{"gene":"SLIRP","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2006,"finding":"SLIRP was identified as an RNA-binding protein containing an RRM domain that binds the STR7 stem-loop substructure of the noncoding RNA SRA (Steroid Receptor RNA Activator), represses nuclear receptor (NR) transactivation in an RRM- and SRA-dependent manner, augments tamoxifen's effect, and modulates SRC-1 association with SRA. SLIRP also colocalizes with the NR coregulator SKIP and reduces SKIP-potentiated NR signaling. SLIRP is recruited to endogenous NR target gene promoters (pS2 and metallothionein), and NCoR promoter recruitment is dependent on SLIRP. The majority of endogenous SLIRP resides in mitochondria.","method":"RNA-binding assays, co-immunoprecipitation, reporter gene assays with RRM mutants, ChIP at endogenous promoters, subcellular fractionation/immunofluorescence","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RRM mutagenesis, co-IP, ChIP, reporter assays) in a focused study; findings replicated by subsequent work","pmids":["16762838"],"is_preprint":false},{"year":2009,"finding":"RNAi-mediated silencing of SLIRP destabilizes oxidative phosphorylation (OxPhos) complexes, causes marked loss of OxPhos enzymatic activity, and results in reduced steady-state levels of mitochondria-encoded mRNAs that encode OxPhos subunits, establishing an essential role for SLIRP in maintaining mitochondrial mRNA homeostasis.","method":"RNAi knockdown in human cells, OxPhos enzymatic activity assays, mitochondrial mRNA quantification","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi knockdown with two independent functional readouts (enzymatic activity and mRNA levels), single lab","pmids":["19680543"],"is_preprint":false},{"year":2012,"finding":"The LRPPRC/SLIRP complex cotranscriptionally binds to coding sequences of mitochondrial mRNAs, suppresses 3′ exonucleolytic mRNA degradation mediated by PNPase/SUV3, and LRPPRC promotes polyadenylation of mtRNAs by mitochondrial poly(A) polymerase (MTPAP) in vitro, thereby stabilizing mitochondrial mRNAs and correlating with their longer cellular half-lives.","method":"Absolute quantification of mitochondrial mRNAs, in vitro polyadenylation assay with MTPAP, RNAi knockdown of complex components, RNA-binding experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical reconstitution of polyadenylation, mRNA quantification, and degradation assays; replicated across multiple studies","pmids":["22661577"],"is_preprint":false},{"year":2015,"finding":"In vivo knockout of Slirp in mice shows: (1) SLIRP stabilizes LRPPRC by protecting it from proteolytic degradation; (2) SLIRP's own stability is completely dependent on LRPPRC; (3) SLIRP is dispensable for polyadenylation of mtDNA-encoded mRNAs (distinct from LRPPRC); (4) SLIRP is required for proper association of mitochondrial mRNAs with the mitoribosome and efficient mitochondrial translation, as shown by deep RNAseq of ribosomal fractions.","method":"Slirp knockout mice, deep RNA sequencing of mitoribosomal fractions, pulse-labeling of mitochondrial translation products, polyadenylation assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal readouts (RNAseq, translation labeling, polyadenylation assays); replicated by subsequent studies","pmids":["26247782"],"is_preprint":false},{"year":2016,"finding":"The LRPPRC-SLIRP heterodimer interface is formed by polar amino acids in SLIRP's single RRM domain (specifically the RNP1 motif) and three neighboring PPR motifs in the second quarter of LRPPRC; unexpectedly, residues predicted to contact RNA in both proteins are instead used for protein-protein interaction. LRPPRC displays broad strong RNA-binding capacity in vitro, whereas SLIRP associates only weakly with RNA.","method":"In vitro RNA-binding assays, mutagenesis of RRM and PPR interface residues, protein-protein interaction studies, complex stability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis of specific interface residues combined with RNA-binding reconstitution; single lab but multiple orthogonal methods","pmids":["27353330"],"is_preprint":false},{"year":2016,"finding":"SLIRP interacts with BCL-2; BCL-2 binds and stabilizes SLIRP protein and regulates mitochondrial mRNA levels. The BH4 domain of BCL-2 is required for maintaining this binding. SLIRP is not involved in mediating BCL-2's protection from apoptosis or oxidative damage.","method":"Affinity purification-mass spectrometry, co-immunoprecipitation with domain deletion mutants, immunofluorescence co-localization","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal co-IP with domain mapping and MS identification, single lab","pmids":["26866271"],"is_preprint":false},{"year":2017,"finding":"SLIRP was identified as a novel G-quadruplex (G4) DNA-binding protein. SLIRP binds G4 DNA directly with Kd values in the low nanomolar range; this binding requires the RRM domain. ChIP-Seq (using CRISPR-Cas9-introduced affinity tag) showed that SLIRP preferentially occupies G-rich genomic regions that can fold into G4 structures.","method":"Quantitative mass spectrometry-based G4-interaction proteomics, in vitro binding assays with Kd measurement, RRM domain mutagenesis, CRISPR-Cas9 affinity tagging + ChIP-Seq","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro Kd measurement with mutagenesis plus genome-wide ChIP-Seq; multiple orthogonal methods in one study","pmids":["28859475"],"is_preprint":false},{"year":2019,"finding":"SLIRP interacts with the majority of the human helicase proteome; these interactions facilitate 2′-O-methylation of nucleosides in rRNA and promote protein translation. SLIRP thus functions as an RNA chaperone.","method":"Quantitative proteomics (interaction screen), 2′-O-methylation mapping of rRNA, translation efficiency assays","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — quantitative proteomic interaction screen with functional methylation and translation readouts; single lab","pmids":["31260285"],"is_preprint":false},{"year":2019,"finding":"Ack1 tyrosine kinase phosphorylation of AR at Tyr-267 disrupts the AR-SLIRP interaction. The noncoding RNA SRA is required for the