity of the base excision protein OGG1 (PubMed:15518571). Enhances the uracil excision activity of UNG1 (PubMed:18973764). Also stimulates the cleavage of the phosphodiester backbone by APEX1 (PubMed:18973764). When located in the mitochondrion, reduces cellular ROS levels and mitochondrial DNA damage (PubMed:23911537). Has also been shown to negatively regulate DNA repair in cells exposed to hydrogen peroxide (PubMed:17049931). Plays a role in regulating transcription as part of the NF-kappa-B p65-p50 complex where it binds to the RELA/p65 subunit, enhances binding of the complex to DNA and promotes transcription of target genes (PubMed:18045535). Represses its own translation by binding to its cognate mRNA (PubMed:20217897). Binds to and protects TP53/p53 from MDM2-mediated ubiquitination (PubMed:19656744). Involved in spindle formation and chromosome movement during mitosis by regulating microtubule polymerization (PubMed:23131551). Involved in induction of apoptosis through its role in activation of CASP8 (PubMed:14988002). Induces neuronal apoptosis by interacting with the E2F1 transcription factor and acting synergistically with it to up-regulate pro-apoptotic proteins BCL2L11/BIM and HRK/Dp5 (PubMed:20605787). Interacts with TRADD following exposure to UV radiation and induces apoptosis by caspase-dependent JNK activation (PubMed:22510408)","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleolus; Mitochondrion inner membrane; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/P23396/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS3","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":10.0},{"gene":"EIF2S3","stoichiometry":10.0},{"gene":"ENY2","stoichiometry":10.0},{"gene":"RACK1","stoichiometry":10.0},{"gene":"RBM8A","stoichiometry":10.0},{"gene":"RPL11","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL5","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"SRP9","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/RPS3","total_profiled":1310},"omim":[{"mim_id":"620074","title":"LTV1 RIBOSOME BIOGENESIS FACTOR; LTV1","url":"https://www.omim.org/entry/620074"},{"mim_id":"618100","title":"MPV17 MITOCHONDRIAL INNER MEMBRANE PROTEIN-LIKE; MPV17L","url":"https://www.omim.org/entry/618100"},{"mim_id":"617508","title":"ZINC FINGER PROTEIN 598; ZNF598","url":"https://www.omim.org/entry/617508"},{"mim_id":"600455","title":"RNA, U15A SMALL NUCLEOLAR; RNU15A","url":"https://www.omim.org/entry/600455"},{"mim_id":"600454","title":"RIBOSOMAL PROTEIN S3; RPS3","url":"https://www.omim.org/entry/600454"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS3"},"hgnc":{"alias_symbol":["FLJ26283","FLJ27450","MGC87870","S3","uS3"],"prev_symbol":[]},"alphafold":{"accession":"P23396","domains":[{"cath_id":"3.30.300.20","chopping":"6-89","consensus_level":"high","plddt":94.2999,"start":6,"end":89},{"cath_id":"3.30.1140.32","chopping":"97-188","consensus_level":"high","plddt":95.955,"start":97,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23396","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23396-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23396-F1-predicted_aligned_error_v6.png","plddt_mean":91.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS3","jax_strain_url":"https://www.jax.org/strain/search?query=RPS3"},"sequence":{"accession":"P23396","fasta_url":"https://rest.uniprot.org/uniprotkb/P23396.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23396/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23396"}},"corpus_meta":[{"pmid":"8876135","id":"PMC_8876135","title":"Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8876135","citation_count":319,"is_preprint":false},{"pmid":"26833239","id":"PMC_26833239","title":"Burden of sickle cell trait and disease in the Uganda Sickle Surveillance Study (US3): a cross-sectional study.","date":"2016","source":"The Lancet. 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mice.","date":"2010","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/20709134","citation_count":43,"is_preprint":false},{"pmid":"30465652","id":"PMC_30465652","title":"Multi-protein bridging factor 1(Mbf1), Rps3 and Asc1 prevent stalled ribosomes from frameshifting.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30465652","citation_count":42,"is_preprint":false},{"pmid":"8257288","id":"PMC_8257288","title":"The pathogenicity of a US3 protein kinase-deficient mutant of herpes simplex virus type 2 in mice.","date":"1993","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8257288","citation_count":42,"is_preprint":false},{"pmid":"24173231","id":"PMC_24173231","title":"Herpes simplex virus 1 protein kinase Us3 phosphorylates viral dUTPase and regulates its catalytic activity in infected cells.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24173231","citation_count":42,"is_preprint":false},{"pmid":"29147007","id":"PMC_29147007","title":"Modulating cellular balance of Rps3 mono-ubiquitination by both Hel2 E3 ligase and Ubp3 deubiquitinase regulates protein quality control.","date":"2017","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29147007","citation_count":42,"is_preprint":false},{"pmid":"16571792","id":"PMC_16571792","title":"U(S)3 and U(S)3.5 protein kinases of herpes simplex virus 1 differ with respect to their functions in blocking apoptosis and in virion maturation and egress.","date":"2006","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/16571792","citation_count":41,"is_preprint":false},{"pmid":"28584194","id":"PMC_28584194","title":"Efficient and Accurate Translation Initiation Directed by TISU Involves RPS3 and RPS10e Binding and Differential Eukaryotic Initiation Factor 1A Regulation.","date":"2017","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28584194","citation_count":40,"is_preprint":false},{"pmid":"17499381","id":"PMC_17499381","title":"A point mutation in the putative ATP binding site of the pseudorabies virus US3 protein kinase prevents Bad phosphorylation and cell survival following apoptosis induction.","date":"2007","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/17499381","citation_count":40,"is_preprint":false},{"pmid":"24741093","id":"PMC_24741093","title":"Herpes simplex virus protein kinases US3 and UL13 modulate VP11/12 phosphorylation, virion packaging, and phosphatidylinositol 3-kinase/Akt signaling activity.