Affinage

SLIRP

SRA stem-loop-interacting RNA-binding protein, mitochondrial · UniProt Q9GZT3

Length
109 aa
Mass
12.3 kDa
Annotated
2026-04-28
19 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLIRP is a mitochondrial matrix RRM-domain protein that functions as an obligate heterodimeric partner of LRPPRC to stabilize mitochondrial mRNAs, protect them from 3′ exonucleolytic degradation by PNPase/SUV3, and facilitate their handoff to the mitoribosome small subunit for translation initiation (PMID:22661577, PMID:26247782, PMID:39134711). SLIRP and LRPPRC are mutually dependent for protein stability; SLIRP uses canonical RRM-domain residues not for RNA binding but for a protein–protein interface with PPR motifs of LRPPRC, while LRPPRC provides the primary RNA-binding activity (PMID:27353330, PMID:39087558). Loss of SLIRP in mice causes 50–70% reduction in mtDNA-encoded mRNA levels, impairs oxidative phosphorylation (particularly complexes I and IV), produces asthenozoospermia, and when combined with heteroplasmic mtDNA mutations leads to embryonic lethality (PMID:26247782, PMID:23976951, PMID:39087558). SLIRP also functions in the nucleus as an SRA noncoding RNA-dependent corepressor of nuclear receptors including androgen receptor, and amplifies mitochondrial dsRNA-driven MDA5/interferon signaling through a positive feedback mechanism (PMID:16762838, PMID:31819114, PMID:40253699).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 High

    The discovery of SLIRP established a new RRM-containing protein that bridges the SRA noncoding RNA to nuclear receptor corepression while predominantly localizing to mitochondria, raising the question of its mitochondrial function.

    Evidence RNA binding assays, reporter transactivation, RRM mutagenesis, ChIP, co-IP, and immunofluorescence in mammalian cells

    PMID:16762838

    Open questions at the time
    • Mitochondrial function entirely unknown
    • Mechanism of SRA-dependent NCoR recruitment unclear
    • Whether nuclear and mitochondrial roles are physiologically separable
  2. 2009 High

    RNAi silencing demonstrated that SLIRP is essential for maintaining steady-state levels of mitochondrial mRNAs encoding OxPhos subunits, establishing it as a mitochondrial mRNA stability factor.

    Evidence RNAi knockdown with mitochondrial mRNA quantification and OxPhos enzymatic activity assays

    PMID:19680543

    Open questions at the time
    • Mechanism of mRNA stabilization unknown
    • Whether SLIRP acts alone or in a complex
    • Direct versus indirect effects on mRNA levels
  3. 2012 High

    Reconstituted biochemistry revealed that the LRPPRC/SLIRP complex cotranscriptionally binds mitochondrial mRNA coding sequences and suppresses 3′ exonucleolytic degradation by PNPase/SUV3, defining the molecular mechanism of mRNA protection.

    Evidence In vitro degradation assays with purified PNPase/SUV3, in vitro polyadenylation assays with MTPAP, and RNA immunoprecipitation

    PMID:22661577

    Open questions at the time
    • Structural basis of complex formation unknown
    • Whether SLIRP or LRPPRC provides RNA-binding specificity
    • Mechanism linking mRNA protection to translation
  4. 2013 Medium

    Slirp knockout mice revealed an in vivo requirement for SLIRP in male fertility, linking mitochondrial mRNA metabolism to sperm midpiece integrity and motility.

    Evidence Slirp knockout mice with immunofluorescence, electron microscopy, and sperm motility assays

    PMID:23976951

    Open questions at the time
    • Whether subfertility reflects general OxPhos deficiency or a sperm-specific SLIRP role
    • Mechanism of SLIRP redistribution to peri-acrosomal region in mature sperm
  5. 2015 High

    In vivo knockout established that SLIRP and LRPPRC are mutually dependent for stability, that SLIRP loss reduces mtDNA-encoded mRNAs by 50–70% and impairs their association with mitoribosomes, but is dispensable for mRNA polyadenylation — separating stabilization from polyadenylation functions.