AR-SLIRP interaction. SLIRP is bound to androgen response elements (AREs) of AR target genes in the absence of androgen, and androgen or heregulin treatment causes SLIRP dissociation from AREs. Whole-transcriptome analysis shows SLIRP knockdown affects a significant subset of androgen-regulated genes, consistent with a corepressor role for SLIRP on AR.","method":"Co-immunoprecipitation, ChIP at endogenous AREs, kinase inhibitor and ligand treatments, transcriptome analysis after SLIRP knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP with pharmacological and genetic perturbations; single lab, multiple readouts","pmids":["31819114"],"is_preprint":false},{"year":2023,"finding":"Deletion of SLIRP in HEK293T cells disturbs mitochondrial translation specifically affecting complexes I and IV but not complexes III and V. SLIRP interacts only with the small subunit (mt-SSU) of the mitochondrial ribosome, suggesting involvement in mitochondrial translation initiation.","method":"SLIRP gene deletion (CRISPR), click-chemistry-based mitochondrial translation labeling, ribosome subunit co-immunoprecipitation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with translation labeling and ribosome co-IP; single lab","pmids":["38203264"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of the LRPPRC-SLIRP complex bound to mRNA and the mitoribosome shows: LRPPRC associates with mitoribosomal proteins mS39 and the N-terminus of mS31 through its helical repeats, forming a corridor for mRNA handoff to the ribosome. SLIRP directly binds the mRNA and also stabilizes LRPPRC. Mitoribosome profiling demonstrated transcript-specific effects on translation efficiency, with COX1 and COX2 translation most affected.","method":"Cryo-EM structure determination, RNA sequencing, metabolic labeling, mitoribosome profiling","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation by ribosome profiling and metabolic labeling; multiple orthogonal methods in one study","pmids":["39134711"],"is_preprint":false},{"year":2024,"finding":"Loss of SLIRP in mice causes selective decrease in complex I levels while other OXPHOS complexes are unaffected. Knock-in mice with mutations disrupting the LRPPRC-SLIRP protein interface show partial LRPPRC degradation, complete SLIRP loss, and impaired mitochondrial translation except for a marked increase in ATP8 synthesis. Combining Slirp knockout with a heteroplasmic pathogenic mtDNA mutation (m.C5024T in tRNAAla) causes additive mitochondrial translation defects leading to embryonic lethality.","method":"Slirp knockout mice, LRPPRC interface knock-in mice, mitochondrial translation labeling, mtDNA heteroplasmy crosses, mouse embryonic fibroblast growth assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo genetic models with defined translation readouts; replicated across multiple mouse lines","pmids":["39087558"],"is_preprint":false},{"year":2024,"finding":"In skeletal muscle, SLIRP (in complex with LRPPRC) is a PGC-1α transcriptional target that regulates mitochondrial structure, respiration, and mtDNA-encoded mRNA pools. Exercise training counteracts mitochondrial defects from LRPPRC/SLIRP loss by increasing mitoribosome translation capacity and mitochondrial quality control, despite sustained low mtDNA-encoded mRNA levels.","method":"Muscle-specific Slirp/Lrpprc knockout mice, exercise training intervention, mitoribosome profiling, respiration assays, Drosophila lifespan assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with multiple functional readouts and cross-species validation; single consortium but multiple approaches","pmids":["39537626"],"is_preprint":false},{"year":2025,"finding":"SLIRP stabilizes mitochondrial double-stranded RNAs (mt-dsRNAs) and promotes their cytosolic release, creating a positive feedback loop: exogenous dsRNA activates MDA5, which upregulates SLIRP, which stabilizes mt-dsRNAs and elevates their cytosolic levels to further activate MDA5 and amplify the interferon response. SLIRP knockdown dampens the interferon response and reduces mt-dsRNA cytosolic levels.","method":"SLIRP knockdown in cell lines and primary patient cells, mt-dsRNA quantification, MDA5 pathway reporter assays, interferon-stimulated gene expression analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with dsRNA quantification and pathway readouts; peer-reviewed; single lab","pmids":["40253699"],"is_preprint":false}],"current_model":"SLIRP is a mitochondrial RNA-binding protein (RRM domain) that forms a stable heterodimer with LRPPRC (via an RRM-PPR protein interface) to cotranscriptionally stabilize mitochondrial mRNAs by suppressing 3′ exonucleolytic degradation; cryo-EM structural work shows that the LRPPRC-SLIRP complex docks onto the mitoribosome (via mS39/mS31) and hands off mRNA directly to the small subunit for translation, with SLIRP also protecting LRPPRC from degradation, interacting with the mt-SSU, facilitating rRNA 2′-O-methylation through helicase interactions, and amplifying innate immune interferon signaling via cytosolic mt-dsRNA stabilization; in the nucleus, SLIRP binds the SRA noncoding RNA and acts as a corepressor of nuclear receptor (including androgen receptor) transactivation in a SRA- and RRM-dependent manner, with its nuclear recruitment and chromatin binding regulated by Ack1-mediated AR phosphorylation and androgen signaling."