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24741093","citation_count":39,"is_preprint":false},{"pmid":"23951282","id":"PMC_23951282","title":"Us3 kinase encoded by herpes simplex virus 1 mediates downregulation of cell surface major histocompatibility complex class I and evasion of CD8+ T cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23951282","citation_count":38,"is_preprint":false},{"pmid":"36567344","id":"PMC_36567344","title":"UBE2J1 inhibits colorectal cancer progression by promoting ubiquitination and degradation of RPS3.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36567344","citation_count":37,"is_preprint":false},{"pmid":"25900216","id":"PMC_25900216","title":"Dissociation of MIF-rpS3 complex and sequential NF-κB activation is involved in IR-induced metastatic conversion of NSCLC.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25900216","citation_count":37,"is_preprint":false},{"pmid":"8046410","id":"PMC_8046410","title":"Identification of a target protein of US3 protein kinase of herpes simplex virus type 2.","date":"1994","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/8046410","citation_count":37,"is_preprint":false},{"pmid":"1355060","id":"PMC_1355060","title":"Location, characterization and expression of lytic enzyme-encoding gene, lytA, of Lactococcus lactis bacteriophage phi US3.","date":"1992","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/1355060","citation_count":37,"is_preprint":false},{"pmid":"33644057","id":"PMC_33644057","title":"Cisplatin-Resistant Gastric Cancer Cells Promote the Chemoresistance of Cisplatin-Sensitive Cells via the Exosomal RPS3-Mediated PI3K-Akt-Cofilin-1 Signaling Axis.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33644057","citation_count":37,"is_preprint":false},{"pmid":"19136132","id":"PMC_19136132","title":"The kinase activity of pseudorabies virus US3 is required for modulation of the actin cytoskeleton.","date":"2009","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/19136132","citation_count":36,"is_preprint":false},{"pmid":"26336993","id":"PMC_26336993","title":"RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26336993","citation_count":35,"is_preprint":false},{"pmid":"22593153","id":"PMC_22593153","title":"Suppression of extracellular signal-regulated kinase activity in herpes simplex virus 1-infected cells by the Us3 protein kinase.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22593153","citation_count":33,"is_preprint":false},{"pmid":"29896662","id":"PMC_29896662","title":"Us3 Protein Kinase Encoded by HSV: The Precise Function and Mechanism on Viral Life Cycle.","date":"2018","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/29896662","citation_count":32,"is_preprint":false},{"pmid":"24021814","id":"PMC_24021814","title":"Crystal structure of the yeast ribosomal protein rpS3 in complex with its chaperone Yar1.","date":"2013","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24021814","citation_count":32,"is_preprint":false},{"pmid":"25878107","id":"PMC_25878107","title":"Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25878107","citation_count":32,"is_preprint":false},{"pmid":"23835241","id":"PMC_23835241","title":"Suppression of apoptosis by pseudorabies virus Us3 protein kinase through the activation of PI3-K/Akt and NF-κB pathways.","date":"2013","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/23835241","citation_count":32,"is_preprint":false},{"pmid":"17908985","id":"PMC_17908985","title":"Herpes simplex virus Us3(-) mutant as oncolytic strategy and synergizes with phosphatidylinositol 3-kinase-Akt targeting molecular therapeutics.","date":"2007","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/17908985","citation_count":32,"is_preprint":false},{"pmid":"34935440","id":"PMC_34935440","title":"The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/34935440","citation_count":31,"is_preprint":false},{"pmid":"12067830","id":"PMC_12067830","title":"Herpes simplex virus type 2 US3 blocks apoptosis induced by sorbitol treatment.","date":"2002","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/12067830","citation_count":30,"is_preprint":false},{"pmid":"17634220","id":"PMC_17634220","title":"In transduced cells, the US3 protein kinase of herpes simplex virus 1 precludes activation and induction of apoptosis by transfected procaspase 3.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17634220","citation_count":30,"is_preprint":false},{"pmid":"35858564","id":"PMC_35858564","title":"Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35858564","citation_count":29,"is_preprint":false},{"pmid":"32555320","id":"PMC_32555320","title":"Latexin deficiency in mice up-regulates inflammation and aggravates colitis through HECTD1/Rps3/NF-κB pathway.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32555320","citation_count":29,"is_preprint":false},{"pmid":"29618645","id":"PMC_29618645","title":"Feline Herpesvirus 1 US3 Blocks the Type I Interferon Signal Pathway by Targeting Interferon Regulatory Factor 3 Dimerization in a Kinase-Independent Manner.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29618645","citation_count":29,"is_preprint":false},{"pmid":"28956756","id":"PMC_28956756","title":"ASC1 and RPS3: new actors in 18S nonfunctional rRNA decay.","date":"2017","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28956756","citation_count":28,"is_preprint":false},{"pmid":"27819319","id":"PMC_27819319","title":"Nuclear import of dimerized ribosomal protein Rps3 in complex with its chaperone Yar1.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27819319","citation_count":28,"is_preprint":false},{"pmid":"24352467","id":"PMC_24352467","title":"Phosphorylation of a herpes simplex virus 1 dUTPase by a viral protein kinase, Us3, dictates viral pathogenicity in the central nervous system but not at the periphery.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24352467","citation_count":28,"is_preprint":false},{"pmid":"7788722","id":"PMC_7788722","title":"The rps3-rpl16-nad3-rps12 gene cluster in rice mitochondrial DNA is transcribed from alternative promoters.","date":"1995","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7788722","citation_count":27,"is_preprint":false},{"pmid":"10854163","id":"PMC_10854163","title":"Identification of the US3 gene product of BHV-1 as a protein kinase and characterization of BHV-1 mutants of the US3 gene.","date":"1999","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/10854163","citation_count":27,"is_preprint":false},{"pmid":"23365433","id":"PMC_23365433","title":"Alphaherpesviral US3 kinase induces cofilin dephosphorylation to reorganize the actin cytoskeleton.