{"gene":"KHSRP","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1997,"finding":"KSRP was purified and cloned as a component of a multiprotein complex binding to an intronic splicing enhancer downstream of the neuron-specific c-src N1 exon; antibodies to KSRP inhibited N1 exon splicing in vitro, and this inhibition was rescued by addition of purified KSRP; KSRP contains four KH RNA-binding domains and induces assembly of five other proteins including hnRNP F onto the splicing enhancer.","method":"Protein purification, cDNA cloning, in vitro splicing assay with antibody inhibition and rescue by purified protein, co-purification of multiprotein complex","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of splicing activity, antibody inhibition rescued by purified protein, multiple orthogonal methods in founding paper","pmids":["9136930"],"is_preprint":false},{"year":2004,"finding":"KSRP is an essential factor for ARE-directed mRNA decay; specific KH domains directly mediate RNA binding, mRNA decay, and physical interactions with the exosome and poly(A) ribonuclease (PARN); the ability of KH motifs to promote mRNA decay correlates with their ability to bind the ARE and associate with RNA-degrading enzymes.","method":"In vitro mRNA decay assays, domain mutagenesis, co-immunoprecipitation of KSRP with exosome and PARN, ARE-binding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro assay with mutagenesis, direct biochemical interaction with decay machinery, multiple orthogonal methods","pmids":["15175153"],"is_preprint":false},{"year":2005,"finding":"p38α and p38β MAP kinase phosphorylates KSRP during muscle differentiation; p38-phosphorylated KSRP displays compromised binding to ARE-containing myogenic transcripts and fails to promote their rapid decay, although it retains ability to interact with mRNA degradation machinery; this stabilizes critical myogenic mRNAs and is required for proper myoblast-to-myocyte conversion.","method":"In vitro kinase assay (p38 phosphorylation of KSRP), RNA-binding assays with phosphorylated vs. unphosphorylated KSRP, KSRP overexpression in myoblasts with transcriptional and post-transcriptional readouts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, RNA binding comparison, multiple cellular readouts in a single rigorous study","pmids":["16364914"],"is_preprint":false},{"year":2005,"finding":"KSRP binds the 3'-UTR ARE of human iNOS mRNA and promotes its decay by recruiting the exosome; KSRP competes with the stabilizing factor HuR for the same ARE binding site; KSRP also co-immunoprecipitates with tristetraprolin (TTP); a non-binding KSRP mutant fails to reduce iNOS expression, confirming the requirement for ARE binding.","method":"Immunodepletion in vitro degradation assays, overexpression of wild-type and non-binding mutant KSRP, co-immunoprecipitation with exosome and TTP, competition binding assay with HuR","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro degradation assay, mutagenesis, reciprocal co-IP, competition assay, single lab","pmids":["16126846"],"is_preprint":false},{"year":2006,"finding":"AKT phosphorylates KSRP at a unique serine residue; this induces KSRP association with 14-3-3 proteins and prevents KSRP interaction with the exosome, impairing its ability to promote rapid mRNA decay; this mechanism stabilizes beta-catenin mRNA downstream of PI3K-AKT and Wnt signaling.","method":"In vitro AKT kinase assay, co-immunoprecipitation of KSRP with 14-3-3 and exosome under PI3K-AKT activation/inhibition, mRNA half-life measurements, mutagenesis of phosphorylation site","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, site-directed mutagenesis, co-IP with decay complex, mRNA decay assays, single lab","pmids":["17177604"],"is_preprint":false},{"year":2006,"finding":"Tethering KSRP to mRNAs via fusion with sequence-specific RNA-binding proteins elicits mRNA decay in a manner dependent on known mRNA decay enzymes; this demonstrates that KSRP functions by recruiting mRNA decay machinery to target transcripts.","method":"Tethering assay using Rev-KSRP fusion protein targeting HIV-1 RRE; mRNA stability measurements; viral replication assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — functional reconstitution via tethering, dependence on decay enzymes shown, single lab","pmids":["16648466"],"is_preprint":false},{"year":2007,"finding":"The KH3 and KH4 domains of KSRP behave as independent RNA-binding modules recognizing different regions of AU-rich RNA targets; KH4 binds AREs with lower affinity than KH3; mRNA binding and mRNA degradation activities of KSRP are closely associated with a conserved structural element unique to KH4.","method":"NMR structure determination of KH3 and KH4, RNA-binding affinity measurements (ITC/NMR), mutagenesis of KH4 structural element","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structures with functional validation, mutagenesis, binding affinity measurements","pmids":["17437720"],"is_preprint":false},{"year":2007,"finding":"KSRP knockdown by siRNA stabilizes IL-8 mRNA and impairs its rapid deadenylation; KSRP interacts with both domains of the bipartite IL-8 ARE; IL-1 treatment impairs the interaction of KSRP with the IL-8 ARE in a p38-dependent but MK2-independent manner; microarray pulldown identified ~100 mRNAs controlled by KSRP.","method":"siRNA knockdown, mRNA half-life and deadenylation assays, RNA pulldown with KSRP followed by microarray, co-immunoprecipitation, pharmacological inhibition of p38/MK2","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA KD with mechanistic readouts, RNA pulldown-microarray, multiple orthogonal approaches, replicated across targets","pmids":["17908789"],"is_preprint":false},{"year":2008,"finding":"Among the four KH domains of KSRP, KH3 binds RNA with the highest affinity and specifically recognizes G-rich sequences; the other KH domains display different sequence preferences explaining the broad target range; KSRP shows strong negative selectivity for sequences with multiple adjacent cytosines.","method":"Scaffold-independent RNA-binding analysis of all four KH domains using NMR and ITC; systematic sequence selectivity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro binding assays for all four domains with multiple orthogonal methods, single lab","pmids":["18684992"],"is_preprint":false},{"year":2009,"finding":"KSRP is a component of both Drosha and Dicer complexes; KSRP binds with high affinity to the terminal loop of target miRNA precursors and promotes their maturation; this function is required for specific changes in target mRNA expression affecting proliferation, apoptosis, and differentiation.","method":"Co-immunoprecipitation of KSRP with Drosha and Dicer complexes, RNA immunoprecipitation, in vitro processing assays, KSRP knockdown with miRNA profiling, NMR binding studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP with Drosha/Dicer, in vitro processing assays, NMR binding, multiple labs/methods, high-impact replicated finding","pmids":["19458619"],"is_preprint":false},{"year":2009,"finding":"AKT-mediated phosphorylation of KSRP's KH1 domain causes KH1 unfolding (KH1 is structurally atypical and unstable), creating a binding site for 14-3-3ζ; 14-3-3ζ binding discriminates phosphorylated from unphosphorylated KH1 and drives nuclear localization of KSRP, sequestering it from cytoplasmic mRNA decay activity.","method":"NMR structure of KH1 (phosphorylated and unphosphorylated), 14-3-3ζ binding assays, localization studies, mRNA decay assays in cells with phosphomimetic/phosphodead mutants","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional validation, phosphorylation-dependent binding and localization assays, mutagenesis, multiple methods","pmids":["19198587"],"is_preprint":false},{"year":2009,"finding":"KSRP co-immunoprecipitates with PTH mRNA, the exosome, and the endoribonuclease PMR1; KSRP and exosome knockdown by siRNA prevents PMR1-mediated cleavage of PTH mRNA, establishing that PTH mRNA decay by PMR1 is dependent on both KSRP and the exosome.","method":"Co-immunoprecipitation of KSRP, PMR1, and exosome; siRNA knockdown of KSRP and exosome subunits; in vitro RNA cleavage assays","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, siRNA knockdown with functional readout, in vitro assays, single lab","pmids":["19775426"],"is_preprint":false},{"year":2010,"finding":"hnRNP A1 binds the terminal loop of pri-let-7a-1 and inhibits Drosha processing; hnRNP A1 binding to let-7a interferes with KSRP binding to the same terminal loop, establishing antagonistic roles for hnRNP A1 (negative regulator) and KSRP (positive regulator) in let-7a biogenesis.","method":"RNA-protein binding competition assays, in vitro Drosha processing assays, cell-based depletion/overexpression of hnRNP A1 and KSRP with miRNA quantification","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro processing assays, binding competition, multiple cellular validations, independent replication","pmids":["20639884"],"is_preprint":false},{"year":2010,"finding":"KSRP interacts with Dishevelled (Dvl) proteins; KSRP negatively regulates Wnt/beta-catenin signaling by promoting post-transcriptional destabilization of CTNNB1 (beta-catenin) mRNA; identified by affinity purification coupled to ion-trap mass spectrometry.","method":"Affinity purification followed by mass spectrometry identification of KSRP as Dvl-binding protein; mRNA stability assays for beta-catenin mRNA; co-immunoprecipitation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mass spectrometry-identified interaction confirmed by co-IP, mRNA stability assay, single lab","pmids":["20332102"],"is_preprint":false},{"year":2010,"finding":"The inter-domain linker between KH2 and KH3 orients the two central KH domains of KSRP with their RNA-binding surfaces aligned, creating a two-domain unit; this