| 2017 |
LARP4 binds poly(A) RNA and poly(A)-binding protein (PABP), and its PABP-interaction domain and RNA-binding module are required for net lengthening of poly(A) tails (PATs) of heterologous mRNAs including ribosomal protein (RP) mRNAs, with concomitant mRNA stabilization. Genetic deletion of LARP4 decreases PAT length and RP mRNA stability. The RNA-binding module is sensitive to poly(A) 3'-termini, consistent with protection from deadenylation. |
Genetic knockout, overexpression, PAT-seq, domain mutagenesis, in-cell assays |
eLife |
High |
28895529
|
| 2015 |
LARP4 mRNA 3'UTR contains a conserved AU-rich element (ARE) that destabilizes mRNA. Tristetraprolin (TTP) binds LARP4 mRNA in vivo and decreases cellular LARP4 levels; TTP knockout cells accumulate higher LARP4. TNF-α stimulation induces a TTP pulse that causes a transient decrease in LARP4 mRNA and protein, establishing LARP4 as a target of TNF-α–TTP post-transcriptional regulation. |
β-globin reporter stability assay, RNA co-immunoprecipitation, TTP gene knockout mouse cells, TNF-α stimulation |
Molecular and Cellular Biology |
High |
26644407
|
| 2020 |
Single-molecule PAT-seq (SM-PAT-seq) transcriptome-wide analysis in LARP4 knockout versus control cells shows LARP4 opposes deadenylation throughout mRNA lifespan, with greatest impact at short poly(A) tails of 30–75 nucleotides. Accelerated deadenylation in KO cells at PATs <75 nt is consistent with greater PABP dissociation in the absence of LARP4. |
SM-PAT-seq (single-molecule nucleotide-resolution transcriptome-wide poly(A) tail sequencing), LARP4 knockout cells, time-course PAT decay analysis |
eLife |
High |
32744499
|
| 2016 |
LARP4 depletion in PC3 and MDA-MB-231 cancer cells increases cell migration, invasion, and invasive protrusions in 3D Matrigel. Overexpression reduces cell elongation. A cancer-associated truncation mutant shows enhanced interaction with PABP and enhanced effects on cell morphology, establishing LARP4 as an inhibitor of cancer cell migration and invasion. |
RNAi depletion, overexpression, transwell migration/invasion assay, 3D Matrigel, Co-immunoprecipitation of PABP with truncation mutant |
Cytoskeleton (Hoboken, N.J.) |
Medium |
27615744
|
| 2020 |
LARP4 knockout in mice destabilizes Nfκb1 mRNAs in CD4+ T cells and reduces secretion of IL-2 and IFN-γ upon T cell activation, placing LARP4 as a regulator of T cell activation-dependent mRNA stabilization. |
BruChase-Seq (transcriptome-wide nascent mRNA stability), Larp4 knockout mouse, cytokine secretion assay |
Nucleic Acids Research |
Medium |
32735645
|
| 2021 |
LARP4 directly binds poly(A) and PABP (PABPC1), contains a PAM2 motif that interacts with the MLLE domain of PABP, and opposes deadenylation by stabilizing PABP on mRNA poly(A) tails. LARP1 and LARP4 are described as sharing these activities to protect mRNA 3' poly(A) tails from deadenylases. |
Review/mechanistic synthesis of prior biochemical data; PAM2-MLLE interaction established by prior in vitro binding assays referenced therein |
RNA Biology |
Medium |
33522422
|
| 2023 |
LARP4 interacts with the mechanosensing immunoglobulin-like repeat 21 (R21) domain of Filamin A (FLNA) through a force-exposed cryptic binding site. The LARP4 region responsible maps to residues around position 277 (F277 in human). A F277A mutation disrupts FLNA binding. FRAP of GFP-LARP4 shows mutant LARP4 diffuses faster than WT. LARP4 knockdown increases cell migration speed, and expression of FLNA-binding-deficient LARP4 fails to rescue, establishing that LARP4–FLNA interaction regulates cell migration. |
Co-immunoprecipitation (in vivo and in vitro), FRAP, proximity ligation assay, site-directed mutagenesis, LARP4 knockdown, cell migration assay |
Frontiers in Cell and Developmental Biology |
Medium |
37169020
|
| 2025 |
The crystal structure of FLNA R21 in complex with the LARP4 peptide (residues Ala269–Asn281) was determined by X-ray crystallography, showing LARP4 forms an extended β strand that binds the cleft formed by β strands C and D of FLNA R21. The LARP4-binding site overlaps with the integrin β tail-binding region, and in vitro assays show LARP4 competes with integrin β7 tails for FLNA R21 binding. Cancer-associated A279Cfs*2 and experimental F277A mutations disrupt binding; N275S alters membrane localization without affecting FLNA binding. |
X-ray crystallography, protein-protein interaction assays, site-directed mutagenesis, cell migration assay, in vitro competition assay |