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23365433","citation_count":26,"is_preprint":false},{"pmid":"32321804","id":"PMC_32321804","title":"Differentiating the Roles of UL16, UL21, and Us3 in the Nuclear Egress of Herpes Simplex Virus Capsids.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32321804","citation_count":25,"is_preprint":false},{"pmid":"19819514","id":"PMC_19819514","title":"Pseudorabies virus US3- and UL49.5-dependent and -independent downregulation of MHC I cell surface expression in different cell types.","date":"2009","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/19819514","citation_count":25,"is_preprint":false},{"pmid":"30475795","id":"PMC_30475795","title":"Interactions between the mRNA and Rps3/uS3 at the entry tunnel of the ribosomal small subunit are important for no-go decay.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30475795","citation_count":24,"is_preprint":false},{"pmid":"30420357","id":"PMC_30420357","title":"Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes.","date":"2019","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30420357","citation_count":24,"is_preprint":false},{"pmid":"14671122","id":"PMC_14671122","title":"Structural and functional analysis of human cytomegalovirus US3 protein.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/14671122","citation_count":24,"is_preprint":false},{"pmid":"34745071","id":"PMC_34745071","title":"Pseudorabies Virus US3 Protein Inhibits IFN-β Production by Interacting With IRF3 to Block Its Activation.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34745071","citation_count":24,"is_preprint":false},{"pmid":"24145029","id":"PMC_24145029","title":"Escherichia coli virulence protein NleH1 interaction with the v-Crk sarcoma virus CT10 oncogene-like protein (CRKL) governs NleH1 inhibition of the ribosomal protein S3 (RPS3)/nuclear factor κB (NF-κB) pathway.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24145029","citation_count":24,"is_preprint":false},{"pmid":"31902487","id":"PMC_31902487","title":"Construction of a US7/US8/UL23/US3-deleted recombinant pseudorabies virus and evaluation of its pathogenicity in dogs.","date":"2019","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31902487","citation_count":24,"is_preprint":false},{"pmid":"16815072","id":"PMC_16815072","title":"Herpes simplex virus US3 protein kinase regulates virus-induced apoptosis in olfactory and vomeronasal chemosensory neurons in vivo.","date":"2006","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/16815072","citation_count":23,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49247,"output_tokens":6929,"usd":0.125838,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15567,"output_tokens":7347,"usd":0.130755,"stage2_stop_reason":"end_turn"},"total_usd":0.256593,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical human/mammalian RPS3 (ribosomal protein S3, also known as uS3) versus papers about the herpes simplex virus US3 kinase, HCMV US3 glycoprotein, and other unrelated genes.\n\nThe HGNC aliases listed include \"uS3\" which is the universal name for ribosomal protein S3. The alias \"US3\" is also listed - however, reviewing the corpus carefully, the vast majority of \"US3\" papers are clearly about the **herpesvirus US3 protein kinase** or **HCMV US3 glycoprotein**, which are viral proteins completely unrelated to the human ribosomal protein RPS3. These are symbol collisions, not orthologs.\n\nPapers genuinely about human/yeast RPS3 (ribosomal protein S3/uS3): 5, 7, 18, 19, 20, 24, 29, 32, 35, 40, 45, 46, 49, 54, 57, 58, 61, 63, 67, 68, 71, 73, 76, 84, 86, 87, 94, 95, 98\n\nI will now extract mechanistic discoveries from these papers only.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"RPS3 induces apoptosis as a third function independent of its DNA repair and ribosomal roles. GFP-rpS3 relocalizes to the nuclear membrane during rpS3-induced apoptosis in lymphocytic cells, and transient expression activates caspase-8/caspase-3 and sensitizes cells to cytokine-induced apoptosis. Deletion analysis showed DNA repair and apoptosis functions use independent domains.\",\n      \"method\": \"GFP fusion live imaging, transient overexpression, caspase activity assays, deletion analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 / Moderate — multiple functional readouts (localization, caspase activation, cytokine sensitization, domain mapping) in a single lab study\",\n      \"pmids\": [\"14988002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IKKβ phosphorylates RPS3 at Ser209, which is required for nuclear translocation of RPS3 and its function as a subunit of NF-κB that directs specific gene transcription. E. coli O157:H7 virulence protein NleH1 specifically inhibits this IKKβ-mediated Ser209 phosphorylation, blocking RPS3 nuclear translocation and NF-κB target gene expression.\",\n      \"method\": \"Phospho-specific mutagenesis, kinase assays, nuclear fractionation, NleH1 bacterial infection model (gnotobiotic piglet), reporter assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct kinase assay identifying phosphorylation site, mutagenesis, fractionation, and in vivo animal model; published in high-quality journal with multiple orthogonal methods\",\n      \"pmids\": [\"21399639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PKCδ phosphorylates RPS3, causing its mobilization from the ribosome to the nucleus for DNA repair. Phosphorylated rpS3 is found only in the non-ribosomal fraction, and its endonuclease activity is increased upon phosphorylation. Knockdown of rpS3 increases sensitivity to genotoxic stress, which is rescued by wild-type but not phosphorylation-defective rpS3.\",\n      \"method\": \"Kinase assay, subcellular fractionation, siRNA knockdown, endonuclease activity assay, rescue experiment with phospho-dead mutant\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase assay, fractionation, functional rescue with mutant; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19059439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"When ROS levels increase, rpS3 accumulates in mitochondria to repair damaged mitochondrial DNA. Nuclear import into mitochondria is regulated by interaction with HSP90 and HSP70 via TOM70. Geldanamycin (HSP90 inhibitor) decreases rpS3–HSP90 interaction and stimulates mitochondrial accumulation of rpS3, which reduces cellular ROS and rescues mtDNA damage.