    Evidence Slirp knockout mice with deep RNA-seq, mitochondrial ribosome fractionation, and pulse-labeling translation assays

    PMID:26247782

    Open questions at the time
    • How SLIRP promotes mRNA loading onto mitoribosomes
    • Whether SLIRP contacts the ribosome directly
    • Structural basis of mutual SLIRP-LRPPRC stabilization
  6. 2016 High

    Mapping of the LRPPRC–SLIRP binding interface showed that SLIRP's RRM domain uses canonical RNA-binding residues (RNP1 motif) for protein–protein interaction with PPR repeats of LRPPRC, resolving the paradox of an RRM protein with weak intrinsic RNA affinity.

    Evidence Mutagenesis of interface residues, in vitro RNA binding assays, pull-down and co-IP

    PMID:27353330

    Open questions at the time
    • No high-resolution atomic structure of the heterodimer
    • Whether mRNA contacts SLIRP or only LRPPRC within the complex
    • Functional consequences of individual interface mutations in vivo
  7. 2017 High

    SLIRP was identified as a high-affinity G-quadruplex DNA-binding protein that preferentially occupies G-rich genomic regions, suggesting a nuclear DNA-structural role beyond its mitochondrial mRNA function.

    Evidence Quantitative MS-based G4 pulldown, in vitro Kd measurements, RRM mutagenesis, and CRISPR-tagged ChIP-Seq

    PMID:28859475

    Open questions at the time
    • Functional consequence of G4 binding on gene expression unknown
    • Whether G4 binding is physiologically relevant given predominant mitochondrial localization
    • Relationship to SRA-dependent nuclear receptor corepression unclear
  8. 2019 Medium

    Two studies expanded SLIRP's functional repertoire: proteomics linked SLIRP to helicase interactions facilitating rRNA 2′-O-methylation and translation, while molecular analysis showed SLIRP is an SRA-dependent androgen receptor corepressor displaced from AREs by androgen signaling.

    Evidence SILAC/MS proteomics with rRNA methylation profiling; co-IP, ChIP, siRNA, and RNA-seq of AR targets

    PMID:31260285 PMID:31819114

    Open questions at the time
    • rRNA methylation role not reconstituted with defined components
    • Whether AR corepression occurs in vivo or is cell-line specific
    • rRNA chaperone function not validated independently
  9. 2023 Medium

    SLIRP deletion in human cells specifically impaired translation of complexes I and IV subunits and revealed a direct interaction between SLIRP and the mitoribosome small subunit, implicating SLIRP in translation initiation rather than only mRNA stability.

    Evidence CRISPR knockout in HEK293T, click-chemistry metabolic labeling, ribosome subunit co-immunoprecipitation

    PMID:38203264

    Open questions at the time
    • Structural basis of small subunit interaction unknown
    • Mechanism of transcript-specific translation effects unclear
    • Single cell line
  10. 2024 High

    Cryo-EM structure of the LRPPRC–SLIRP–mRNA–mitoribosome complex revealed a molecular corridor for mRNA handoff: LRPPRC contacts mS39 and mS31 via helical repeats while SLIRP directly binds mRNA, and mitoribosome profiling showed transcript-specific translation effects with COX1/COX2 most affected — providing the first atomic-level mechanism for mitochondrial translation initiation by this complex.

    Evidence Cryo-EM structure, RNA-seq, metabolic labeling, and mitoribosome profiling

    PMID:39134711

    Open questions at the time
    • Mechanism determining transcript-specific translation sensitivity
    • Dynamic conformational changes during mRNA handoff not captured
    • Structure represents a single state
  11. 2024 High

    Genetic epistasis experiments using Lrpprc interface knock-in mutations combined with Slirp KO and heteroplasmic mtDNA mutations demonstrated that disruption of the LRPPRC–SLIRP complex preferentially reduces complex I, and that SLIRP loss synergizes with tRNA mutations to cause embryonic lethality.