},"narrative":{"mechanistic_narrative":"SLIRP is a small RRM-domain RNA-binding protein that functions principally in mitochondrial gene expression, where it forms a stable heterodimer with LRPPRC to maintain the steady-state pool of mtDNA-encoded mRNAs and support oxidative phosphorylation [PMID:19680543, PMID:22661577]. The complex binds cotranscriptionally to mitochondrial mRNA coding sequences and suppresses 3′ exonucleolytic degradation by PNPase/SUV3, thereby extending transcript half-life [PMID:22661577]. Within the heterodimer, the partnership is built on an unexpected protein-protein interface: polar residues of SLIRP's RNP1 motif engage three PPR motifs of LRPPRC, repurposing surfaces predicted to bind RNA, so that LRPPRC carries the strong RNA-binding activity while SLIRP binds RNA only weakly and reciprocally protects LRPPRC from proteolysis [PMID:26247782, PMID:27353330]. Beyond stabilization, SLIRP is required for efficient mitochondrial translation—it loads mRNAs onto the mitoribosome and associates with the small subunit, and cryo-EM shows the LRPPRC-SLIRP complex docking onto the mitoribosome via mS39/mS31 to form a corridor that hands mRNA off to the small subunit, with transcript-specific effects on COX1, COX2, and complex I/IV biogenesis [PMID:26247782, PMID:38203264, PMID:39134711, PMID:39087558]. In skeletal muscle, SLIRP is a PGC-1α transcriptional target that couples mitochondrial biogenesis to the mtDNA-encoded mRNA pool [PMID:39537626]. Independently of its mitochondrial role, SLIRP binds the noncoding RNA SRA and acts as a corepressor of nuclear receptor transactivation, including the androgen receptor, in an RRM- and SRA-dependent manner; its occupancy at androgen response elements is released upon androgen signaling and disrupted by Ack1-mediated AR phosphorylation [PMID:16762838, PMID:31819114]. SLIRP also stabilizes mitochondrial double-stranded RNA and promotes its cytosolic release to amplify MDA5-driven interferon responses [PMID:40253699].","teleology":[{"year":2006,"claim":"Established SLIRP's first molecular identity by showing it is an RRM protein that binds the SRA noncoding RNA and represses nuclear receptor transactivation, defining an unexpected nuclear corepressor role while noting most of the protein is mitochondrial.","evidence":"RNA-binding assays, co-IP, reporter assays with RRM mutants, ChIP at endogenous promoters, and subcellular fractionation in human cells","pmids":["16762838"],"confidence":"High","gaps":["Did not resolve how the same protein partitions between nucleus and mitochondria","Mechanism of corepression on chromatin not defined at the structural level"]},{"year":2009,"claim":"Demonstrated that SLIRP is functionally required for mitochondrial mRNA homeostasis, linking its loss to destabilized OxPhos complexes and reduced mtDNA-encoded transcripts.","evidence":"RNAi knockdown with OxPhos enzymatic activity assays and mitochondrial mRNA quantification in human cells","pmids":["19680543"],"confidence":"Medium","gaps":["Did not identify the partner protein or the degradation pathway being countered","Single-lab knockdown without genetic rescue"]},{"year":2012,"claim":"Mechanistically placed SLIRP in the LRPPRC complex that cotranscriptionally coats mRNA coding regions and blocks 3′ exonucleolytic decay, explaining transcript stabilization.","evidence":"Absolute mtRNA quantification, in vitro polyadenylation with MTPAP, and RNAi of complex components","pmids":["22661577"],"confidence":"High","gaps":["Relative contributions of SLIRP versus LRPPRC to stabilization not separated","Did not establish in vivo requirement"]},{"year":2015,"claim":"In vivo knockout disentangled SLIRP from LRPPRC functions, showing SLIRP mutually stabilizes LRPPRC, is dispensable for polyadenylation, and is required for mitoribosome association and efficient translation.","evidence":"Slirp knockout mice with deep RNAseq of mitoribosomal fractions and translation pulse-labeling","pmids":["26247782"],"confidence":"High","gaps":["Structural basis of mitoribosome engagement not defined","Did not explain transcript-specific translation effects"]},{"year":2016,"claim":"Defined the LRPPRC-SLIRP interface at residue level, revealing the surprising repurposing of RNA-binding surfaces for protein-protein contact and that LRPPRC, not SLIRP, carries strong RNA binding.","evidence":"In vitro RNA-binding and interface mutagenesis of RRM/PPR residues with complex stability assays","pmids":["27353330"],"confidence":"High","gaps":["How SLIRP contributes to RNA recognition within the complex left unresolved","No full-length complex structure"]},{"year":2016,"claim":"Identified BCL-2 as a stabilizing partner of SLIRP that modulates mitochondrial mRNA levels, while excluding SLIRP from BCL-2's anti-apoptotic function.","evidence":"Affinity purification-MS, reciprocal co-IP with BCL-2 domain deletion mutants, immunofluorescence","pmids":["26866271"],"confidence":"Medium","gaps":["Functional consequence of BCL-2 binding for translation untested","Single-lab interaction without in vivo validation"]},{"year":2017,"claim":"Revealed an unanticipated nucleic-acid activity, showing SLIRP binds G-quadruplex DNA with nanomolar affinity via its RRM and occupies G-rich genomic regions, broadening its functional repertoire.","evidence":"G4-interaction proteomics, in vitro Kd binding with RRM mutagenesis, and CRISPR-tagged ChIP-Seq","pmids":["28859475"],"confidence":"High","gaps":["Biological consequence of G4 binding not established","Relationship to its SRA/nuclear receptor role unclear"]},{"year":2019,"claim":"Positioned SLIRP as an RNA chaperone interacting with the helicase proteome to facilitate rRNA 2′-O-methylation and promote translation.","evidence":"Quantitative proteomic interaction screen, rRNA 2′-O-methylation mapping, and translation efficiency assays","pmids":["31260285"],"confidence":"Medium","gaps":["Direct helicase partners not individually validated","Causal link between methylation changes and translation not isolated"]},{"year":2019,"claim":"Connected SLIRP's nuclear corepressor activity to signaling control, showing Ack1-mediated AR Tyr-267 phosphorylation and androgen treatment release SLIRP from androgen response elements in an SRA-dependent manner.","evidence":"Co-IP, ChIP at endogenous AREs, kinase/ligand perturbations, and transcriptome analysis after SLIRP knockdown","pmids":["31819114"],"confidence":"Medium","gaps":["How SLIRP physically silences AR target genes not resolved","Single-lab; nuclear pool quantification not addressed"]},{"year":2024,"claim":"Provided the structural basis for translation handoff, showing the LRPPRC-SLIRP complex docks on the mitoribosome through mS39/mS31 to form an mRNA corridor to the small subunit, with transcript-specific translation effects.","evidence":"Cryo-EM structure with ribosome profiling and metabolic labeling","pmids":["39134711"],"confidence":"High","gaps":["Dynamics