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, pharmacological inhibition (geldanamycin), mtDNA damage assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP for binding partners, fractionation with functional consequence, pharmacological perturbation; single lab\",\n      \"pmids\": [\"23911537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mammalian rpS3 functions as a broad-specificity base-damage endonuclease, cleaving DNA containing AP sites, thymine glycols, pyrimidine dimers, and other UV-damaged lesions. It lacks glycosylase activity but has endonuclease activity on multiple DNA lesions. Its activity is inhibited by MgCl2 on AP DNA but not on UV-irradiated DNA.\",\n      \"method\": \"In vitro endonuclease assay on defined DNA substrates, supercoiled vs. relaxed DNA substrates, MgCl2 inhibition experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro biochemical assay with multiple substrates, single lab, no mutagenesis or structural validation\",\n      \"pmids\": [\"15707971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The ankyrin repeat protein Yar1 (yeast) directly interacts with ribosomal protein Rps3, accompanies newly synthesized Rps3 from cytoplasm to nucleus where it assembles into pre-ribosomal subunits, and protects Rps3 from aggregation in vitro and increases its solubility in vivo. Yar1 acts as a specific chaperone for Rps3.\",\n      \"method\": \"Co-immunoprecipitation, in vitro aggregation assay, yeast genetics (deletion strains, suppression by RPS3 overexpression), 20S pre-rRNA accumulation and 40S export assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated, in vitro aggregation protection, genetic epistasis (suppression), multiple orthogonal methods\",\n      \"pmids\": [\"22570489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of yeast rpS3 in complex with its chaperone Yar1 resolved at 2.8 Å. The structure explains how Yar1 protects rpS3 from aggregation while facilitating nuclear import, and suggests a stepwise exchange of molecular partners during ribosome assembly.\",\n      \"method\": \"X-ray crystallography at 2.8 Å resolution\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional interpretation; single study but highest-quality method\",\n      \"pmids\": [\"24021814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Newly synthesized Rps3 forms a dimer associated with one Yar1 chaperone molecule. Nuclear import of Rps3 proceeds via the classical importin α/β (Kap60/Kap95) pathway, which recognizes an N-terminal NLS in Rps3 directly adjacent to the Yar1-binding site. Kap60 binding to the Rps3 NLS displaces Yar1 in vitro, yet a trimeric Rps3/Yar1/Kap60 complex can be reconstituted in vitro and is detected in vivo.\",\n      \"method\": \"In vitro reconstitution of protein complexes, pull-down assays, affinity purifications, NLS mapping by mutagenesis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution of trimeric complex, mutagenesis of NLS, multiple orthogonal binding assays\",\n      \"pmids\": [\"27819319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yar1 (yeast) physically interacts with Rps3 and with Ltv1 (a pre-40S particle component). Genetic and biochemical evidence shows Yar1 and Ltv1 function in 40S subunit production. Overexpression of RPS3 suppresses stress sensitivity and ribosome biogenesis defects of Δyar1 but not Δltv1 mutants, placing Yar1 upstream of/at Rps3 in the assembly pathway.\",\n      \"method\": \"Co-immunoprecipitation, yeast genetic epistasis (suppression by RPS3 overexpression), polysome profiling\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, genetic suppression, polysome profiling; single lab with multiple methods\",\n      \"pmids\": [\"15611164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rps3/uS3 resides in the mRNA entry channel of the 40S subunit and contacts mRNA via conserved residues Arg116 and Arg117. Substitutions at these residues reduce bulk translation initiation, diminish near-cognate UUG start codon selection, and increase discrimination against AUG in poor Kozak context. In vitro reconstitution showed these residues stabilize TC binding to 48S PICs with UUG codons (closed PIN state), and Arg116/117 are crucial for PIC-mRNA contacts at the entry channel.\",\n      \"method\": \"In vitro reconstitution of 48S PICs, yeast genetics (UUG selection assays), mutagenesis of conserved residues, translation initiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined mutants, multiple genetic readouts, mechanistic link to specific residues\",\n      \"pmids\": [\"28223523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RPS3 is the major TISU-element binding protein at the A site of the 48S ribosomal complex. Upon 80S complex formation, RPS3 interaction weakens and binding switches to RPS10e. TISU-directed translation initiation is particularly dependent on eIF1A, which interacts with both RPS3 and RPS10e.\",\n      \"method\": \"Site-specific UV cross-linking of ribosomal complexes assembled on TISU mRNA, comprehensive mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — UV cross-linking directly identifies RPS3 as A-site contact protein, single lab\",\n      \"pmids\": [\"28584194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rps3/uS3 acts with Mbf1 and Asc1/RACK1 to prevent +1 frameshifting at inhibitory CGA-CGA codon pairs in yeast. Mutations in RPS3 near the mRNA entry site allow frameshifting. Mbf1 and Rps3 cooperate to maintain reading frame of stalled ribosomes. Frameshifting involves competition between codons entering the A site when the P-site CGA codon destabilizes elongation.\",\n      \"method\": \"Yeast genetic analysis, frameshifting reporter assays, double mutant analysis (epistasis)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple mutants, functional reporter assays; single lab\",\n      \"pmids\": [\"30465652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sequential ubiquitination of uS3/Rps3 at lysine 212 is required for 18S non-functional rRNA decay (NRD). Mag2-mediated monoubiquitination followed by Hel2- and Rsp5-mediated K63-linked polyubiquitination triggers dissociation of the non-functional 80S ribosome into subunits, which requires the ATPase activity of Slh1 (Rqt2), as well as Asc1 and Dom34.