    Evidence Knock-in mice with interface-disrupting mutations crossed with Slirp KO and mtDNA mutant lines; BN-PAGE, mitochondrial translation labeling

    PMID:39087558

    Open questions at the time
    • Why complex I is preferentially affected remains unclear
    • Whether humans with SLIRP mutations present mitochondrial disease
    • Tissue-specific thresholds for SLIRP requirement not defined
  12. 2024 High

    Muscle-specific SLIRP knockout showed that the LRPPRC–SLIRP complex is a PGC-1α transcriptional target whose loss impairs mitochondrial structure and respiration, but exercise training can partially compensate by increasing mitoribosome capacity.

    Evidence Muscle-specific Slirp KO mice, exercise intervention, mitoribosome profiling, Seahorse respirometry, Drosophila lifespan assay

    PMID:39537626

    Open questions at the time
    • Mechanism by which exercise increases mitoribosome capacity independently of mRNA levels
    • Whether compensatory translation upregulation is SLIRP-independent
  13. 2025 Medium

    SLIRP was identified as a positive feedback amplifier of innate immune signaling: MDA5 activation upregulates SLIRP, which stabilizes mitochondrial dsRNAs that leak to the cytosol and further activate MDA5, augmenting the interferon response — connecting mitochondrial RNA metabolism to antiviral defense.

    Evidence siRNA knockdown, MDA5 activation assays, cytosolic mt-dsRNA quantification, interferon measurement, rescue in autoimmune patient cells

    PMID:40253699

    Open questions at the time
    • Whether SLIRP stabilizes mt-dsRNA through the same LRPPRC complex mechanism
    • Mechanism of cytosolic mt-dsRNA release unknown
    • In vivo validation in animal models lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis by which transcript-specific translation sensitivity arises, whether SLIRP mutations cause Mendelian mitochondrial disease in humans, and how the nuclear (G4-binding, NR corepression) and mitochondrial (mRNA stabilization/translation) functions are coordinated or compartmentally segregated.
  • No human disease-causing SLIRP mutations reported
  • No structure of SLIRP bound to G4 DNA or SRA RNA
  • Mechanism partitioning SLIRP between mitochondria and nucleus unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005739 mitochondrion 10 GO:0005634 nucleus 3
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-8953854 Metabolism of RNA 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-168256 Immune System 1
Partners
BCL2LRPPRCMDA5MS31MS39NCOR1SRC-1
Complex memberships
LRPPRC/SLIRP heterodimer