of mRNA transfer not captured","Does not explain why specific transcripts depend more on the complex"]},{"year":2024,"claim":"In vivo genetics refined the translation phenotype, showing SLIRP loss selectively reduces complex I, interface mutations cause LRPPRC destabilization and ATP8 dysregulation, and SLIRP loss is synthetically lethal with a pathogenic mtDNA mutation.","evidence":"Slirp knockout and interface knock-in mice, translation labeling, and heteroplasmy crosses","pmids":["39087558"],"confidence":"High","gaps":["Mechanism of transcript-selective translation effects unresolved","ATP8 increase mechanism not explained"]},{"year":2024,"claim":"Placed SLIRP within the PGC-1α mitochondrial biogenesis program in muscle and showed exercise can partially compensate for its loss by boosting mitoribosome capacity.","evidence":"Muscle-specific Slirp/Lrpprc knockout mice with exercise intervention, mitoribosome profiling, and Drosophila lifespan assays","pmids":["39537626"],"confidence":"Medium","gaps":["How exercise compensates despite low mRNA levels not mechanistically resolved","Single consortium"]},{"year":2025,"claim":"Identified a role in innate immunity, showing SLIRP stabilizes mitochondrial dsRNA and promotes its cytosolic release to amplify MDA5-driven interferon signaling in a positive feedback loop.","evidence":"SLIRP knockdown in cell lines and patient cells, mt-dsRNA quantification, and MDA5/interferon pathway readouts","pmids":["40253699"],"confidence":"Medium","gaps":["Whether mt-dsRNA stabilization is direct or via the LRPPRC complex unclear","Mechanism of cytosolic release not defined"]},{"year":null,"claim":"How SLIRP's distinct activities—mitochondrial mRNA stabilization, nuclear receptor corepression, G4 DNA binding, and immune dsRNA stabilization—are coordinated and spatially partitioned within the cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model explaining nuclear versus mitochondrial pool regulation","Mechanism of transcript-selective translation control unknown","Functional significance of G4 DNA binding undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,4,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,3,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,9,10,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]}],"complexes":["LRPPRC-SLIRP complex","mitochondrial small ribosomal subunit (mt-SSU)"],"partners":["LRPPRC","BCL2","AR","SRA","MS39","MS31"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZT3","full_name":"SRA stem-loop-interacting RNA-binding protein, mitochondrial","aliases":[],"length_aa":109,"mass_kda":12.3,"function":"RNA-binding protein that acts as a nuclear receptor corepressor. Probably acts by binding the SRA RNA, and repressing the SRA-mediated nuclear receptor coactivation. Binds the STR7 loop of SRA RNA. Also able to repress glucocorticoid (GR), androgen (AR), thyroid (TR) and VDR-mediated transactivation","subcellular_location":"Mitochondrion; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9GZT3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLIRP","classification":"Not Classified","n_dependent_lines":195,"n_total_lines":1208,"dependency_fraction":0.16142384105960264},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM3","stoichiometry":0.2},{"gene":"PABPC4","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SLIRP","total_profiled":1310},"omim":[{"mim_id":"613669","title":"MITOCHONDRIAL POLY(A) POLYMERASE; MTPAP","url":"https://www.omim.org/entry/613669"},{"mim_id":"610211","title":"SRA STEM LOOP-INTERACTING RNA-BINDING PROTEIN; SLIRP","url":"https://www.omim.org/entry/610211"},{"mim_id":"607544","title":"LEUCINE-RICH PPR MOTIF-CONTAINING PROTEIN; LRPPRC","url":"https://www.omim.org/entry/607544"},{"mim_id":"220111","title":"MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5","url":"https://www.omim.org/entry/220111"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLIRP"},"hgnc":{"alias_symbol":["DC50"],"prev_symbol":["C14orf156"]},"alphafold":{"accession":"Q9GZT3","domains":[{"cath_id":"3.30.70.330","chopping":"19-92","consensus_level":"high","plddt":91.3964,"start":19,"end":92}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZT3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZT3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZT3-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLIRP","jax_strain_url":"https://www.jax.org/strain/search?query=SLIRP"},"sequence":{"accession":"Q9GZT3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZT3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZT3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZT3"}},"corpus_meta":[{"pmid":"22661577","id":"PMC_22661577","title":"LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes polyadenylation in human mitochondria.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22661577","citation_count":162,"is_preprint":false},{"pmid":"19680543","id":"PMC_19680543","title":"A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19680543","citation_count":129,"is_preprint":false},{"pmid":"16762838","id":"PMC_16762838","title":"SLIRP, a small SRA binding protein, is a nuclear receptor corepressor.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16762838","citation_count":110,"is_preprint":false},{"pmid":"26247782","id":"PMC_26247782","title":"SLIRP Regulates the Rate of Mitochondrial Protein Synthesis and Protects LRPPRC from Degradation.","date":"2015","source":"PLoS 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fertility.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23976951","citation_count":21,"is_preprint":false},{"pmid":"39087558","id":"PMC_39087558","title":"LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39087558","citation_count":18,"is_preprint":false},{"pmid":"39537626","id":"PMC_39537626","title":"The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39537626","citation_count":15,"is_preprint":false},{"pmid":"26866271","id":"PMC_26866271","title":"Affinity purification-mass spectrometry analysis of bcl-2 interactome identified SLIRP as a novel interacting protein.