\",\n      \"method\": \"Yeast genetics, sucrose gradient fractionation, ubiquitination site mapping (K212), E3 ligase deletion mutants, ATPase mutant analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific ubiquitination site identified, multiple E3 ligase mutants tested, functional dissociation assay, replicated with multiple genetic perturbations\",\n      \"pmids\": [\"30893611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The balance of Rps3 mono-ubiquitination is controlled by reciprocal action of Hel2 E3 ligase (ubiquitination) and Ubp3 deubiquitinase (deubiquitination) in yeast, and their mammalian counterparts RNF123 and USP10 in mammalian cells. Rps3 mono-ubiquitination is coupled to ribosome quality control and autophagy.\",\n      \"method\": \"Co-immunoprecipitation, yeast genetic analysis, ubiquitination assays, autophagosome localization\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, genetic analysis, and localization; single lab with multiple approaches\",\n      \"pmids\": [\"29147007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Asc1/RACK1 and Rps3 are factors in 18S nonfunctional rRNA decay (NRD) in yeast. A small region of the Rps3 C-terminal tail subject to post-translational modification is crucial for 18S NRD. Complete stabilization of mutant 18S rRNA occurs in dom34Δ;asc1Δ double mutants, indicating two genetically separable NRD pathways.\",\n      \"method\": \"Yeast genetic analysis, Northern blot for mutant 18S rRNA levels, epistasis in double mutants\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis, direct measurement of rRNA stability, C-terminal tail PTM mapping; single lab\",\n      \"pmids\": [\"28956756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Residues of Rps3 at the mRNA entry tunnel of the ribosomal small subunit are important for No-Go Decay (NGD). Mutations in these entry-channel contact residues significantly reduce accumulation of NGD cleavage products, render cells sensitive to NGD-triggering agents, and are distinct from effects on ribosome ubiquitination, suggesting Rps3 plays a role in the endonucleolytic cleavage step of NGD independent of upstream RQC events.\",\n      \"method\": \"Yeast genetics with site-directed mutagenesis of mRNA-contact residues, NGD reporter assay, cleavage product Northern blot, sensitivity assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutagenesis, functional NGD reporter, multiple genetic backgrounds tested; single lab\",\n      \"pmids\": [\"30475795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RPS3 functions as an RNA-binding protein that stabilizes SIRT1 mRNA post-transcriptionally by binding to AUUUA motifs in the 3' UTR (positions 3448-3530) of SIRT1 mRNA, thereby promoting HCC tumorigenesis.\",\n      \"method\": \"RNA-seq, RIP (RNA immunoprecipitation), gain/loss-of-function assays, 3' UTR binding site mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RIP demonstrating binding, specific binding site mapping, functional consequence via gain/loss of function; single lab\",\n      \"pmids\": [\"30517713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NleC metalloprotease of A/E pathogens cleaves p65, generating a p65(1-38) fragment that interferes with the interaction between p65 and RPS3, disrupting RPS3's role as a 'specifier' subunit of NF-κB for proinflammatory gene transcription. This amplifies the effect of cleaving a small percentage of p65.\",\n      \"method\": \"Co-immunoprecipitation, cleavage assays, mouse infection model (C. rodentium), NF-κB reporter assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating p65–RPS3 interaction disruption, in vivo mouse infection model, mechanistic cleavage assays; single lab\",\n      \"pmids\": [\"25756944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E. coli NleH1 virulence effector prevents nuclear translocation of RPS3 to inhibit NF-κB by binding to CRKL, which interacts with IKKβ. NleH1 kinase activity is required to phosphorylate CRKL, and CRKL knockdown prevents NleH1 from inhibiting RPS3 nuclear translocation. Neither RPS3 nor IKKβ is a direct NleH1 kinase substrate.\",\n      \"method\": \"Large-scale kinase substrate screen (~9,000 proteins), co-immunoprecipitation, siRNA knockdown, nuclear fractionation, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate screen, co-IP, knockdown rescue, mutagenesis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24145029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNF138 E3 ubiquitin ligase ubiquitinates nuclear rpS3 in irradiated GBM cells, leading to ubiquitin-dependent degradation of rpS3 and consequent radioresistance. In ΔRNF138 cells, nuclear rpS3 accumulates and interacts with DDIT3, leading to DDIT3-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, interactome analysis, RNF138 knockout, in vivo xenograft model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, KO with defined phenotype, in vivo validation; single lab\",\n      \"pmids\": [\"29371697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The E2-E3 ubiquitin complex UBE2J1-TRIM25 physically interacts with RPS3 and targets it for poly-ubiquitination and degradation at the K214 residue, leading to reduced RPS3 levels, restraint of NF-κB nuclear translocation, and inactivation of NF-κB signaling in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K214), overexpression/knockdown with NF-κB pathway readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination site identification (K214), co-IP of E2-E3-substrate complex, functional NF-κB readout; single lab\",\n      \"pmids\": [\"36567344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"circPLCE1-encoded protein circPLCE1-411 promotes ubiquitin-dependent degradation of RPS3 by binding to the HSP90α/RPS3 complex and facilitating dissociation of RPS3 from HSP90α, thereby reducing NF-κB nuclear translocation in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS protein identification, gain/loss of function assays, in vivo xenograft model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP showing complex disruption, LC-MS identification, functional in vivo validation; single lab\",\n      \"pmids\": [\"34412652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Latexin (LXN) forms a functional complex with HECTD1 (E3 ubiquitin ligase) and Rps3. LXN deficiency enhances the HECTD1–Rps3 interaction, promoting ubiquitination and degradation of IκBα (a HECTD1 substrate), thereby enhancing NF-κB inflammatory responses. Ectopic LXN expression leads to IκBα accumulation.