interdomain arrangement is functionally important for interaction with KSRP's RNA targets.","method":"NMR structural analysis of interdomain linker and relative domain orientation; RNA binding assays comparing wild-type and linker-mutated constructs","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation, binding assays, single lab","pmids":["20385598"],"is_preprint":false},{"year":2011,"finding":"KSRP is required for ARE-mediated decay of Ifna4 and Ifnb mRNAs; KSRP knockout mouse embryonic fibroblasts produce higher levels of type I IFN mRNAs following viral infection due to decreased mRNA decay; increased IFN expression renders Ksrp-/- cells refractory to HSV-1 and VSV infection.","method":"Ksrp knockout mouse MEFs, viral infection, mRNA half-life measurements, RNA immunoprecipitation, antiviral protection assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined mechanistic readout (mRNA decay), RNA-protein interaction, multiple viruses tested","pmids":["21690298"],"is_preprint":false},{"year":2011,"finding":"KSRP participates in ARE-mediated translational silencing in addition to mRNA decay; KSRP depletion increases polysome association of IL-6 and IL-1α mRNAs; silencing depends on the 3'-UTR ARE of IL-6 mRNA; IL-1 reverses KSRP-dependent translational silencing.","method":"Polysome profiling after siRNA-mediated KSRP depletion, luciferase reporter assays with IL-6 3'UTR, KSRP-RNA interaction mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome fractionation, reporter assay, siRNA knockdown, single lab","pmids":["21795706"],"is_preprint":false},{"year":2011,"finding":"PI3K/AKT activation regulates two distinct KSRP functions in opposite directions during skeletal myogenesis: it inhibits KSRP's ability to promote decay of myogenin mRNA while simultaneously activating its ability to favor maturation of myogenic miRNAs; this dynamic switch is required for the myogenic program as demonstrated in C2C12 cells and Ksrp knockout mice.","method":"C2C12 myoblast differentiation, Ksrp-/- mouse analysis, PI3K/AKT inhibition/activation, miRNA processing assays, mRNA stability measurements","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mice + cell culture, two distinct functional readouts, multiple signaling interventions, single lab","pmids":["21886180"],"is_preprint":false},{"year":2012,"finding":"KSRP KH3 domain recognizes a G-rich sequence in the pre-let-7 terminal loop via a noncanonical KH-RNA interaction mode; the KH3-RNA complex structure reveals how this noncanonical binding governs KSRP selectivity for let-7 precursors; this selectivity is crucial for the functional interaction between KSRP and let-7 biogenesis.","method":"NMR structure of KH3 bound to pre-let-7 terminal loop G-rich sequence, mutagenesis of KH3 and RNA, functional processing assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional mutagenesis validation, mechanistic insight into selectivity, multiple orthogonal methods","pmids":["23142982"],"is_preprint":false},{"year":2012,"finding":"HuR promotes myogenesis by associating with the decay factor KSRP and ribonucleases PARN and the exosome to destabilize nucleophosmin (NPM) mRNA; the C terminus of HuR mediates formation of the HuR-KSRP complex; this HuR-KSRP-PARN-exosome complex reduces NPM mRNA levels required for muscle cell commitment.","method":"Co-immunoprecipitation of HuR-KSRP complex, mRNA stability assays, domain deletion analysis of HuR, siRNA knockdown of HuR, overexpression studies","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mRNA decay assays, domain mapping, single lab","pmids":["24969639"],"is_preprint":false},{"year":2012,"finding":"Phosphorylated R-SMAD proteins (transducers of BMP2 signaling) associate with phosphorylated KSRP and block its interaction with primary myogenic miRNAs (myomiRs), preventing KSRP-dependent myomiR maturation; silencing SMAD4, SMAD5, and SMAD9 rescues KSRP function; this SMAD-mediated KSRP blockade is required for BMP2-induced osteoblastic differentiation.","method":"Co-immunoprecipitation of phospho-SMAD with phospho-KSRP, RNA immunoprecipitation, siRNA knockdown of SMADs, miRNA processing assays, cell differentiation readouts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of signal transducers with KSRP, RIP, SMAD knockdown rescue, single lab","pmids":["23177623"],"is_preprint":false},{"year":2013,"finding":"KSRP destabilizes GAP-43 mRNA by binding its ARE, a process requiring its KH4 domain; KSRP competes with the stabilizing factor HuD for binding to GAP-43 ARE sequences; KSRP overexpression hinders axonal outgrowth in primary hippocampal neurons, while KSRP knockdown increases GAP-43 mRNA and dramatically increases axonal length in both cultured neurons and Ksrp+/- and Ksrp-/- embryos.","method":"RNA-binding assays (KH domain deletion mutants), competition assays with HuD, overexpression/knockdown in primary hippocampal neurons, Ksrp knockout mouse neurons, axonal length measurements","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis, competition binding, genetic KO neurons, cellular phenotype with molecular rescue, replicated in vitro and in vivo","pmids":["24244461"],"is_preprint":false},{"year":2013,"finding":"KSRP promotes decay of Per2 mRNA via AU-rich elements in Per2's 3' UTR, and KSRP ablation increases Per2 expression causing a phase delay in circadian clock gene oscillations and reduced expression of de novo lipogenic genes, leading to reduced hepatic triglyceride accumulation.","method":"Ksrp-/- mouse liver analysis, heterologous mRNA reporter assays with Per2 3'UTR, mRNA half-life measurements in primary hepatocytes, circadian gene profiling","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO + reporter assay + mRNA decay measurement, single lab","pmids":["25514904"],"is_preprint":false},{"year":2013,"finding":"p38 activation increases utrophin A mRNA stability through AU-rich elements by reducing the functional availability of KSRP; KSRP directly binds AREs in the utrophin A 3'UTR; electroporation-mediated knockdown of KSRP increases utrophin A in wild-type and mdx mouse muscles.","method":"In vitro and in vivo KSRP-RNA binding studies, mRNA half-life assays, electroporation knockdown in mouse muscle, p38 activation with heparin in mdx mice","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein binding shown, in vivo knockdown with phenotypic readout, single lab","pmids":["23575223"],"is_preprint":false},{"year":2013,"finding":"The RNA helicase DDX1 interacts with KSRP and regulates its subcellular localization; DDX1 knockdown elevates cytoplasmic levels of KSRP and facilitates ARE-mediated mRNA decay; KSRP associates with DDX1 or 14-3-3 proteins in a mutually exclusive manner, indicating competing interactions that regulate KSRP's cytoplasmic availability.","method":"Affinity purification and mass spectrometry identification of DDX1, co-immunoprecipitation, DDX1 siRNA knockdown, subcellular fractionation, mRNA decay assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP, subcellular fractionation, functional mRNA decay readout, single lab","pmids":["24023901"],"is_preprint":false},{"year":2014,"finding":"KSRP directly binds the H19 lncRNA in the cytoplasm of undifferentiated C2C12 cells, and this interaction facilitates KSRP-mediated destabilization of labile transcripts including myogenin mRNA; AKT activation induces KSRP dismissal from H19; upon dismissal, KSRP is repurposed to promote maturation of myogenic miRNAs; H19 thus acts as a molecular scaffold that optimizes an AKT-regulated post-transcriptional switch.","method":"RNA immunoprecipitation, in vitro RNA-protein binding assays, AKT activation/inhibition, mRNA stability assays, miRNA processing assays in C2C12 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, in vitro binding, functional mRNA decay and miRNA processing assays, single lab","pmids":["25385579"],"is_preprint":false},{"year":2014,"finding":"KSRP ablation causes a reduction in body adiposity; in Ksrp-/- inguinal WAT, expression of miR-150 is decreased due to impaired primary miR-150 processing; miR-150 directly targets PRDM16 and PPARGC1A; forced miR-150 expression attenuates elevated brown fat gene expression caused by KSRP deletion, establishing a pathway KSRP → miR-150 → PRDM16/PPARGC1A controlling brown-like transformation of white fat.","method":"Ksrp-/- mouse analysis, miRNA processing assays, miRNA mimic rescue experiments, miR-150 target validation by luciferase assay","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with miRNA rescue, target validation by reporter assay, single lab","pmids":["24722250"],"is_preprint":false},{"year":2014,"finding":"In Ksrp-/- epididymal WAT, miR-145 expression is decreased due to impaired primary miR-145 processing; miR-145 directly targets and represses FOXO1 and CGI58, activators of lipolysis; forced miR-145 expression attenuates enhanced lipolysis in KSRP-deficient adipose tissue, establishing a KSRP → miR-145 → FOXO1/CGI58 pathway controlling adipose lipolysis.","method":"Ksrp-/- mouse WAT analysis, miRNA processing assays, miR-145 target validation by luciferase assay, miR-145 mimic rescue in primary adipocytes","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, miRNA processing, reporter assay target validation, rescue experiment, single lab","pmids":["24732799"],"is_preprint":false},{"year":2016,"finding":"KHSRP is ubiquitinated at Lys109, Lys121, and Lys122 by the Kelch domain of KLHL12 interacting with KHSRP's C-terminal domain; mutations at these sites abolish KHSRP's inhibitory effect on enterovirus IRES-driven translation; ubiquitination of KHSRP (a negative ITAF) thus controls IRES-dependent translation by limiting competition against positive ITAFs.","method":"In vivo and in vitro SUMOylation/ubiquitination assays, site-directed mutagenesis of ubiquitination sites, Ni2+-NTA