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/26866271","citation_count":12,"is_preprint":false},{"pmid":"31819114","id":"PMC_31819114","title":"Interaction between androgen receptor and coregulator SLIRP is regulated by Ack1 tyrosine kinase and androgen.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31819114","citation_count":10,"is_preprint":false},{"pmid":"31260285","id":"PMC_31260285","title":"SLIRP Interacts with Helicases to Facilitate 2'-O-Methylation of rRNA and to Promote Translation.","date":"2019","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/31260285","citation_count":8,"is_preprint":false},{"pmid":"34426662","id":"PMC_34426662","title":"Pathogenic SLIRP variants as a novel cause of autosomal recessive mitochondrial encephalomyopathy with complex I and IV deficiency.","date":"2021","source":"European journal of human genetics : 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Protein SLIRP Affects Biosynthesis of Cytochrome c Oxidase Subunits in HEK293T Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38203264","citation_count":1,"is_preprint":false},{"pmid":"41274398","id":"PMC_41274398","title":"Mitochondria-located circRCP regulates redox homeostasis via stabilizing LRPPRC/SLIRP complex to promote bladder urothelial carcinoma tumorigenesis.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41274398","citation_count":0,"is_preprint":false},{"pmid":"42049860","id":"PMC_42049860","title":"SLIRP maintains energy metabolism homeostasis in colorectal cancer by stabilizing mitochondrial-encoded mRNAs.","date":"2026","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/42049860","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.19.671158","title":"Development of Degraders and 2-pyridinecarboxyaldehyde (2-PCA) as a recruitment Ligand for FBXO22","date":"2025-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.19.671158","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.31.673396","title":"Targeted degradation of pathogenic TDP-43 proteins in amyotrophic lateral sclerosis using the AUTOTAC platform","date":"2025-09-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.31.673396","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.01.621520","title":"Androgen receptor interactions provide insight into steroid mediated metabolic shifts in endocrine resistant breast cancer","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.01.621520","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.13.632817","title":"Discovery of molecular glues by modeling ternary complex conformational ensembles and thermodynamic stability","date":"2025-01-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.13.632817","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13003,"output_tokens":3945,"usd":0.049092,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11843,"output_tokens":4420,"usd":0.084858,"stage2_stop_reason":"end_turn"},"total_usd":0.13395,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"SLIRP was identified as an RNA-binding protein containing an RRM domain that binds the STR7 stem-loop substructure of the noncoding RNA SRA (Steroid Receptor RNA Activator), represses nuclear receptor (NR) transactivation in an RRM- and SRA-dependent manner, augments tamoxifen's effect, and modulates SRC-1 association with SRA. SLIRP also colocalizes with the NR coregulator SKIP and reduces SKIP-potentiated NR signaling. SLIRP is recruited to endogenous NR target gene promoters (pS2 and metallothionein), and NCoR promoter recruitment is dependent on SLIRP. The majority of endogenous SLIRP resides in mitochondria.\",\n      \"method\": \"RNA-binding assays, co-immunoprecipitation, reporter gene assays with RRM mutants, ChIP at endogenous promoters, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RRM mutagenesis, co-IP, ChIP, reporter assays) in a focused study; findings replicated by subsequent work\",\n      \"pmids\": [\"16762838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RNAi-mediated silencing of SLIRP destabilizes oxidative phosphorylation (OxPhos) complexes, causes marked loss of OxPhos enzymatic activity, and results in reduced steady-state levels of mitochondria-encoded mRNAs that encode OxPhos subunits, establishing an essential role for SLIRP in maintaining mitochondrial mRNA homeostasis.\",\n      \"method\": \"RNAi knockdown in human cells, OxPhos enzymatic activity assays, mitochondrial mRNA quantification\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi knockdown with two independent functional readouts (enzymatic activity and mRNA levels), single lab\",\n      \"pmids\": [\"19680543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The LRPPRC/SLIRP complex cotranscriptionally binds to coding sequences of mitochondrial mRNAs, suppresses 3′ exonucleolytic mRNA degradation mediated by PNPase/SUV3, and LRPPRC promotes polyadenylation of mtRNAs by mitochondrial poly(A) polymerase (MTPAP) in vitro, thereby stabilizing mitochondrial mRNAs and correlating with their longer cellular half-lives.\",\n      \"method\": \"Absolute quantification of mitochondrial mRNAs, in vitro polyadenylation assay with MTPAP, RNAi knockdown of complex components, RNA-binding experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical reconstitution of polyadenylation, mRNA quantification, and degradation assays; replicated across multiple studies\",\n      \"pmids\": [\"22661577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In vivo knockout of Slirp in mice shows: (1) SLIRP stabilizes LRPPRC by protecting it from proteolytic degradation; (2) SLIRP's own stability is completely dependent on LRPPRC; (3) SLIRP is dispensable for polyadenylation of mtDNA-encoded mRNAs (distinct from LRPPRC); (4) SLIRP is required for proper association of mitochondrial mRNAs with the mitoribosome and efficient mitochondrial translation, as shown by deep RNAseq of ribosomal fractions.