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, IκBα ubiquitination assay, LXN knockout mouse model (DSS-colitis)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — proteomics-identified complex, co-IP, ubiquitination assay, in vivo colitis model; single lab\",\n      \"pmids\": [\"32555320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPS3 physically interacts with MIF (macrophage migration inhibitory factor) under unirradiated conditions. Ionizing radiation induces dissociation of the MIF-rpS3 complex, activating NF-κB and its target genes. MIF-rpS3 dissociation also modulates epithelial-mesenchymal transition marker expression and pro-inflammatory cytokine secretion.\",\n      \"method\": \"Co-immunoprecipitation, xenograft tumor model, NF-κB reporter assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP demonstrating complex and its IR-induced disruption, limited mechanistic follow-up on how dissociation activates NF-κB\",\n      \"pmids\": [\"25900216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LCN2 promotes NF-κB activation by binding to RPS3 and enhancing the interaction between RPS3 and p65 in oral squamous cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, LCN2 overexpression/knockdown, NF-κB activity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, single lab, limited mechanistic detail on how LCN2-RPS3 interaction enhances p65 binding\",\n      \"pmids\": [\"31819048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cancer-associated eIF1A N-terminal tail mutations diminish eIF1A interaction with RPS3 and RPS10, retaining the ribosome in an open state that facilitates scanning of long 5' UTR-containing cell cycle genes.\",\n      \"method\": \"Co-immunoprecipitation, ribosome profiling, eIF1A knockdown/mutation, reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP demonstrating eIF1A–RPS3 interaction, functional ribosome profiling, mutagenesis; single lab\",\n      \"pmids\": [\"30420357\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPS3 (uS3) is a multifunctional ribosomal protein of the 40S small subunit that contacts mRNA at the entry channel to stabilize preinitiation complexes and promote accurate start codon selection; outside the ribosome it acts as a DNA damage endonuclease (switched to this role by PKCδ-dependent phosphorylation), serves as a nuclear 'specifier' subunit of NF-κB whose nuclear translocation is gated by IKKβ-mediated phosphorylation at Ser209, participates in ribosome quality control through sequential ubiquitination (monoubiquitination by Hel2/RNF123 balanced by Ubp3/USP10 deubiquitinase, followed by K63-polyubiquitination to trigger 18S NRD subunit dissociation), is chaperoned from cytoplasm to nucleus by Yar1 (whose crystal structure with RPS3 has been solved), and undergoes ubiquitin-dependent degradation by UBE2J1-TRIM25 (at K214) or RNF138 to modulate NF-κB signaling and apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPS3 (uS3) is a multifunctional protein of the 40S small ribosomal subunit that contributes both to canonical translation and to a set of moonlighting roles in DNA repair, ribosome quality control, and NF-\\u03baB signaling [#9, #1, #12]. Within the ribosome it occupies the mRNA entry channel, where conserved residues Arg116/Arg117 stabilize mRNA contacts and tune translation initiation: their substitution reduces bulk initiation, alters near-cognate UUG start codon selection, and shifts discrimination against poorly contexted AUG codons [#9]. It also contacts mRNA at the A site of the 48S complex as the major TISU-element binding protein, an interaction coordinated with eIF1A and handed off to RPS10e upon 80S formation [#10, #25]. Through these entry-channel contacts RPS3 maintains translational fidelity, preventing +1 frameshifting at inhibitory codon pairs together with Mbf1 and Asc1/RACK1 [#11] and participating in No-Go Decay endonucleolytic cleavage [#15]. RPS3 is a target of ribosome quality control: sequential ubiquitination at lysine 212 \\u2014 monoubiquitination followed by Hel2/Rsp5-mediated K63-linked polyubiquitination, balanced by the Ubp3/USP10 (mammalian RNF123/USP10) deubiquitinase axis \\u2014 triggers dissociation of nonfunctional 80S ribosomes during 18S nonfunctional rRNA decay [#12, #13, #14]. Biogenesis of RPS3 depends on the ankyrin-repeat chaperone Yar1, which binds nascent Rps3, prevents its aggregation, and accompanies it to the nucleus, with import proceeding via the importin \\u03b1/\\u03b2 pathway recognizing an N-terminal NLS adjacent to the Yar1-binding site [#5, #6, #7]. Outside the ribosome, RPS3 acts as a base-damage endonuclease cleaving AP sites, thymine glycols, and UV lesions [#4], a role mobilized by PKC\\u03b4-dependent phosphorylation that relocalizes it from the ribosome to repair nuclear and (under ROS, via HSP90/HSP70/TOM70) mitochondrial DNA [#2, #3]. As a 'specifier' subunit of NF-\\u03baB, RPS3 directs p65 to specific proinflammatory target genes; its nuclear translocation requires IKK\\u03b2-mediated phosphorylation at Ser209, a step targeted by bacterial effectors NleH1 and NleC [#1, #17, #18]. RPS3 abundance and signaling output are further controlled by ubiquitin-dependent degradation through UBE2J1-TRIM25 (at K214) and RNF138, modulating NF-\\u03baB activity and apoptosis [#20, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that RPS3 carries an apoptotic function genetically separable from its ribosomal and DNA-repair roles, first framing RPS3 as a multifunctional protein.\",\n      \"evidence\": \"GFP-fusion imaging, overexpression with caspase activity assays, and domain deletion mapping in lymphocytic cells\",\n      \"pmids\": [\"14988002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking nuclear-membrane relocalization to caspase-8/3 activation not defined\", \"Physiological trigger for the apoptotic function not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that RPS3 has intrinsic broad-specificity DNA endonuclease activity, providing the biochemical basis for its non-ribosomal DNA-repair role.