| 2006 |
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. |
RNA-binding assays, co-immunoprecipitation, reporter gene assays with RRM mutants, ChIP at endogenous promoters, subcellular fractionation/immunofluorescence |
Molecular cell |
High |
16762838
|
| 2009 |
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. |
RNAi knockdown in human cells, OxPhos enzymatic activity assays, mitochondrial mRNA quantification |
PLoS genetics |
Medium |
19680543
|
| 2012 |
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. |
Absolute quantification of mitochondrial mRNAs, in vitro polyadenylation assay with MTPAP, RNAi knockdown of complex components, RNA-binding experiments |
Nucleic acids research |
High |
22661577
|
| 2015 |
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. |
Slirp knockout mice, deep RNA sequencing of mitoribosomal fractions, pulse-labeling of mitochondrial translation products, polyadenylation assays |
PLoS genetics |
High |
26247782
|
| 2016 |
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. |
In vitro RNA-binding assays, mutagenesis of RRM and PPR interface residues, protein-protein interaction studies, complex stability assays |
Nucleic acids research |
High |
27353330
|
| 2016 |
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. |
Affinity purification-mass spectrometry, co-immunoprecipitation with domain deletion mutants, immunofluorescence co-localization |
Cell death & disease |
Medium |
26866271
|
| 2017 |
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. |
Quantitative mass spectrometry-based G4-interaction proteomics, in vitro binding assays with Kd measurement, RRM domain mutagenesis, CRISPR-Cas9 affinity tagging + ChIP-Seq |
Journal of the American Chemical Society |
High |
28859475
|
| 2019 |
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. |
Quantitative proteomics (interaction screen), 2′-O-methylation mapping of rRNA, translation efficiency assays |
Journal of the American Chemical Society |
Medium |
31260285
|
| 2019 |
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. |
Co-immunoprecipitation, ChIP at endogenous AREs, kinase inhibitor and ligand treatments, transcriptome analysis after SLIRP knockdown |
Scientific reports |
Medium |
31819114
|
| 2023 |
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. |
SLIRP gene deletion (CRISPR), click-chemistry-based mitochondrial translation labeling, ribosome subunit co-immunoprecipitation |
International journal of molecular sciences |
Medium |
38203264
|
| 2024 |
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. |
Cryo-EM structure determination, RNA sequencing, metabolic labeling, mitoribosome profiling |
Nature structural & molecular biology |
High |
39134711
|
| 2024 |
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. |
Slirp knockout mice, LRPPRC interface knock-in mice, mitochondrial translation labeling, mtDNA heteroplasmy crosses, mouse embryonic fibroblast growth assays |
Nucleic acids research |
High |
39087558
|
| 2024 |
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. |
Muscle-specific Slirp/Lrpprc knockout mice, exercise training intervention, mitoribosome profiling, respiration assays, Drosophila lifespan assay |
Nature communications |
Medium |
39537626
|
| 2025 |
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. |
SLIRP knockdown in cell lines and primary patient cells, mt-dsRNA quantification, MDA5 pathway reporter assays, interferon-stimulated gene expression analysis |
Cell reports |
Medium |
40253699
|