\",\n      \"method\": \"Slirp knockout mice, deep RNA sequencing of mitoribosomal fractions, pulse-labeling of mitochondrial translation products, polyadenylation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal readouts (RNAseq, translation labeling, polyadenylation assays); replicated by subsequent studies\",\n      \"pmids\": [\"26247782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The LRPPRC-SLIRP heterodimer interface is formed by polar amino acids in SLIRP's single RRM domain (specifically the RNP1 motif) and three neighboring PPR motifs in the second quarter of LRPPRC; unexpectedly, residues predicted to contact RNA in both proteins are instead used for protein-protein interaction. LRPPRC displays broad strong RNA-binding capacity in vitro, whereas SLIRP associates only weakly with RNA.\",\n      \"method\": \"In vitro RNA-binding assays, mutagenesis of RRM and PPR interface residues, protein-protein interaction studies, complex stability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis of specific interface residues combined with RNA-binding reconstitution; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27353330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLIRP interacts with BCL-2; BCL-2 binds and stabilizes SLIRP protein and regulates mitochondrial mRNA levels. The BH4 domain of BCL-2 is required for maintaining this binding. SLIRP is not involved in mediating BCL-2's protection from apoptosis or oxidative damage.\",\n      \"method\": \"Affinity purification-mass spectrometry, co-immunoprecipitation with domain deletion mutants, immunofluorescence co-localization\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal co-IP with domain mapping and MS identification, single lab\",\n      \"pmids\": [\"26866271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLIRP was identified as a novel G-quadruplex (G4) DNA-binding protein. SLIRP binds G4 DNA directly with Kd values in the low nanomolar range; this binding requires the RRM domain. ChIP-Seq (using CRISPR-Cas9-introduced affinity tag) showed that SLIRP preferentially occupies G-rich genomic regions that can fold into G4 structures.\",\n      \"method\": \"Quantitative mass spectrometry-based G4-interaction proteomics, in vitro binding assays with Kd measurement, RRM domain mutagenesis, CRISPR-Cas9 affinity tagging + ChIP-Seq\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro Kd measurement with mutagenesis plus genome-wide ChIP-Seq; multiple orthogonal methods in one study\",\n      \"pmids\": [\"28859475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLIRP interacts with the majority of the human helicase proteome; these interactions facilitate 2′-O-methylation of nucleosides in rRNA and promote protein translation. SLIRP thus functions as an RNA chaperone.\",\n      \"method\": \"Quantitative proteomics (interaction screen), 2′-O-methylation mapping of rRNA, translation efficiency assays\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — quantitative proteomic interaction screen with functional methylation and translation readouts; single lab\",\n      \"pmids\": [\"31260285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ack1 tyrosine kinase phosphorylation of AR at Tyr-267 disrupts the AR-SLIRP interaction. The noncoding RNA SRA is required for the AR-SLIRP interaction. SLIRP is bound to androgen response elements (AREs) of AR target genes in the absence of androgen, and androgen or heregulin treatment causes SLIRP dissociation from AREs. Whole-transcriptome analysis shows SLIRP knockdown affects a significant subset of androgen-regulated genes, consistent with a corepressor role for SLIRP on AR.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at endogenous AREs, kinase inhibitor and ligand treatments, transcriptome analysis after SLIRP knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP with pharmacological and genetic perturbations; single lab, multiple readouts\",\n      \"pmids\": [\"31819114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Deletion of SLIRP in HEK293T cells disturbs mitochondrial translation specifically affecting complexes I and IV but not complexes III and V. SLIRP interacts only with the small subunit (mt-SSU) of the mitochondrial ribosome, suggesting involvement in mitochondrial translation initiation.\",\n      \"method\": \"SLIRP gene deletion (CRISPR), click-chemistry-based mitochondrial translation labeling, ribosome subunit co-immunoprecipitation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with translation labeling and ribosome co-IP; single lab\",\n      \"pmids\": [\"38203264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the LRPPRC-SLIRP complex bound to mRNA and the mitoribosome shows: LRPPRC associates with mitoribosomal proteins mS39 and the N-terminus of mS31 through its helical repeats, forming a corridor for mRNA handoff to the ribosome. SLIRP directly binds the mRNA and also stabilizes LRPPRC. Mitoribosome profiling demonstrated transcript-specific effects on translation efficiency, with COX1 and COX2 translation most affected.\",\n      \"method\": \"Cryo-EM structure determination, RNA sequencing, metabolic labeling, mitoribosome profiling\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation by ribosome profiling and metabolic labeling; multiple orthogonal methods in one study\",\n      \"pmids\": [\"39134711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of SLIRP in mice causes selective decrease in complex I levels while other OXPHOS complexes are unaffected. Knock-in mice with mutations disrupting the LRPPRC-SLIRP protein interface show partial LRPPRC degradation, complete SLIRP loss, and impaired mitochondrial translation except for a marked increase in ATP8 synthesis. Combining Slirp knockout with a heteroplasmic pathogenic mtDNA mutation (m.C5024T in tRNAAla) causes additive mitochondrial translation defects leading to embryonic lethality.\",\n      \"method\": \"Slirp knockout mice, LRPPRC interface knock-in mice, mitochondrial translation labeling, mtDNA heteroplasmy crosses, mouse embryonic fibroblast growth assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo genetic models with defined translation readouts; replicated across multiple mouse lines\",\n      \"pmids\": [\"39087558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In skeletal muscle, SLIRP (in complex with LRPPRC) is a PGC-1α transcriptional target that regulates mitochondrial structure, respiration, and mtDNA-encoded mRNA pools. Exercise training counteracts mitochondrial defects from LRPPRC/SLIRP loss by increasing mitoribosome translation capacity and mitochondrial quality control, despite sustained low mtDNA-encoded mRNA levels.