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SLIRP was identified as an RNA recognition motif (RRM)-containing protein that binds to a functional stem-loop substructure of the SRA noncoding RNA (STR7) and represses nuclear receptor (NR) transactivation in an SRA- and RRM-dependent manner. SLIRP modulates SRC-1 association with SRA, colocalizes with NCoR at endogenous promoters (pS2 and metallothionein) in a SRA-dependent manner, and the majority of endogenous SLIRP resides in mitochondria. RNA binding assays, reporter transactivation assays, RRM mutagenesis, ChIP, co-immunoprecipitation, immunofluorescence Molecular cell High 16762838
2009 SLIRP plays an essential role in maintaining mitochondrial-localized mRNA transcripts encoding OxPhos subunits; RNAi silencing of SLIRP destabilizes OxPhos complexes and causes marked loss of OxPhos enzymatic activity. RNAi knockdown, OxPhos enzymatic activity assays, mitochondrial mRNA quantification PLoS genetics High 19680543
2012 The LRPPRC/SLIRP complex cotranscriptionally binds to coding sequences of mitochondrial mRNAs, suppresses 3′ exonucleolytic mRNA degradation mediated by PNPase and SUV3, and LRPPRC promotes polyadenylation of mRNAs by mitochondrial poly(A) polymerase (MTPAP) in vitro. Absolute mRNA quantification, in vitro degradation assays with PNPase/SUV3, in vitro polyadenylation assay with MTPAP, RIP Nucleic acids research High 22661577
2015 SLIRP stabilizes LRPPRC by protecting it from proteolytic degradation; in vivo knockout of Slirp in mice causes 50–70% reduction in mtDNA-encoded mRNA steady-state levels and impairs mRNA association with the mitochondrial ribosome and efficient translation, but is dispensable for mRNA polyadenylation. SLIRP is also completely dependent on LRPPRC for its own stability. Slirp knockout mice, deep RNAseq of mitochondrial ribosomal fractions, mitochondrial ribosome fractionation, pulse-labeling translation assays PLoS genetics High 26247782
2016 SLIRP forms a heterodimeric complex with LRPPRC via polar amino acids in its single RRM domain (including residues in the RNP1 motif) interacting with three neighboring PPR motifs in LRPPRC. Unexpectedly, these interface residues — predicted to bind RNA — are instead used for protein-protein interaction. LRPPRC displays broad strong RNA binding in vitro while SLIRP associates only weakly with RNA. In vitro RNA binding assays, mutagenesis of interface residues, pull-down/co-IP to map binding interface, structural analysis Nucleic acids research High 27353330
2016 BCL-2 interacts with SLIRP in mitochondria (validated by affinity purification-MS, co-immunoprecipitation, and immunofluorescence); BCL-2 stabilizes SLIRP protein and regulates mitochondrial mRNA levels through this interaction, with the BH4 domain of BCL-2 required for the binding. Affinity purification-mass spectrometry, co-immunoprecipitation, immunofluorescence, BH4-domain deletion mutant experiments Cell death & disease Medium 26866271
2017 SLIRP was identified as a G-quadruplex (G4) DNA-binding protein; it binds directly to G4 structures derived from the human telomere and cMYC/cKIT promoters with Kd values in the low nanomolar range, with binding requiring its RRM domain. ChIP-Seq shows SLIRP preferentially occupies G-rich genomic regions capable of forming G4 structures. Quantitative mass spectrometry-based G4 pulldown, in vitro binding assays with purified SLIRP, RRM domain mutant, CRISPR-Cas9 affinity tag + 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, revealing a role for SLIRP as an RNA chaperone. Quantitative proteomics (SILAC/MS), rRNA methylation profiling, translation assays Journal of the American Chemical Society Medium 31260285
2019 Interaction between androgen receptor (AR) and SLIRP requires the noncoding RNA SRA and is disrupted by Ack1 kinase activity, androgen treatment, or heregulin. In the absence of androgen, SLIRP occupies androgen-responsive elements (AREs) of AR target genes; androgen/heregulin treatment causes SLIRP dissociation from AREs. SLIRP functions as a context-dependent corepressor of AR. Co-immunoprecipitation, ChIP, siRNA knockdown, whole-transcriptome analysis (RNA-seq), kinase inhibition experiments Scientific reports Medium 31819114
2013 SLIRP protein localizes to mitochondria in diploid testicular cells but redistributes to the peri-acrosomal region and tail in mature sperm; SLIRP knockout male mice are sub-fertile with asthenozoospermia, disrupted midpiece/annulus junction, and altered mitochondrial morphology in sperm. SLIRP knockout mice, immunofluorescence localization, electron microscopy, sperm motility assays PloS one Medium 23976951
2023 Deletion of the SLIRP gene in HEK293T cells disturbs mitochondrial translation, leading to dysfunction of complexes I and IV but not complexes III and V. SLIRP interacts specifically with the small subunit of the mitochondrial ribosome, suggesting involvement in the regulation of mitochondrial translation initiation. SLIRP gene deletion (CRISPR), click-chemistry-based metabolic labeling of newly synthesized mitochondrial proteins, 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 reveals that LRPPRC associates with mitoribosomal proteins mS39 and the N-terminus of mS31 via its helical repeats, forming a corridor for mRNA handoff. SLIRP directly binds mRNA and also stabilizes LRPPRC. Mitoribosome profiling shows transcript-specific effects on translation efficiency, with COX1 and COX2 (MT-CO1/MT-CO2) translation being most affected. Cryo-electron microscopy structure, RNA sequencing, metabolic labeling, mitoribosome profiling Nature structural & molecular biology High 39134711
2024 Disruption of LRPPRC-SLIRP complex formation via knock-in mutations in mice causes partial LRPPRC degradation and complete SLIRP loss; loss of SLIRP reduces complex I levels while other OXPHOS complexes are unaffected. In Lrpprc knock-in livers, mitochondrial translation is impaired except for increased ATP8 synthesis. Combined Slirp KO and heteroplasmic mtDNA mutation (m.C5024T tRNAAla) causes additive translation defects and embryonic lethality. Knock-in mice with interface-disrupting mutations, Slirp KO crossed with mtDNA mutant mice, blue-native PAGE for OXPHOS complex quantification, mitochondrial translation labeling Nucleic acids research High 39087558
2024 SLIRP in complex with LRPPRC is a PGC-1α transcriptional target that regulates mitochondrial structure, respiration, and mtDNA-encoded mRNA pools in skeletal muscle. Exercise training counteracts SLIRP/LRPPRC deficiency-induced mitochondrial defects by increasing mitoribosome translation capacity and mitochondrial quality control, despite sustained low mtDNA-encoded mRNA levels. Muscle-specific SLIRP knockout in mice, exercise training intervention, mitoribosome profiling, Seahorse respirometry, Drosophila lifespan assay Nature communications High 39537626
2025 SLIRP functions as a positive feedback amplifier of mitochondrial dsRNA (mt-dsRNA)-triggered antiviral signaling: MDA5 activation by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and elevates their cytosolic levels to further activate MDA5, augmenting the interferon response. SLIRP knockdown dampens the interferon response and reduces cytosolic mt-dsRNA levels. siRNA knockdown, MDA5 activation assays, mt-dsRNA quantification (cytosolic fractionation), interferon response measurement, rescue experiments in autoimmune patient primary cells Cell reports Medium 40253699
2025 CircRCP (a mitochondria-located circRNA) forms a ternary RNA-protein complex with LRPPRC and SLIRP, enhancing the stability of the LRPPRC/SLIRP complex and protecting LRPPRC from ubiquitination and proteasomal degradation. RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assay, circRNA knockdown with ROS/apoptosis readouts Cancer letters Low 41274398