Journal of Molecular Biology |
High |
40466905
|
| 2024 |
LARP4's conserved region-2 (CR2; positions 615–625) directly binds RACK1 (a ribosome-associated protein) at RACK1 propellers 5 and 6 (residues 200–317), as established by yeast two-hybrid mapping, in vitro binding, AlphaFold2-Multimer prediction, and confirmed by CR2 mutations that abolish RACK1 and ribosome association. CR2 mutations reduce LARP4's ability to stabilize ARE-containing mRNAs and impair LARP4-mediated translational efficiency of ARE-mRNAs, while PABP association is less affected, indicating independent interactions. |
Yeast two-hybrid domain mapping, in vitro binding assay, AlphaFold2-Multimer structural prediction, site-directed mutagenesis, polysome profiling, luciferase reporter assay, Co-immunoprecipitation |
Nucleic Acids Research |
High |
39898547
|
| 2024 |
LARP4 preprint (same study as PMID 39898547): CR2 of LARP4 (positions 615–625) directly binds RACK1 region 200–317; CR2 mutations abolish RACK1/ribosome association without equally affecting PABP; LARP4 promotes translational efficiency of ARE-containing mRNAs via this CR2–RACK1 interaction. |
Yeast two-hybrid, in vitro binding, mutagenesis, polysome profiling, nanoLuc reporter assay |
bioRxivpreprint |
Medium |
39554137
|
| 2024 |
LARP4 binds nuclear-encoded mitochondrial mRNAs (NEMmRNAs), particularly those encoding respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs). LARP4 depletion significantly reduces RCCP and MRP protein levels by quantitative proteomics and reduces mitochondrial function; LARP4 re-expression rescues mitochondrial respiratory function. |
CLIP-seq (systematic RBP-RNA target analysis across 150 RBPs), quantitative proteomics after LARP4 depletion, mitochondrial function assays, rescue by LARP4 re-expression |
RNA (New York, N.Y.) |
Medium |
38164626
|
| 2024 |
PEDV coronavirus infection induces nuclear-to-cytoplasmic shuttling of LARP4 via a CRM1-independent pathway. Cytoplasmic LARP4 binds the 3'UTR of PEDV mRNA with assistance from PABPC1 to facilitate viral mRNA translation. LARP4 knockdown reduces PABPC1-induced 3'UTR translation activity. Purified prokaryotic LARP4 and PABPC1 together enhance PEDV mRNA translation in a rabbit reticulocyte lysate (RRL) system. |
Subcellular fractionation/localization, LARP4 knockdown, RRL in vitro translation assay, reporter assays |
Veterinary Microbiology |
Medium |
39182469
|
| 2025 |
LARP4 drives hypertranslation in exhausted/dysfunctional intratumoral T cells by selectively enhancing translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion, and enhances anti-tumor effector persistence. LARP4 knockdown in CAR-T cells prevents terminal exhaustion. |
Conditional Larp4 knockout in T cells, translatome profiling, mitochondrial function assays, in vivo tumor models, CAR-T cell functional assays |
Nature Immunology |
High |
40696044
|
| 2025 |
Conditional knockout of LARP4 in naive CD4+ T cells enhances quiescence and dampens quiescence exit by altering stability of mRNAs important for T cell activation, impairing differentiation into helper T cell subsets. A peptide inhibitor of LARP4 (LIPEP) mimics LARP4 deficiency and ameliorates autoimmune and allergic responses in mouse models. |
Conditional knockout mouse, mRNA stability analysis, T cell differentiation assays, peptide inhibitor in vivo mouse disease models |
Nature Biomedical Engineering |
High |
41102557
|
| 2024 |
LARP4 cooperates with TENT5C cytoplasmic poly(A) polymerase in erythropoiesis: LARP4/5 depletion leads to downregulation and poly(A) tail shortening of globin mRNAs. Proteomic experiments revealed a transient but specific association of TENT5C with LARP4/5. Lack of TENT5C catalytic activity is accompanied by compensatory upregulation of LARP4/5, indicating functional redundancy in protecting globin mRNA poly(A) tails. |
Proteomics (Co-AP/MS), poly(A) tail length sequencing, LARP4/5 depletion, TENT5C catalytic mutant knock-in mice |
bioRxivpreprint |
Medium |
bio_10.1101_2024.11.14.623596
|
| 2017 |
The LARP4 mRNA contains a translation-dependent coding region determinant (CRD) of instability comprising <10% of codons; synonymous substitutions accommodating tRNA dynamics cause >20-fold variation in LARP4 mRNA levels. Overexpression of the most limiting tRNA increases LARP4 protein levels, indicating LARP4 expression is controlled by codon-tRNA matching during translation. |
Synonymous codon substitution, tRNA overexpression, mRNA level measurement |
eLife |
Medium |
28895529
|