\",\n      \"method\": \"Muscle-specific Slirp/Lrpprc knockout mice, exercise training intervention, mitoribosome profiling, respiration assays, Drosophila lifespan assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with multiple functional readouts and cross-species validation; single consortium but multiple approaches\",\n      \"pmids\": [\"39537626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLIRP stabilizes mitochondrial double-stranded RNAs (mt-dsRNAs) and promotes their cytosolic release, creating a positive feedback loop: exogenous dsRNA activates MDA5, which upregulates SLIRP, which stabilizes mt-dsRNAs and elevates their cytosolic levels to further activate MDA5 and amplify the interferon response. SLIRP knockdown dampens the interferon response and reduces mt-dsRNA cytosolic levels.\",\n      \"method\": \"SLIRP knockdown in cell lines and primary patient cells, mt-dsRNA quantification, MDA5 pathway reporter assays, interferon-stimulated gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with dsRNA quantification and pathway readouts; peer-reviewed; single lab\",\n      \"pmids\": [\"40253699\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLIRP is a mitochondrial RNA-binding protein (RRM domain) that forms a stable heterodimer with LRPPRC (via an RRM-PPR protein interface) to cotranscriptionally stabilize mitochondrial mRNAs by suppressing 3′ exonucleolytic degradation; cryo-EM structural work shows that the LRPPRC-SLIRP complex docks onto the mitoribosome (via mS39/mS31) and hands off mRNA directly to the small subunit for translation, with SLIRP also protecting LRPPRC from degradation, interacting with the mt-SSU, facilitating rRNA 2′-O-methylation through helicase interactions, and amplifying innate immune interferon signaling via cytosolic mt-dsRNA stabilization; in the nucleus, SLIRP binds the SRA noncoding RNA and acts as a corepressor of nuclear receptor (including androgen receptor) transactivation in a SRA- and RRM-dependent manner, with its nuclear recruitment and chromatin binding regulated by Ack1-mediated AR phosphorylation and androgen signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLIRP is a small RRM-domain RNA-binding protein that functions principally in mitochondrial gene expression, where it forms a stable heterodimer with LRPPRC to maintain the steady-state pool of mtDNA-encoded mRNAs and support oxidative phosphorylation [#1, #2]. The complex binds cotranscriptionally to mitochondrial mRNA coding sequences and suppresses 3′ exonucleolytic degradation by PNPase/SUV3, thereby extending transcript half-life [#2]. Within the heterodimer, the partnership is built on an unexpected protein-protein interface: polar residues of SLIRP's RNP1 motif engage three PPR motifs of LRPPRC, repurposing surfaces predicted to bind RNA, so that LRPPRC carries the strong RNA-binding activity while SLIRP binds RNA only weakly and reciprocally protects LRPPRC from proteolysis [#3, #4]. Beyond stabilization, SLIRP is required for efficient mitochondrial translation—it loads mRNAs onto the mitoribosome and associates with the small subunit, and cryo-EM shows the LRPPRC-SLIRP complex docking onto the mitoribosome via mS39/mS31 to form a corridor that hands mRNA off to the small subunit, with transcript-specific effects on COX1, COX2, and complex I/IV biogenesis [#3, #9, #10, #11]. In skeletal muscle, SLIRP is a PGC-1α transcriptional target that couples mitochondrial biogenesis to the mtDNA-encoded mRNA pool [#12]. Independently of its mitochondrial role, SLIRP binds the noncoding RNA SRA and acts as a corepressor of nuclear receptor transactivation, including the androgen receptor, in an RRM- and SRA-dependent manner; its occupancy at androgen response elements is released upon androgen signaling and disrupted by Ack1-mediated AR phosphorylation [#0, #8]. SLIRP also stabilizes mitochondrial double-stranded RNA and promotes its cytosolic release to amplify MDA5-driven interferon responses [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SLIRP's first molecular identity by showing it is an RRM protein that binds the SRA noncoding RNA and represses nuclear receptor transactivation, defining an unexpected nuclear corepressor role while noting most of the protein is mitochondrial.\",\n      \"evidence\": \"RNA-binding assays, co-IP, reporter assays with RRM mutants, ChIP at endogenous promoters, and subcellular fractionation in human cells\",\n      \"pmids\": [\"16762838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the same protein partitions between nucleus and mitochondria\", \"Mechanism of corepression on chromatin not defined at the structural level\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that SLIRP is functionally required for mitochondrial mRNA homeostasis, linking its loss to destabilized OxPhos complexes and reduced mtDNA-encoded transcripts.\",\n      \"evidence\": \"RNAi knockdown with OxPhos enzymatic activity assays and mitochondrial mRNA quantification in human cells\",\n      \"pmids\": [\"19680543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the partner protein or the degradation pathway being countered\", \"Single-lab knockdown without genetic rescue\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mechanistically placed SLIRP in the LRPPRC complex that cotranscriptionally coats mRNA coding regions and blocks 3′ exonucleolytic decay, explaining transcript stabilization.\",\n      \"evidence\": \"Absolute mtRNA quantification, in vitro polyadenylation with MTPAP, and RNAi of complex components\",\n      \"pmids\": [\"22661577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of SLIRP versus LRPPRC to stabilization not separated\", \"Did not establish in vivo requirement\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"In vivo knockout disentangled SLIRP from LRPPRC functions, showing SLIRP mutually stabilizes LRPPRC, is dispensable for polyadenylation, and is required for mitoribosome association and efficient translation.