\",\n      \"evidence\": \"In vitro endonuclease assays on defined AP, thymine glycol, and UV-damaged DNA substrates\",\n      \"pmids\": [\"15707971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic residue identified by mutagenesis\", \"No structural model of the active site\", \"In vivo contribution to repair not established here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that PKC\\u03b4 phosphorylation switches RPS3 from a ribosomal to a DNA-repair function by mobilizing it to the nucleus and enhancing endonuclease activity.\",\n      \"evidence\": \"Kinase assay, subcellular fractionation, siRNA knockdown with phospho-dead mutant rescue against genotoxic stress\",\n      \"pmids\": [\"19059439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite not mapped\", \"Quantitative partition between ribosomal and nuclear pools not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the repair role to mitochondria, showing ROS-driven mitochondrial accumulation of RPS3 regulated by an HSP90/HSP70-TOM70 import axis.\",\n      \"evidence\": \"Co-IP, fractionation, geldanamycin inhibition, and mtDNA damage assays\",\n      \"pmids\": [\"23911537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mtDNA endonuclease activity in organello not shown\", \"Relationship to nuclear repair pool unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified IKK\\u03b2 phosphorylation of RPS3 at Ser209 as the gate for its nuclear translocation and function as an NF-\\u03baB specifier subunit directing gene-specific transcription.\",\n      \"evidence\": \"Phospho-specific mutagenesis, kinase assays, nuclear fractionation, gnotobiotic piglet infection with NleH1, reporter assays\",\n      \"pmids\": [\"21399639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RPS3 confers promoter specificity to NF-\\u03baB not mechanistically resolved\", \"Generality across stimuli beyond infection not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the chaperone Yar1 as a dedicated escort for Rps3 in 40S biogenesis, placing it in the ribosome assembly pathway alongside Ltv1.\",\n      \"evidence\": \"Reciprocal co-IP, genetic suppression by RPS3 overexpression, polysome profiling in yeast\",\n      \"pmids\": [\"15611164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order of Yar1 vs Ltv1 action only inferred genetically\", \"Structural basis of binding not addressed here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed Yar1 directly binds Rps3, protects it from aggregation, and accompanies it from cytoplasm to nucleus, defining it as a specific Rps3 chaperone.\",\n      \"evidence\": \"Co-IP, in vitro aggregation assays, yeast deletion/suppression genetics, pre-rRNA and 40S export assays\",\n      \"pmids\": [\"22570489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hand-off from Yar1 to nuclear assembly factors not yet defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis for Yar1-mediated protection of Rps3 and stepwise partner exchange during assembly.\",\n      \"evidence\": \"X-ray crystallography of the yeast Rps3\\u2013Yar1 complex at 2.8 \\u00c5\",\n      \"pmids\": [\"24021814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of import-competent intermediates absent\", \"No human RPS3 structure in this context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the import logic, showing the importin \\u03b1/\\u03b2 pathway recognizes an Rps3 NLS adjacent to the Yar1 site, with Kap60 displacing Yar1 yet a trimeric complex being possible.\",\n      \"evidence\": \"In vitro reconstitution, pull-downs, affinity purification, and NLS mutagenesis\",\n      \"pmids\": [\"27819319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo sequence of Yar1 release versus import not directly timed\", \"Dimerization functional significance unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Pinpointed Rps3 entry-channel residues Arg116/Arg117 as direct mRNA contacts that govern start codon selection accuracy and PIC stabilization.\",\n      \"evidence\": \"In vitro 48S PIC reconstitution, UUG-selection genetics, and conserved-residue mutagenesis\",\n      \"pmids\": [\"28223523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution to scanning dynamics in vivo not fully quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified RPS3 as the major TISU-element A-site contact protein, coordinated with eIF1A and exchanged for RPS10e upon 80S assembly.\",\n      \"evidence\": \"Site-specific UV cross-linking of complexes on TISU mRNA and mutagenesis\",\n      \"pmids\": [\"28584194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the RPS3\\u2192RPS10e switch unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that eIF1A's interaction with RPS3 (and RPS10) sets the ribosome's open/closed conformational state, with cancer eIF1A mutations weakening this contact to favor scanning of long 5' UTRs.\",\n      \"evidence\": \"Co-IP, ribosome profiling, eIF1A mutation/knockdown, reporter assays\",\n      \"pmids\": [\"30420357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct conformational measurement of RPS3 contact not performed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that entry-tunnel Rps3 residues mediate the endonucleolytic cleavage step of No-Go Decay, separable from ribosome ubiquitination.\",\n      \"evidence\": \"Structure-guided mutagenesis, NGD reporter, cleavage-product Northern blot, sensitivity assays in yeast\",\n      \"pmids\": [\"30475795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Rps3 itself catalyzes cleavage or recruits a nuclease unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that Rps3 maintains reading frame at inhibitory codon pairs, acting with Mbf1 and Asc1/RACK1 to suppress +1 frameshifting.\",\n      \"evidence\": \"Yeast genetics, frameshifting reporters, double-mutant epistasis\",\n      \"pmids\": [\"30465652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of frame maintenance at the entry site not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected Rps3 ubiquitination to quality control, defining a Hel2/RNF123 (ubiquitination) versus Ubp3/USP10 (deubiquitination) balance coupled to RQC and autophagy.