pulldown, co-immunoprecipitation of KLHL12-KHSRP, IRES-luciferase reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination assay, site mutagenesis, co-IP identification of E3 ligase adaptor, functional reporter assay, single lab with multiple methods","pmids":["27899653"],"is_preprint":false},{"year":2016,"finding":"miR-27b-3p-mediated silencing of KHSRP is required for TGF-β-induced EMT in mammary gland cells; KHSRP controls levels of mature miR-192-5p (targeting EMT factors) and promotes epithelial-type alternative splicing of pre-mRNAs including Cd44 and Fgfr2; KHSRP and hnRNPA1 cooperate in a ribonucleoprotein complex to promote epithelial exon usage.","method":"miR-27b-3p overexpression/knockdown, KHSRP knockdown/overexpression, genome-wide RNA-seq and miRNA-seq, co-immunoprecipitation of KHSRP-hnRNPA1 complex, splicing assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide sequencing, co-IP, functional EMT readout, single lab","pmids":["27396342"],"is_preprint":false},{"year":2017,"finding":"KHSRP is modified by SUMO1 at the major site K87; this modification inhibits KHSRP's interaction with pri-miRNA/Drosha-DGCR8 complex and promotes KHSRP translocation from nucleus to cytoplasm; SUMOylation consequently impairs processing of pre-miRNAs from pri-miRNAs with G-rich terminal loops (TL-G-Rich miRNAs including let-7 family), leading to tumorigenesis.","method":"In vivo and in vitro SUMOylation assays, site-directed mutagenesis (K87), nuclear/cytosol fractionation, immunofluorescence, RIP, high-throughput miRNA sequencing, xenograft tumor models","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vivo and in vitro SUMOylation, mutagenesis, localization, RIP, miRNA-seq, functional tumor assays, multiple orthogonal methods","pmids":["29020972"],"is_preprint":false},{"year":2017,"finding":"KHSRP associates with the regulatory domain of RIG-I to maintain the receptor in an inactive state and attenuate its sensing of viral RNA; KHSRP knockdown enhances RIG-I antiviral signaling and reduces viral replication both in vitro and in vivo.","method":"RNAi screens integrated with interactome data, co-immunoprecipitation of KHSRP with RIG-I regulatory domain, RIG-I signaling assays upon KHSRP knockdown, in vitro and in vivo viral infection models","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying specific domain interaction, functional signaling assay, in vivo validation, single lab","pmids":["28248290"],"is_preprint":false},{"year":2002,"finding":"Xenopus KSRP homolog VgRBP71 binds to mRNAs localized to either vegetal or animal hemispheres in oocytes but does not accumulate at the vegetal cortex with the mRNA; VgRBP71 interacts with Prrp (another Vg1 localization element-binding protein) in a manner that does not require Vg1 mRNA.","method":"Xenopus oocyte expression library screen, in vivo RNA-protein binding assays, co-immunoprecipitation of VgRBP71-Prrp interaction, localization studies","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo binding assay in Xenopus, co-IP of protein complex, localization analysis; ortholog study","pmids":["12421702"],"is_preprint":false},{"year":2002,"finding":"KSRP/FBP2 is cleaved by caspase-3 and caspase-7 at two sites: after Asp102 and after Asp183; the second cleavage site is only recognized in protein produced in cells (not in vitro translated protein), indicating that cellular context beyond primary sequence affects caspase recognition.","method":"In vitro caspase cleavage of KSRP with caspase-3 and -7, comparison of cellular vs. in vitro translated KSRP, site identification by mass spectrometry","journal":"Protein and peptide letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro cleavage assay, site identification, single lab, limited mechanistic follow-up","pmids":["12553859"],"is_preprint":false},{"year":2022,"finding":"Khsrp mRNA localizes into peripheral nerve axons and is locally translated following axon injury; axonal KSRP levels rapidly increase after sciatic nerve injury and remain elevated; KHSRP binds to mRNAs with 3'UTR AU-rich elements (Gap43, Snap25, Fubp1) and targets them to the cytoplasmic exosome for degradation; Ksrp-/- mice show increased axonal levels of these target mRNAs and accelerated nerve regeneration in vivo.","method":"Targeted proteomics of axoplasm, Ksrp-/- mouse nerve injury model, local translation assay with axon ligation, RNA immunoprecipitation, mRNA stability measurements in axons, in vivo nerve regeneration assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — targeted proteomics, genetic KO with in vivo regeneration phenotype, local translation assay, RIP, multiple target mRNAs validated","pmids":["35556128"],"is_preprint":false},{"year":2022,"finding":"KHSRP regulates monocytic differentiation through both transcriptional and post-transcriptional mechanisms; KHSRP occupies specific genomic sites at promoter and enhancer regions to regulate hematopoietic gene transcription, and binds to pre-mRNA intronic regions to modulate alternative splicing; KHSRP has co-regulatory effects at both transcriptional and post-transcriptional levels on MOGOH and ADARB1.","method":"ChIP-seq, RNA-seq, CLIP-seq in CD34+ cells during monocytic differentiation, functional knockdown studies","journal":"Blood science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq with functional knockdown, single lab, genome-wide analysis","pmids":["36518592"],"is_preprint":false},{"year":2024,"finding":"KHSRP directly interacts with SF3B1 (splicing factor 3b subunit 1) and enhances SF3B1 binding to intronic branch sites, thereby promoting pre-mRNA splicing; KHSRP knockdown causes intron retention and exacerbates liver injury in acute liver failure models.","method":"Co-immunoprecipitation of KHSRP-SF3B1 interaction, RNA-seq analysis of splicing defects in KHSRP-knockdown cells and murine ALF models, splicing inhibitor experiments in vivo, proteomic and transcriptomic analyses","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mechanistic readout, in vivo functional validation, single lab","pmids":["39187547"],"is_preprint":false},{"year":2024,"finding":"KHSRP functions as an m6A-binding protein; KHSRP recognizes m6A modifications and stabilizes FAK pathway mRNAs including MET, ITGAV, and ITGB1 in an m6A-dependent manner, leading to activation of downstream FAK signaling and promotion of pancreatic ductal adenocarcinoma progression.","method":"m6A-RIP, RNA immunoprecipitation, KHSRP knockdown/overexpression with mRNA stability assays, FAK pathway activity assays, in vivo xenograft models, PROTAC-mediated KHSRP degradation","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP, mRNA stability assay, in vivo model, multiple target mRNAs, single lab","pmids":["39120596"],"is_preprint":false},{"year":2024,"finding":"SIRT7 is a deacetylase of KHSRP; androgen stimulation impairs SIRT7 interaction with KHSRP, leading to increased KHSRP acetylation; acetylated KHSRP has impaired mRNA decay activity for DDR-related mRNAs, promoting prostate cancer tumorigenesis.","method":"Co-immunoprecipitation of SIRT7-KHSRP interaction, acetylation assays under androgen stimulation, RNA-seq and GSEA for DDR gene changes, xenograft tumor growth with acetylation-site mutants","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying deacetylase, functional mRNA decay assays, in vivo xenograft, single lab","pmids":["38501452"],"is_preprint":false},{"year":2015,"finding":"KHSRP and hnRNPA1 form a ribonucleoprotein complex and cooperate to promote epithelial-type exon usage during splicing; combined silencing of both prevents RESV-dependent inclusion of epithelial-type exons in Cd44 pre-mRNA; hnRNP A1 also tethers KSRP to an exonic splicing silencer (ESS16) and KSRP binding to ESS16 requires hnRNP A1.","method":"Co-immunoprecipitation of KHSRP-hnRNPA1 complex, combined siRNA knockdown, splicing assays, 2D gel and mass spectrometry identification in erythroleukemia cells","journal":"American journal of cancer research / Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, MS identification, combinatorial knockdown, splicing assay, single lab each","pmids":["26101706","28088441"],"is_preprint":false}],"current_model":"KHSRP/KSRP is a multifunctional single-strand nucleic acid-binding protein with four KH domains (KH3 having highest affinity for G-rich sequences, KH4 bearing a noncanonical structural element critical for ARE recognition and mRNA decay) that operates through at least three core post-transcriptional mechanisms: (1) it recruits the exosome, PARN, and PMR1 to AU-rich elements in target mRNA 3'-UTRs to promote rapid mRNA decay and translational silencing; (2) it is an integral component of both Drosha and Dicer complexes, binding G-rich terminal loops of select miRNA precursors to promote their maturation (e.g., let-7, miR-155, miR-129, myomiRs, miR-150, miR-145); and (3) it associates with hnRNP A1, SF3B1, and intronic/exonic elements to regulate alternative pre-mRNA splicing; these functions are regulated by multiple post-translational modifications — AKT-dependent phosphorylation of KH1 causes its unfolding, 14-3-3ζ binding, and nuclear sequestration; p38-dependent phosphorylation impairs ARE binding; KLHL12-mediated ubiquitination at K109/K121/K122 controls IRES-driven translation; SUMO1 modification at K87 inhibits Drosha complex interaction and promotes nuclear-to-cytoplasmic translocation; SIRT7 acts as a deacetylase to oppose androgen-induced KHSRP acetylation that impairs DDR mRNA decay; additionally, KHSRP associates with RIG-I's regulatory domain to suppress innate immune sensing, binds the H19 lncRNA as a molecular scaffold, and acts as an m6A reader to stabilize specific target mRNAs in cancer contexts."