\",\n      \"evidence\": \"Slirp knockout mice with deep RNAseq of mitoribosomal fractions and translation pulse-labeling\",\n      \"pmids\": [\"26247782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mitoribosome engagement not defined\", \"Did not explain transcript-specific translation effects\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the LRPPRC-SLIRP interface at residue level, revealing the surprising repurposing of RNA-binding surfaces for protein-protein contact and that LRPPRC, not SLIRP, carries strong RNA binding.\",\n      \"evidence\": \"In vitro RNA-binding and interface mutagenesis of RRM/PPR residues with complex stability assays\",\n      \"pmids\": [\"27353330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLIRP contributes to RNA recognition within the complex left unresolved\", \"No full-length complex structure\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified BCL-2 as a stabilizing partner of SLIRP that modulates mitochondrial mRNA levels, while excluding SLIRP from BCL-2's anti-apoptotic function.\",\n      \"evidence\": \"Affinity purification-MS, reciprocal co-IP with BCL-2 domain deletion mutants, immunofluorescence\",\n      \"pmids\": [\"26866271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of BCL-2 binding for translation untested\", \"Single-lab interaction without in vivo validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed an unanticipated nucleic-acid activity, showing SLIRP binds G-quadruplex DNA with nanomolar affinity via its RRM and occupies G-rich genomic regions, broadening its functional repertoire.\",\n      \"evidence\": \"G4-interaction proteomics, in vitro Kd binding with RRM mutagenesis, and CRISPR-tagged ChIP-Seq\",\n      \"pmids\": [\"28859475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological consequence of G4 binding not established\", \"Relationship to its SRA/nuclear receptor role unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Positioned SLIRP as an RNA chaperone interacting with the helicase proteome to facilitate rRNA 2′-O-methylation and promote translation.\",\n      \"evidence\": \"Quantitative proteomic interaction screen, rRNA 2′-O-methylation mapping, and translation efficiency assays\",\n      \"pmids\": [\"31260285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct helicase partners not individually validated\", \"Causal link between methylation changes and translation not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SLIRP's nuclear corepressor activity to signaling control, showing Ack1-mediated AR Tyr-267 phosphorylation and androgen treatment release SLIRP from androgen response elements in an SRA-dependent manner.\",\n      \"evidence\": \"Co-IP, ChIP at endogenous AREs, kinase/ligand perturbations, and transcriptome analysis after SLIRP knockdown\",\n      \"pmids\": [\"31819114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SLIRP physically silences AR target genes not resolved\", \"Single-lab; nuclear pool quantification not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural basis for translation handoff, showing the LRPPRC-SLIRP complex docks on the mitoribosome through mS39/mS31 to form an mRNA corridor to the small subunit, with transcript-specific translation effects.\",\n      \"evidence\": \"Cryo-EM structure with ribosome profiling and metabolic labeling\",\n      \"pmids\": [\"39134711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of mRNA transfer not captured\", \"Does not explain why specific transcripts depend more on the complex\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vivo genetics refined the translation phenotype, showing SLIRP loss selectively reduces complex I, interface mutations cause LRPPRC destabilization and ATP8 dysregulation, and SLIRP loss is synthetically lethal with a pathogenic mtDNA mutation.\",\n      \"evidence\": \"Slirp knockout and interface knock-in mice, translation labeling, and heteroplasmy crosses\",\n      \"pmids\": [\"39087558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of transcript-selective translation effects unresolved\", \"ATP8 increase mechanism not explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SLIRP within the PGC-1α mitochondrial biogenesis program in muscle and showed exercise can partially compensate for its loss by boosting mitoribosome capacity.\",\n      \"evidence\": \"Muscle-specific Slirp/Lrpprc knockout mice with exercise intervention, mitoribosome profiling, and Drosophila lifespan assays\",\n      \"pmids\": [\"39537626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How exercise compensates despite low mRNA levels not mechanistically resolved\", \"Single consortium\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a role in innate immunity, showing SLIRP stabilizes mitochondrial dsRNA and promotes its cytosolic release to amplify MDA5-driven interferon signaling in a positive feedback loop.\",\n      \"evidence\": \"SLIRP knockdown in cell lines and patient cells, mt-dsRNA quantification, and MDA5/interferon pathway readouts\",\n      \"pmids\": [\"40253699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mt-dsRNA stabilization is direct or via the LRPPRC complex unclear\", \"Mechanism of cytosolic release not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLIRP's distinct activities—mitochondrial mRNA stabilization, nuclear receptor corepression, G4 DNA binding, and immune dsRNA stabilization—are coordinated and spatially partitioned within the cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model explaining nuclear versus mitochondrial pool regulation\", \"Mechanism of transcript-selective translation control unknown\", \"Functional significance of G4 DNA binding undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 4, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"LRPPRC-SLIRP complex\", \"mitochondrial small ribosomal subunit (mt-SSU)\"],\n    \"partners\": [\"LRPPRC\", \"BCL2\", \"AR\", \"SRA\", \"mS39\", \"mS31\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}