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 LRPPRC/SLIRP suppresses PNPase-mediated mRNA decay and promotes polyadenylation in human mitochondria. Nucleic acids research 158 22661577
2009 A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis. PLoS genetics 128 19680543
2006 SLIRP, a small SRA binding protein, is a nuclear receptor corepressor. Molecular cell 109 16762838
2015 SLIRP Regulates the Rate of Mitochondrial Protein Synthesis and Protects LRPPRC from Degradation. PLoS genetics 82 26247782
2017 Identification of SLIRP as a G Quadruplex-Binding Protein. Journal of the American Chemical Society 50 28859475
2016 SLIRP stabilizes LRPPRC via an RRM-PPR protein interface. Nucleic acids research 46 27353330
2024 Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome. Nature structural & molecular biology 30 39134711
2013 Loss of the nuclear receptor corepressor SLIRP compromises male fertility. PloS one 20 23976951
2024 LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation. Nucleic acids research 16 39087558
2024 The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms. Nature communications 12 39537626
2016 Affinity purification-mass spectrometry analysis of bcl-2 interactome identified SLIRP as a novel interacting protein. Cell death & disease 12 26866271
2019 Interaction between androgen receptor and coregulator SLIRP is regulated by Ack1 tyrosine kinase and androgen. Scientific reports 10 31819114
2021 Pathogenic SLIRP variants as a novel cause of autosomal recessive mitochondrial encephalomyopathy with complex I and IV deficiency. European journal of human genetics : EJHG 7 34426662
2019 SLIRP Interacts with Helicases to Facilitate 2'-O-Methylation of rRNA and to Promote Translation. Journal of the American Chemical Society 7 31260285
2020 Effects of SLIRP on Sperm Motility and Oxidative Stress. BioMed research international 4 33150185
2025 SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases. Cell reports 2 40253699
2024 SLIRP promotes autoimmune diseases by amplifying antiviral signaling via positive feedback regulation. bioRxiv : the preprint server for biology 1 38915695
2023 Mitochondrial Protein SLIRP Affects Biosynthesis of Cytochrome c Oxidase Subunits in HEK293T Cells. International journal of molecular sciences 1 38203264
2025 Mitochondria-located circRCP regulates redox homeostasis via stabilizing LRPPRC/SLIRP complex to promote bladder urothelial carcinoma tumorigenesis. Cancer letters 0 41274398