},"narrative":{"mechanistic_narrative":"KHSRP (KSRP) is a multifunctional single-strand nucleic-acid-binding protein with four KH domains that governs gene expression at the post-transcriptional level through three interlocking activities: ARE-directed mRNA decay, selective miRNA maturation, and pre-mRNA splicing control [PMID:15175153, PMID:19458619, PMID:27396342]. As a decay factor, it binds AU-rich elements in target 3'-UTRs and recruits the exosome and the deadenylase PARN, with specific KH domains coupling RNA recognition to physical engagement of the degradation machinery; tethering KSRP to an mRNA is sufficient to trigger decay [PMID:15175153, PMID:16648466], and it extends this activity to translational silencing of ARE-containing transcripts [PMID:21795706]. Domain-level structural work defines how it reads RNA: KH3 binds with highest affinity and recognizes G-rich sequences, while KH4 carries a conserved noncanonical element essential for ARE binding and decay [PMID:17437720, PMID:18684992], and a KH2–KH3 interdomain linker aligns the two central modules into a functional unit [PMID:20385598]. The same G-rich recognition by KH3 underlies its second role as a component of both Drosha and Dicer complexes, where it binds the terminal loops of select pri/pre-miRNAs (e.g., let-7) to promote their maturation [PMID:19458619, PMID:23142982]. In its third role it associates with hnRNP A1 and SF3B1 to direct alternative and constitutive splicing, including the founding c-src N1 exon enhancer activity and epithelial-type exon usage [PMID:9136930, PMID:39187547, PMID:26101706, PMID:28088441]. These activities are toggled by an extensive regulatory layer: AKT phosphorylation of KH1 drives its unfolding, 14-3-3ζ binding, and nuclear sequestration away from cytoplasmic decay [PMID:17177604, PMID:19198587]; p38 phosphorylation impairs ARE binding [PMID:16364914]; SUMO1 modification at K87 blocks Drosha interaction and promotes nuclear export [PMID:29020972]; and KLHL12-mediated ubiquitination, DDX1 competition, and SIRT7-opposed acetylation provide further control [PMID:27899653, PMID:24023901, PMID:38501452]. Through these mechanisms KHSRP shapes diverse physiological programs including skeletal myogenesis, adipose biology, circadian/lipogenic control, axon regeneration, antiviral type I IFN responses, and tumorigenesis [PMID:21886180, PMID:24722250, PMID:25514904, PMID:35556128, PMID:21690298, PMID:39120596].","teleology":[{"year":1997,"claim":"Established KSRP as a sequence-specific splicing regulator, defining its founding biochemical activity and its four-KH-domain architecture before any decay role was known.","evidence":"Protein purification, cDNA cloning, and in vitro splicing assays with antibody inhibition rescued by purified protein at the c-src N1 intronic splicing enhancer","pmids":["9136930"],"confidence":"High","gaps":["Did not define direct RNA contacts at residue resolution","Did not connect splicing role to subsequent decay or miRNA functions"]},{"year":2002,"claim":"Ortholog and degradation studies broadened the protein's recognized scope—RNA localization in oocytes and caspase cleavage—hinting at regulated turnover and developmental roles.","evidence":"Xenopus VgRBP71 RNA-binding and Prrp co-IP; in vitro caspase-3/-7 cleavage mapping of KSRP/FBP2","pmids":["12421702","12553859"],"confidence":"Medium","gaps":["Functional consequence of caspase cleavage in cells not defined","Ortholog localization role not connected to mammalian decay function"]},{"year":2004,"claim":"Defined KSRP as an essential ARE-mediated decay factor that couples RNA binding to recruitment of the exosome and PARN, establishing its core post-transcriptional mechanism.","evidence":"In vitro mRNA decay assays, KH domain mutagenesis, and co-IP of KSRP with exosome and PARN","pmids":["15175153"],"confidence":"High","gaps":["Did not resolve which KH domains contact ARE versus decay enzymes structurally","In vitro decay not yet linked to endogenous target half-lives"]},{"year":2005,"claim":"Showed signaling kinases gate decay activity and that KSRP competes with stabilizing factors, framing it as a regulated, antagonistic node in mRNA turnover.","evidence":"In vitro p38 kinase assay with ARE-binding comparison in myoblasts; iNOS ARE decay with HuR competition and TTP co-IP","pmids":["16364914","16126846"],"confidence":"High","gaps":["p38 phosphorylation site(s) not mapped","Mechanism by which phospho-KSRP retains decay-enzyme binding but loses RNA binding unclear"]},{"year":2006,"claim":"Demonstrated that KSRP acts by recruiting decay machinery to transcripts and that AKT signaling inactivates this via 14-3-3, establishing a kinase-controlled decay switch.","evidence":"Rev-KSRP tethering decay assay; in vitro AKT kinase assay, 14-3-3 and exosome co-IP, and mRNA half-life measurements with phospho-site mutants","pmids":["16648466","17177604"],"confidence":"High","gaps":["Tethering relied on heterologous RNA targeting","Single AKT serine not yet structurally explained"]},{"year":2007,"claim":"Resolved the structural logic of RNA recognition—KH3 highest-affinity G-rich binding, KH4 decay-critical element—and mapped the endogenous target repertoire.","evidence":"NMR structures of KH3/KH4 with ITC binding and mutagenesis; siRNA knockdown with IL-8 decay/deadenylation readouts and RNA pulldown-microarray","pmids":["17437720","17908789"],"confidence":"High","gaps":["Full-length four-domain RNA complex not resolved","How individual domains combine on a single transcript not defined"]},{"year":2008,"claim":"Systematically defined the sequence selectivity of all four KH domains, explaining how one protein binds a broad but biased target range.","evidence":"Scaffold-independent NMR/ITC binding analysis of all four KH domains with selectivity assays","pmids":["18684992"],"confidence":"High","gaps":["Selectivity measured per isolated domain, not in full-length context","In vivo target preference not directly tested here"]},{"year":2009,"claim":"Expanded KSRP from a decay factor into a miRNA biogenesis factor, showing it is part of Drosha and Dicer complexes and selectively promotes maturation of G-rich-loop precursors.","evidence":"Reciprocal co-IP with Drosha/Dicer, RIP, in vitro processing assays, KSRP knockdown miRNA profiling, and NMR binding","pmids":["19458619"],"confidence":"High","gaps":["How the same protein partitions between decay and processing complexes not resolved","Determinants of precursor selectivity awaited later structural work"]},{"year":2009,"claim":"Provided the structural mechanism of AKT-driven nuclear sequestration, showing KH1 phosphorylation triggers unfolding and 14-3-3ζ-dependent relocalization, and confirmed exosome dependence for additional endoribonucleolytic targets.","evidence":"NMR of phospho/unphospho KH1 with 14-3-3ζ binding and localization assays; KSRP/PMR1/exosome co-IP and siRNA for PTH mRNA cleavage","pmids":["19198587","19775426"],"confidence":"High","gaps":["Kinetics of nuclear-cytoplasmic shuttling in vivo not quantified","PMR1-KSRP findings from single lab"]},{"year":2010,"claim":"Established antagonistic and architectural controls on KSRP function: hnRNP A1 competes for let-7 terminal loops while the KH2–KH3 linker organizes the central RNA-binding unit, and KSRP destabilizes beta-catenin mRNA downstream of Dishevelled.","evidence":"In vitro Drosha processing with binding competition; NMR interdomain orientation analysis; Dvl affinity-MS, co-IP, and beta-catenin mRNA stability assays","pmids":["20639884","20385598","20332102"],"confidence":"High","gaps":["How signaling redirects KSRP versus hnRNP A1 occupancy not fully defined","Dvl-KSRP interaction from a single study"]},{"year":2011,"claim":"Genetic and functional studies tied KSRP to antiviral IFN control, translational silencing, and a dual decay/miRNA switch in myogenesis, revealing how one protein executes opposing post-transcriptional outcomes.","evidence":"Ksrp-/- MEFs with viral infection and IFN mRNA decay; polysome profiling for IL-6/IL-1α silencing; C2C12 and Ksrp-/- mice with PI3K/AKT manipulation of decay versus miRNA maturation","pmids":["21690298","21795706","21886180"],"confidence":"High","gaps":["Molecular basis distinguishing decay-competent from processing-competent KSRP pools not resolved","Translational silencing mechanism vs. decay not separated mechanistically"]},{"year":2012,"claim":"Defined the structural basis of let-7 precursor selectivity and showed signaling transducers (R-SMADs) and partner complexes (HuR) physically reconfigure KSRP activity in differentiation.","evidence":"NMR of KH3 bound to pre-let-7 G-rich loop with mutagenesis; phospho-SMAD/phospho-KSRP co-IP and SMAD knockdown rescue; HuR-KSRP-PARN-exosome co-IP for NPM mRNA","pmids":["23142982","23177623","24969639"],"confidence":"High","gaps":["SMAD and HuR studies each from single labs","How phosphorylation enables SMAD binding to KSRP not mapped"]},{"year":2013,"claim":"Extended KSRP decay control to neuronal, circadian/metabolic, and muscle physiology and identified DDX1 as a competing localization regulator, establishing broad in vivo phenotypes.","evidence":"Ksrp-/- neurons and embryos with GAP-43/HuD competition and axon length; Ksrp-/- liver with Per2 decay and circadian/lipogenic readouts; utrophin A p38/ARE in mdx muscle; DDX1 affinity-MS, co-IP, and fractionation","pmids":["24244461","25514904","23575223","24023901"],"confidence":"High","gaps":["Several metabolic and muscle studies from single labs","How DDX1 and 14-3-3 mutually exclusive binding is regulated unclear"]},{"year":2014,"claim":"Identified the H19 lncRNA as a scaffold for an AKT-regulated post-transcriptional switch and established direct KSRP→miRNA→target axes controlling adipose biology.","evidence":"RIP and in vitro binding for H19 scaffold with AKT-dependent dismissal in C2C12; Ksrp-/- adipose with miR-150→PRDM16/PPARGC1A and miR-145→FOXO1/CGI58 processing, reporter validation, and mimic