\",\n      \"evidence\": \"Co-IP, yeast genetics, ubiquitination assays, autophagosome localization across yeast and mammalian cells\",\n      \"pmids\": [\"29147007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional outcome of the autophagy link not fully defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed Rps3 within the 18S nonfunctional rRNA decay machinery via its modified C-terminal tail, alongside Asc1/RACK1 in genetically separable NRD pathways.\",\n      \"evidence\": \"Yeast genetics, Northern blot of mutant 18S rRNA, double-mutant epistasis\",\n      \"pmids\": [\"28956756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the C-terminal modification not determined here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the molecular trigger of 18S NRD: sequential ubiquitination of Rps3 at K212 drives ATPase-dependent dissociation of nonfunctional ribosomes.\",\n      \"evidence\": \"Yeast genetics, sucrose gradient fractionation, K212 site mapping, E3-ligase and Slh1 ATPase mutants\",\n      \"pmids\": [\"30893611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how K212 ubiquitin signals subunit splitting unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-ribosomal RNA-binding role: RPS3 stabilizes SIRT1 mRNA via 3' UTR AUUUA motifs to promote hepatocellular carcinoma.\",\n      \"evidence\": \"RNA-seq, RIP, binding-site mapping, gain/loss-of-function assays\",\n      \"pmids\": [\"30517713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breadth of RPS3-stabilized mRNA targets not defined\", \"Link to ribosomal pool unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed bacterial NleC indirectly disrupts RPS3's NF-\\u03baB specifier function by cleaving p65 to a fragment that blocks the p65\\u2013RPS3 interaction.\",\n      \"evidence\": \"Co-IP, cleavage assays, C. rodentium mouse infection, NF-\\u03baB reporters\",\n      \"pmids\": [\"25756944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometric basis of amplification not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined how NleH1 inhibits RPS3 nuclear translocation by acting through CRKL\\u2013IKK\\u03b2 rather than directly phosphorylating RPS3 or IKK\\u03b2.\",\n      \"evidence\": \"Large-scale kinase substrate screen, co-IP, siRNA rescue, fractionation, mutagenesis\",\n      \"pmids\": [\"24145029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CRKL phosphorylation feeds into IKK\\u03b2 activity not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Suggested an MIF\\u2013RPS3 complex sequesters RPS3, with ionizing radiation triggering dissociation to activate NF-\\u03baB.\",\n      \"evidence\": \"Co-IP, xenograft model, NF-\\u03baB reporters\",\n      \"pmids\": [\"25900216\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single co-IP without reciprocal validation of the dissociation mechanism\", \"How dissociation mechanistically activates NF-\\u03baB unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Suggested LCN2 enhances NF-\\u03baB by binding RPS3 and strengthening RPS3\\u2013p65 interaction in oral cancer cells.\",\n      \"evidence\": \"Co-IP, LCN2 overexpression/knockdown, NF-\\u03baB activity assay\",\n      \"pmids\": [\"31819048\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single co-IP with limited mechanistic detail on how binding enhances p65 association\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified RNF138 as an E3 ligase that degrades nuclear rpS3 to confer radioresistance, with rpS3 otherwise driving DDIT3-dependent apoptosis.\",\n      \"evidence\": \"Co-IP, interactome analysis, RNF138 knockout, xenograft model in GBM\",\n      \"pmids\": [\"29371697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on rpS3 not mapped here\", \"Mechanism of rpS3\\u2013DDIT3 apoptosis not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed Rps3 in a LXN\\u2013HECTD1 complex regulating I\\u03baB\\u03b1 turnover and thereby NF-\\u03baB inflammatory output.\",\n      \"evidence\": \"Proteomics, co-IP, I\\u03baB\\u03b1 ubiquitination assay, LXN-knockout colitis mouse model\",\n      \"pmids\": [\"32555320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of Rps3 versus HECTD1 in I\\u03baB\\u03b1 ubiquitination not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed circPLCE1-411 promotes RPS3 degradation by displacing it from HSP90\\u03b1, dampening NF-\\u03baB nuclear translocation in colorectal cancer.\",\n      \"evidence\": \"Co-IP, LC-MS identification, gain/loss-of-function, xenograft model\",\n      \"pmids\": [\"34412652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating the degradation not identified here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined UBE2J1-TRIM25 as an E2-E3 pair that polyubiquitinates RPS3 at K214 for degradation, restraining NF-\\u03baB signaling in colorectal cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, K214 mutagenesis, NF-\\u03baB pathway readouts\",\n      \"pmids\": [\"36567344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between K214 (degradation) and K212/K214 RQC ubiquitination not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RPS3's distinct functional pools \\u2014 ribosomal, DNA-repair endonuclease, NF-\\u03baB specifier, and mRNA stabilizer \\u2014 are quantitatively partitioned and coordinately regulated within a cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating phosphorylation, ubiquitination, and partner-binding switches\", \"Catalytic residues of the DNA endonuclease activity not defined\", \"Structural basis of the NF-\\u03baB specifier role missing\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 10, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [4, 15]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 17]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 5, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [12, 13, 14, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 17, 20]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 17, 22]}\n    ],\n    \"complexes\": [\n      \"40S ribosomal small subunit\",\n      \"NF-\\u03baB (p65-RPS3 specifier complex)\",\n      \"RPS3-Yar1 chaperone complex\",\n      \"UBE2J1-TRIM25 E2-E3 complex\"\n    ],\n    \"partners\": [\n      \"YAR1\",\n      \"RELA\",\n      \"IKBKB\",\n      \"EIF1AX\",\n      \"HSP90AA1\",\n      \"TRIM25\",\n      \"RNF138\",\n      \"HECTD1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}