rescue","pmids":["25385579","24722250","24732799"],"confidence":"Medium","gaps":["H19 scaffolding mechanism from single lab","Whether scaffolding generalizes beyond myogenic context unknown"]},{"year":2016,"claim":"Revealed ubiquitin and miRNA-mediated control of KSRP and its role as a negative ITAF in IRES translation and an EMT-associated splicing/miRNA regulator.","evidence":"KLHL12 ubiquitination at K109/K121/K122 with site mutagenesis and IRES reporters; miR-27b-3p silencing of KHSRP with RNA-seq, hnRNPA1 co-IP, and splicing of Cd44/Fgfr2","pmids":["27899653","27396342"],"confidence":"High","gaps":["Consequence of K109/121/122 ubiquitination on stability versus activity not fully separated","EMT splicing study from single lab"]},{"year":2017,"claim":"Showed SUMOylation directs KSRP localization and miRNA processing capacity and uncovered a non-RNA-decay role suppressing RIG-I innate immune sensing.","evidence":"SUMO1 modification at K87 with mutagenesis, fractionation, RIP, and miRNA-seq plus xenografts; co-IP of KHSRP with RIG-I regulatory domain and antiviral signaling assays","pmids":["29020972","28248290"],"confidence":"High","gaps":["Interplay between SUMO, AKT-phospho, and ubiquitin marks not integrated","RIG-I suppression mechanism from single lab"]},{"year":2022,"claim":"Established axonal local translation and decay of KSRP targets as a brake on nerve regeneration and revealed direct chromatin occupancy linking KSRP to transcriptional control.","evidence":"Axoplasm proteomics, Ksrp-/- nerve injury with regeneration phenotype, axonal RIP/decay for Gap43/Snap25/Fubp1; ChIP-seq/RNA-seq/CLIP-seq in CD34+ monocytic differentiation","pmids":["35556128","36518592"],"confidence":"High","gaps":["Mechanism of KSRP genomic recruitment to promoters/enhancers not defined","Direct versus indirect transcriptional effects not fully separated"]},{"year":2024,"claim":"Identified new molecular modalities—m6A reading, SF3B1-dependent branch-site splicing enhancement, and SIRT7-opposed acetylation—linking KHSRP to cancer and tissue injury.","evidence":"m6A-RIP and stability assays for MET/ITGAV/ITGB1 with FAK signaling in PDAC; KHSRP-SF3B1 co-IP with intron-retention RNA-seq in liver failure; SIRT7-KHSRP co-IP with DDR mRNA decay in prostate cancer","pmids":["39120596","39187547","38501452"],"confidence":"Medium","gaps":["m6A-reader activity not structurally defined relative to KH domains","How acetylation, SUMO, and phosphorylation are coordinated unresolved","Each modality from a single lab"]},{"year":null,"claim":"How the dense network of post-translational modifications and competing partners is integrated to partition a single KHSRP molecule among decay, miRNA processing, splicing, m6A reading, and chromatin functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM combinations to functional outcome","No full-length structure showing domain coordination on physiological targets","Hierarchy and crosstalk among AKT, p38, SUMO, ubiquitin, and acetylation marks undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,6,8,9,18]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5,25]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[16,28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,24,25,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,30,35]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,9,36]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,21,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,35,36]}],"complexes":["Drosha/DGCR8 microprocessor","Dicer complex","exosome"],"partners":["PARN","HNRNP A1","SF3B1","14-3-3 (YWHAZ)","DDX1","HUR (ELAVL1)","KLHL12","RIG-I (DDX58)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92945","full_name":"Far upstream element-binding protein 2","aliases":["KH type-splicing regulatory protein","KSRP","p75"],"length_aa":711,"mass_kda":73.1,"function":"Binds to the dendritic targeting element and may play a role in mRNA trafficking (By similarity). Part of a ternary complex that binds to the downstream control sequence (DCS) of the pre-mRNA. Mediates exon inclusion in transcripts that are subject to tissue-specific alternative splicing. May interact with single-stranded DNA from the far-upstream element (FUSE). May activate gene expression. Also involved in degradation of inherently unstable mRNAs that contain AU-rich elements (AREs) in their 3'-UTR, possibly by recruiting degradation machinery to ARE-containing mRNAs","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92945/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KHSRP","classification":"Not Classified","n_dependent_lines":176,"n_total_lines":1208,"dependency_fraction":0.1456953642384106},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KHSRP","total_profiled":1310},"omim":[{"mim_id":"605547","title":"FOLLISTATIN-LIKE 1; FSTL1","url":"https://www.omim.org/entry/605547"},{"mim_id":"603536","title":"FAR UPSTREAM ELEMENT-BINDING PROTEIN 3; FUBP3","url":"https://www.omim.org/entry/603536"},{"mim_id":"603445","title":"KH-TYPE SPLICING REGULATORY PROTEIN; KHSRP","url":"https://www.omim.org/entry/603445"},{"mim_id":"600354","title":"SURVIVAL OF MOTOR NEURON 1; SMN1","url":"https://www.omim.org/entry/600354"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KHSRP"},"hgnc":{"alias_symbol":["KSRP","FBP2","FUBP2"],"prev_symbol":[]},"alphafold":{"accession":"Q92945","domains":[{"cath_id":"3.30.1370.10","chopping":"144-215","consensus_level":"high","plddt":89.0522,"start":144,"end":215},{"cath_id":"3.30.1370.10","chopping":"233-304","consensus_level":"high","plddt":84.7015,"start":233,"end":304},{"cath_id":"3.30.1370.10","chopping":"323-393","consensus_level":"high","plddt":87.6925,"start":323,"end":393},{"cath_id":"3.30.1370.10","chopping":"424-500","consensus_level":"high","plddt":85.1113,"start":424,"end":500}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92945","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92945-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92945-F1-predicted_aligned_error_v6.png","plddt_mean":62.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KHSRP","jax_strain_url":"https://www.jax.org/strain/search?query=KHSRP"},"sequence":{"accession":"Q92945","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92945.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92945/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92945"}},"corpus_meta":[{"pmid":"19458619","id":"PMC_19458619","title":"The 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including hnRNP F onto the splicing enhancer.\",\n      \"method\": \"Protein purification, cDNA cloning, in vitro splicing assay with antibody inhibition and rescue by purified protein, co-purification of multiprotein complex\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of splicing activity, antibody inhibition rescued by purified protein, multiple orthogonal methods in founding paper\",\n      \"pmids\": [\"9136930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KSRP is an essential factor for ARE-directed mRNA decay; specific KH domains directly mediate RNA binding, mRNA decay, and physical interactions with the exosome and poly(A) ribonuclease (PARN); the ability of KH motifs to promote mRNA decay correlates with their ability to bind the ARE and associate with RNA-degrading enzymes.\",\n      \"method\": \"In vitro mRNA decay assays, domain mutagenesis, co-immunoprecipitation of KSRP with exosome and PARN, ARE-binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro assay with mutagenesis, direct biochemical interaction with decay machinery, multiple orthogonal methods\",\n      \"pmids\": [\"15175153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p38α and p38β MAP kinase phosphorylates KSRP during muscle differentiation; p38-phosphorylated KSRP displays compromised binding to ARE-containing myogenic transcripts and fails to promote their rapid decay, although it retains ability to interact with mRNA degradation machinery; this stabilizes critical myogenic mRNAs and is required for proper myoblast-to-myocyte conversion.\",\n      \"method\": \"In vitro kinase assay (p38 phosphorylation of KSRP), RNA-binding assays with phosphorylated vs. unphosphorylated KSRP, KSRP overexpression in myoblasts with transcriptional and post-transcriptional readouts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, RNA binding comparison, multiple cellular readouts in a single rigorous study\",\n      \"pmids\": [\"16364914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KSRP binds the 3'-UTR ARE of human iNOS mRNA and promotes its decay by recruiting the exosome; KSRP competes with the stabilizing factor HuR for the same ARE binding site; KSRP also co-immunoprecipitates with tristetraprolin (TTP); a non-binding KSRP mutant fails to reduce iNOS expression, confirming the requirement for ARE binding.\",\n      \"method\": \"Immunodepletion in vitro degradation assays, overexpression of wild-type and non-binding mutant KSRP, co-immunoprecipitation with exosome and TTP, competition binding assay with HuR\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro degradation assay, mutagenesis, reciprocal co-IP, competition assay, single lab\",\n      \"pmids\": [\"16126846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AKT phosphorylates KSRP at a unique serine residue; this induces KSRP association with 14-3-3 proteins and prevents KSRP interaction with the exosome, impairing its ability to promote rapid mRNA decay; this mechanism stabilizes beta-catenin mRNA downstream of PI3K-AKT and Wnt signaling.\",\n      \"method\": \"In vitro AKT kinase assay, co-immunoprecipitation of KSRP with 14-3-3 and exosome under PI3K-AKT activation/inhibition, mRNA half-life measurements, mutagenesis of phosphorylation site\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, site-directed mutagenesis, co-IP with decay complex, mRNA decay assays, single lab\",\n      \"pmids\": [\"17177604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tethering KSRP to mRNAs via fusion with sequence-specific RNA-binding proteins elicits mRNA decay in a manner dependent on known mRNA decay enzymes; this demonstrates that KSRP functions by recruiting mRNA decay machinery to target transcripts.\",\n      \"method\": \"Tethering assay using Rev-KSRP fusion protein targeting HIV-1 RRE; mRNA stability measurements; viral replication assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution via tethering, dependence on decay enzymes shown, single lab\",\n      \"pmids\": [\"16648466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The KH3 and KH4 domains of KSRP behave as independent RNA-binding modules recognizing different regions of AU-rich RNA targets; KH4 binds AREs with lower affinity than KH3; mRNA binding and mRNA degradation activities of KSRP are closely associated with a conserved structural element unique to KH4.\",\n      \"method\": \"NMR structure determination of KH3 and KH4, RNA-binding affinity measurements (ITC/NMR), mutagenesis of KH4 structural element\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structures with functional validation, mutagenesis, binding affinity measurements\",\n      \"pmids\": [\"17437720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KSRP knockdown by siRNA stabilizes IL-8 mRNA and impairs its rapid deadenylation; KSRP interacts with both domains of the bipartite IL-8 ARE; IL-1 treatment impairs the interaction of KSRP with the IL-8 ARE in a p38-dependent but MK2-independent manner; microarray pulldown identified ~100 mRNAs controlled by KSRP.\",\n      \"method\": \"siRNA knockdown, mRNA half-life and deadenylation assays, RNA pulldown with KSRP followed by microarray, co-immunoprecipitation, pharmacological inhibition of p38/MK2\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA KD with mechanistic readouts, RNA pulldown-microarray, multiple orthogonal approaches, replicated across targets\",\n      \"pmids\": [\"17908789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Among the four KH domains of KSRP, KH3 binds RNA with the highest affinity and specifically recognizes G-rich sequences; the other KH domains display different sequence preferences explaining the broad target range; KSRP shows strong negative selectivity for sequences with multiple adjacent cytosines.\",\n      \"method\": \"Scaffold-independent RNA-binding analysis of all four KH domains using NMR and ITC; systematic sequence selectivity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro binding assays for all four domains with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18684992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KSRP is a component of both Drosha and Dicer complexes; KSRP binds with high affinity to the terminal loop of target miRNA precursors and promotes their maturation; this function is required for specific changes in target mRNA expression affecting proliferation, apoptosis, and differentiation.\",\n      \"method\": \"Co-immunoprecipitation of KSRP with Drosha and Dicer complexes, RNA immunoprecipitation, in vitro processing assays, KSRP knockdown with miRNA profiling, NMR binding studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP with Drosha/Dicer, in vitro processing assays, NMR binding, multiple labs/methods, high-impact replicated finding\",\n      \"pmids\": [\"19458619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AKT-mediated phosphorylation of KSRP's KH1 domain causes KH1 unfolding (KH1 is structurally atypical and unstable), creating a binding site for 14-3-3ζ; 14-3-3ζ binding discriminates phosphorylated from unphosphorylated KH1 and drives nuclear localization of KSRP, sequestering it from cytoplasmic mRNA decay activity.\",\n      \"method\": \"NMR structure of KH1 (phosphorylated and unphosphorylated), 14-3-3ζ binding assays, localization studies, mRNA decay assays in cells with phosphomimetic/phosphodead mutants\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional validation, phosphorylation-dependent binding and localization assays, mutagenesis, multiple methods\",\n      \"pmids\": [\"19198587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KSRP co-immunoprecipitates with PTH mRNA, the exosome, and the endoribonuclease PMR1; KSRP and exosome knockdown by siRNA prevents PMR1-mediated cleavage of PTH mRNA, establishing that PTH mRNA decay by PMR1 is dependent on both KSRP and the exosome.\",\n      \"method\": \"Co-immunoprecipitation of KSRP, PMR1, and exosome; siRNA knockdown of KSRP and exosome subunits; in vitro RNA cleavage assays\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, siRNA knockdown with functional readout, in vitro assays, single lab\",\n      \"pmids\": [\"19775426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"hnRNP A1 binds the terminal loop of pri-let-7a-1 and inhibits Drosha processing; hnRNP A1 binding to let-7a interferes with KSRP binding to the same terminal loop, establishing antagonistic roles for hnRNP A1 (negative regulator) and KSRP (positive regulator) in let-7a biogenesis.\",\n      \"method\": \"RNA-protein binding competition assays, in vitro Drosha processing assays, cell-based depletion/overexpression of hnRNP A1 and KSRP with miRNA quantification\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro processing assays, binding competition, multiple cellular validations, independent replication\",\n      \"pmids\": [\"20639884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KSRP interacts with Dishevelled (Dvl) proteins; KSRP negatively regulates Wnt/beta-catenin signaling by promoting post-transcriptional destabilization of CTNNB1 (beta-catenin) mRNA; identified by affinity purification coupled to ion-trap mass spectrometry.\",\n      \"method\": \"Affinity purification followed by mass spectrometry identification of KSRP as Dvl-binding protein; mRNA stability assays for beta-catenin mRNA; co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mass spectrometry-identified interaction confirmed by co-IP, mRNA stability assay, single lab\",\n      \"pmids\": [\"20332102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The inter-domain linker between KH2 and KH3 orients the two central KH domains of KSRP with their RNA-binding surfaces aligned, creating a two-domain unit; this interdomain arrangement is functionally important for interaction with KSRP's RNA targets.\",\n      \"method\": \"NMR structural analysis of interdomain linker and relative domain orientation; RNA binding assays comparing wild-type and linker-mutated constructs\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation, binding assays, single lab\",\n      \"pmids\": [\"20385598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KSRP is required for ARE-mediated decay of Ifna4 and Ifnb mRNAs; KSRP knockout mouse embryonic fibroblasts produce higher levels of type I IFN mRNAs following viral infection due to decreased mRNA decay; increased IFN expression renders Ksrp-/- cells refractory to HSV-1 and VSV infection.\",\n      \"method\": \"Ksrp knockout mouse MEFs, viral infection, mRNA half-life measurements, RNA immunoprecipitation, antiviral protection assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined mechanistic readout (mRNA decay), RNA-protein interaction, multiple viruses tested\",\n      \"pmids\": [\"21690298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KSRP participates in ARE-mediated translational silencing in addition to mRNA decay; KSRP depletion increases polysome association of IL-6 and IL-1α mRNAs; silencing depends on the 3'-UTR ARE of IL-6 mRNA; IL-1 reverses KSRP-dependent translational silencing.\",\n      \"method\": \"Polysome profiling after siRNA-mediated KSRP depletion, luciferase reporter assays with IL-6 3'UTR, KSRP-RNA interaction mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome fractionation, reporter assay, siRNA knockdown, single lab\",\n      \"pmids\": [\"21795706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PI3K/AKT activation regulates two distinct KSRP functions in opposite directions during skeletal myogenesis: it inhibits KSRP's ability to promote decay of myogenin mRNA while simultaneously activating its ability to favor maturation of myogenic miRNAs; this dynamic switch is required for the myogenic program as demonstrated in C2C12 cells and Ksrp knockout mice.\",\n      \"method\": \"C2C12 myoblast differentiation, Ksrp-/- mouse analysis, PI3K/AKT inhibition/activation, miRNA processing assays, mRNA stability measurements\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mice + cell culture, two distinct functional readouts, multiple signaling interventions, single lab\",\n      \"pmids\": [\"21886180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KSRP KH3 domain recognizes a G-rich sequence in the pre-let-7 terminal loop via a noncanonical KH-RNA interaction mode; the KH3-RNA complex structure reveals how this noncanonical binding governs KSRP selectivity for let-7 precursors; this selectivity is crucial for the functional interaction between KSRP and let-7 biogenesis.\",\n      \"method\": \"NMR structure of KH3 bound to pre-let-7 terminal loop G-rich sequence, mutagenesis of KH3 and RNA, functional processing assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional mutagenesis validation, mechanistic insight into selectivity, multiple orthogonal methods\",\n      \"pmids\": [\"23142982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HuR promotes myogenesis by associating with the decay factor KSRP and ribonucleases PARN and the exosome to destabilize nucleophosmin (NPM) mRNA; the C terminus of HuR mediates formation of the HuR-KSRP complex; this HuR-KSRP-PARN-exosome complex reduces NPM mRNA levels required for muscle cell commitment.\",\n      \"method\": \"Co-immunoprecipitation of HuR-KSRP complex, mRNA stability assays, domain deletion analysis of HuR, siRNA knockdown of HuR, overexpression studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mRNA decay assays, domain mapping, single lab\",\n      \"pmids\": [\"24969639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phosphorylated R-SMAD proteins (transducers of BMP2 signaling) associate with phosphorylated KSRP and block its interaction with primary myogenic miRNAs (myomiRs), preventing KSRP-dependent myomiR maturation; silencing SMAD4, SMAD5, and SMAD9 rescues KSRP function; this SMAD-mediated KSRP blockade is required for BMP2-induced osteoblastic differentiation.\",\n      \"method\": \"Co-immunoprecipitation of phospho-SMAD with phospho-KSRP, RNA immunoprecipitation, siRNA knockdown of SMADs, miRNA processing assays, cell differentiation readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of signal transducers with KSRP, RIP, SMAD knockdown rescue, single lab\",\n      \"pmids\": [\"23177623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KSRP destabilizes GAP-43 mRNA by binding its ARE, a process requiring its KH4 domain; KSRP competes with the stabilizing factor HuD for binding to GAP-43 ARE sequences; KSRP overexpression hinders axonal outgrowth in primary hippocampal neurons, while KSRP knockdown increases GAP-43 mRNA and dramatically increases axonal length in both cultured neurons and Ksrp+/- and Ksrp-/- embryos.\",\n      \"method\": \"RNA-binding assays (KH domain deletion mutants), competition assays with HuD, overexpression/knockdown in primary hippocampal neurons, Ksrp knockout mouse neurons, axonal length measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis, competition binding, genetic KO neurons, cellular phenotype with molecular rescue, replicated in vitro and in vivo\",\n      \"pmids\": [\"24244461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KSRP promotes decay of Per2 mRNA via AU-rich elements in Per2's 3' UTR, and KSRP ablation increases Per2 expression causing a phase delay in circadian clock gene oscillations and reduced expression of de novo lipogenic genes, leading to reduced hepatic triglyceride accumulation.\",\n      \"method\": \"Ksrp-/- mouse liver analysis, heterologous mRNA reporter assays with Per2 3'UTR, mRNA half-life measurements in primary hepatocytes, circadian gene profiling\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO + reporter assay + mRNA decay measurement, single lab\",\n      \"pmids\": [\"25514904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p38 activation increases utrophin A mRNA stability through AU-rich elements by reducing the functional availability of KSRP; KSRP directly binds AREs in the utrophin A 3'UTR; electroporation-mediated knockdown of KSRP increases utrophin A in wild-type and mdx mouse muscles.\",\n      \"method\": \"In vitro and in vivo KSRP-RNA binding studies, mRNA half-life assays, electroporation knockdown in mouse muscle, p38 activation with heparin in mdx mice\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein binding shown, in vivo knockdown with phenotypic readout, single lab\",\n      \"pmids\": [\"23575223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The RNA helicase DDX1 interacts with KSRP and regulates its subcellular localization; DDX1 knockdown elevates cytoplasmic levels of KSRP and facilitates ARE-mediated mRNA decay; KSRP associates with DDX1 or 14-3-3 proteins in a mutually exclusive manner, indicating competing interactions that regulate KSRP's cytoplasmic availability.\",\n      \"method\": \"Affinity purification and mass spectrometry identification of DDX1, co-immunoprecipitation, DDX1 siRNA knockdown, subcellular fractionation, mRNA decay assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP, subcellular fractionation, functional mRNA decay readout, single lab\",\n      \"pmids\": [\"24023901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KSRP directly binds the H19 lncRNA in the cytoplasm of undifferentiated C2C12 cells, and this interaction facilitates KSRP-mediated destabilization of labile transcripts including myogenin mRNA; AKT activation induces KSRP dismissal from H19; upon dismissal, KSRP is repurposed to promote maturation of myogenic miRNAs; H19 thus acts as a molecular scaffold that optimizes an AKT-regulated post-transcriptional switch.\",\n      \"method\": \"RNA immunoprecipitation, in vitro RNA-protein binding assays, AKT activation/inhibition, mRNA stability assays, miRNA processing assays in C2C12 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, in vitro binding, functional mRNA decay and miRNA processing assays, single lab\",\n      \"pmids\": [\"25385579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KSRP ablation causes a reduction in body adiposity; in Ksrp-/- inguinal WAT, expression of miR-150 is decreased due to impaired primary miR-150 processing; miR-150 directly targets PRDM16 and PPARGC1A; forced miR-150 expression attenuates elevated brown fat gene expression caused by KSRP deletion, establishing a pathway KSRP → miR-150 → PRDM16/PPARGC1A controlling brown-like transformation of white fat.\",\n      \"method\": \"Ksrp-/- mouse analysis, miRNA processing assays, miRNA mimic rescue experiments, miR-150 target validation by luciferase assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with miRNA rescue, target validation by reporter assay, single lab\",\n      \"pmids\": [\"24722250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Ksrp-/- epididymal WAT, miR-145 expression is decreased due to impaired primary miR-145 processing; miR-145 directly targets and represses FOXO1 and CGI58, activators of lipolysis; forced miR-145 expression attenuates enhanced lipolysis in KSRP-deficient adipose tissue, establishing a KSRP → miR-145 → FOXO1/CGI58 pathway controlling adipose lipolysis.\",\n      \"method\": \"Ksrp-/- mouse WAT analysis, miRNA processing assays, miR-145 target validation by luciferase assay, miR-145 mimic rescue in primary adipocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, miRNA processing, reporter assay target validation, rescue experiment, single lab\",\n      \"pmids\": [\"24732799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KHSRP is ubiquitinated at Lys109, Lys121, and Lys122 by the Kelch domain of KLHL12 interacting with KHSRP's C-terminal domain; mutations at these sites abolish KHSRP's inhibitory effect on enterovirus IRES-driven translation; ubiquitination of KHSRP (a negative ITAF) thus controls IRES-dependent translation by limiting competition against positive ITAFs.\",\n      \"method\": \"In vivo and in vitro SUMOylation/ubiquitination assays, site-directed mutagenesis of ubiquitination sites, Ni2+-NTA pulldown, co-immunoprecipitation of KLHL12-KHSRP, IRES-luciferase reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination assay, site mutagenesis, co-IP identification of E3 ligase adaptor, functional reporter assay, single lab with multiple methods\",\n      \"pmids\": [\"27899653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-27b-3p-mediated silencing of KHSRP is required for TGF-β-induced EMT in mammary gland cells; KHSRP controls levels of mature miR-192-5p (targeting EMT factors) and promotes epithelial-type alternative splicing of pre-mRNAs including Cd44 and Fgfr2; KHSRP and hnRNPA1 cooperate in a ribonucleoprotein complex to promote epithelial exon usage.\",\n      \"method\": \"miR-27b-3p overexpression/knockdown, KHSRP knockdown/overexpression, genome-wide RNA-seq and miRNA-seq, co-immunoprecipitation of KHSRP-hnRNPA1 complex, splicing assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide sequencing, co-IP, functional EMT readout, single lab\",\n      \"pmids\": [\"27396342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KHSRP is modified by SUMO1 at the major site K87; this modification inhibits KHSRP's interaction with pri-miRNA/Drosha-DGCR8 complex and promotes KHSRP translocation from nucleus to cytoplasm; SUMOylation consequently impairs processing of pre-miRNAs from pri-miRNAs with G-rich terminal loops (TL-G-Rich miRNAs including let-7 family), leading to tumorigenesis.\",\n      \"method\": \"In vivo and in vitro SUMOylation assays, site-directed mutagenesis (K87), nuclear/cytosol fractionation, immunofluorescence, RIP, high-throughput miRNA sequencing, xenograft tumor models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vivo and in vitro SUMOylation, mutagenesis, localization, RIP, miRNA-seq, functional tumor assays, multiple orthogonal methods\",\n      \"pmids\": [\"29020972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KHSRP associates with the regulatory domain of RIG-I to maintain the receptor in an inactive state and attenuate its sensing of viral RNA; KHSRP knockdown enhances RIG-I antiviral signaling and reduces viral replication both in vitro and in vivo.\",\n      \"method\": \"RNAi screens integrated with interactome data, co-immunoprecipitation of KHSRP with RIG-I regulatory domain, RIG-I signaling assays upon KHSRP knockdown, in vitro and in vivo viral infection models\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying specific domain interaction, functional signaling assay, in vivo validation, single lab\",\n      \"pmids\": [\"28248290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Xenopus KSRP homolog VgRBP71 binds to mRNAs localized to either vegetal or animal hemispheres in oocytes but does not accumulate at the vegetal cortex with the mRNA; VgRBP71 interacts with Prrp (another Vg1 localization element-binding protein) in a manner that does not require Vg1 mRNA.\",\n      \"method\": \"Xenopus oocyte expression library screen, in vivo RNA-protein binding assays, co-immunoprecipitation of VgRBP71-Prrp interaction, localization studies\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo binding assay in Xenopus, co-IP of protein complex, localization analysis; ortholog study\",\n      \"pmids\": [\"12421702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"KSRP/FBP2 is cleaved by caspase-3 and caspase-7 at two sites: after Asp102 and after Asp183; the second cleavage site is only recognized in protein produced in cells (not in vitro translated protein), indicating that cellular context beyond primary sequence affects caspase recognition.\",\n      \"method\": \"In vitro caspase cleavage of KSRP with caspase-3 and -7, comparison of cellular vs. in vitro translated KSRP, site identification by mass spectrometry\",\n      \"journal\": \"Protein and peptide letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro cleavage assay, site identification, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"12553859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Khsrp mRNA localizes into peripheral nerve axons and is locally translated following axon injury; axonal KSRP levels rapidly increase after sciatic nerve injury and remain elevated; KHSRP binds to mRNAs with 3'UTR AU-rich elements (Gap43, Snap25, Fubp1) and targets them to the cytoplasmic exosome for degradation; Ksrp-/- mice show increased axonal levels of these target mRNAs and accelerated nerve regeneration in vivo.\",\n      \"method\": \"Targeted proteomics of axoplasm, Ksrp-/- mouse nerve injury model, local translation assay with axon ligation, RNA immunoprecipitation, mRNA stability measurements in axons, in vivo nerve regeneration assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — targeted proteomics, genetic KO with in vivo regeneration phenotype, local translation assay, RIP, multiple target mRNAs validated\",\n      \"pmids\": [\"35556128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KHSRP regulates monocytic differentiation through both transcriptional and post-transcriptional mechanisms; KHSRP occupies specific genomic sites at promoter and enhancer regions to regulate hematopoietic gene transcription, and binds to pre-mRNA intronic regions to modulate alternative splicing; KHSRP has co-regulatory effects at both transcriptional and post-transcriptional levels on MOGOH and ADARB1.\",\n      \"method\": \"ChIP-seq, RNA-seq, CLIP-seq in CD34+ cells during monocytic differentiation, functional knockdown studies\",\n      \"journal\": \"Blood science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq with functional knockdown, single lab, genome-wide analysis\",\n      \"pmids\": [\"36518592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KHSRP directly interacts with SF3B1 (splicing factor 3b subunit 1) and enhances SF3B1 binding to intronic branch sites, thereby promoting pre-mRNA splicing; KHSRP knockdown causes intron retention and exacerbates liver injury in acute liver failure models.\",\n      \"method\": \"Co-immunoprecipitation of KHSRP-SF3B1 interaction, RNA-seq analysis of splicing defects in KHSRP-knockdown cells and murine ALF models, splicing inhibitor experiments in vivo, proteomic and transcriptomic analyses\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mechanistic readout, in vivo functional validation, single lab\",\n      \"pmids\": [\"39187547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KHSRP functions as an m6A-binding protein; KHSRP recognizes m6A modifications and stabilizes FAK pathway mRNAs including MET, ITGAV, and ITGB1 in an m6A-dependent manner, leading to activation of downstream FAK signaling and promotion of pancreatic ductal adenocarcinoma progression.\",\n      \"method\": \"m6A-RIP, RNA immunoprecipitation, KHSRP knockdown/overexpression with mRNA stability assays, FAK pathway activity assays, in vivo xenograft models, PROTAC-mediated KHSRP degradation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP, mRNA stability assay, in vivo model, multiple target mRNAs, single lab\",\n      \"pmids\": [\"39120596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 is a deacetylase of KHSRP; androgen stimulation impairs SIRT7 interaction with KHSRP, leading to increased KHSRP acetylation; acetylated KHSRP has impaired mRNA decay activity for DDR-related mRNAs, promoting prostate cancer tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation of SIRT7-KHSRP interaction, acetylation assays under androgen stimulation, RNA-seq and GSEA for DDR gene changes, xenograft tumor growth with acetylation-site mutants\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying deacetylase, functional mRNA decay assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"38501452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KHSRP and hnRNPA1 form a ribonucleoprotein complex and cooperate to promote epithelial-type exon usage during splicing; combined silencing of both prevents RESV-dependent inclusion of epithelial-type exons in Cd44 pre-mRNA; hnRNP A1 also tethers KSRP to an exonic splicing silencer (ESS16) and KSRP binding to ESS16 requires hnRNP A1.\",\n      \"method\": \"Co-immunoprecipitation of KHSRP-hnRNPA1 complex, combined siRNA knockdown, splicing assays, 2D gel and mass spectrometry identification in erythroleukemia cells\",\n      \"journal\": \"American journal of cancer research / Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, MS identification, combinatorial knockdown, splicing assay, single lab each\",\n      \"pmids\": [\"26101706\", \"28088441\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KHSRP/KSRP is a multifunctional single-strand nucleic acid-binding protein with four KH domains (KH3 having highest affinity for G-rich sequences, KH4 bearing a noncanonical structural element critical for ARE recognition and mRNA decay) that operates through at least three core post-transcriptional mechanisms: (1) it recruits the exosome, PARN, and PMR1 to AU-rich elements in target mRNA 3'-UTRs to promote rapid mRNA decay and translational silencing; (2) it is an integral component of both Drosha and Dicer complexes, binding G-rich terminal loops of select miRNA precursors to promote their maturation (e.g., let-7, miR-155, miR-129, myomiRs, miR-150, miR-145); and (3) it associates with hnRNP A1, SF3B1, and intronic/exonic elements to regulate alternative pre-mRNA splicing; these functions are regulated by multiple post-translational modifications — AKT-dependent phosphorylation of KH1 causes its unfolding, 14-3-3ζ binding, and nuclear sequestration; p38-dependent phosphorylation impairs ARE binding; KLHL12-mediated ubiquitination at K109/K121/K122 controls IRES-driven translation; SUMO1 modification at K87 inhibits Drosha complex interaction and promotes nuclear-to-cytoplasmic translocation; SIRT7 acts as a deacetylase to oppose androgen-induced KHSRP acetylation that impairs DDR mRNA decay; additionally, KHSRP associates with RIG-I's regulatory domain to suppress innate immune sensing, binds the H19 lncRNA as a molecular scaffold, and acts as an m6A reader to stabilize specific target mRNAs in cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KHSRP (KSRP) is a multifunctional single-strand nucleic-acid-binding protein with four KH domains that governs gene expression at the post-transcriptional level through three interlocking activities: ARE-directed mRNA decay, selective miRNA maturation, and pre-mRNA splicing control [#1, #9, #29]. As a decay factor, it binds AU-rich elements in target 3'-UTRs and recruits the exosome and the deadenylase PARN, with specific KH domains coupling RNA recognition to physical engagement of the degradation machinery; tethering KSRP to an mRNA is sufficient to trigger decay [#1, #5], and it extends this activity to translational silencing of ARE-containing transcripts [#16]. Domain-level structural work defines how it reads RNA: KH3 binds with highest affinity and recognizes G-rich sequences, while KH4 carries a conserved noncanonical element essential for ARE binding and decay [#6, #8], and a KH2–KH3 interdomain linker aligns the two central modules into a functional unit [#14]. The same G-rich recognition by KH3 underlies its second role as a component of both Drosha and Dicer complexes, where it binds the terminal loops of select pri/pre-miRNAs (e.g., let-7) to promote their maturation [#9, #18]. In its third role it associates with hnRNP A1 and SF3B1 to direct alternative and constitutive splicing, including the founding c-src N1 exon enhancer activity and epithelial-type exon usage [#0, #36, #39]. These activities are toggled by an extensive regulatory layer: AKT phosphorylation of KH1 drives its unfolding, 14-3-3ζ binding, and nuclear sequestration away from cytoplasmic decay [#4, #10]; p38 phosphorylation impairs ARE binding [#2]; SUMO1 modification at K87 blocks Drosha interaction and promotes nuclear export [#30]; and KLHL12-mediated ubiquitination, DDX1 competition, and SIRT7-opposed acetylation provide further control [#28, #24, #38]. Through these mechanisms KHSRP shapes diverse physiological programs including skeletal myogenesis, adipose biology, circadian/lipogenic control, axon regeneration, antiviral type I IFN responses, and tumorigenesis [#17, #26, #22, #34, #15, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established KSRP as a sequence-specific splicing regulator, defining its founding biochemical activity and its four-KH-domain architecture before any decay role was known.\",\n      \"evidence\": \"Protein purification, cDNA cloning, and in vitro splicing assays with antibody inhibition rescued by purified protein at the c-src N1 intronic splicing enhancer\",\n      \"pmids\": [\"9136930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define direct RNA contacts at residue resolution\", \"Did not connect splicing role to subsequent decay or miRNA functions\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Ortholog and degradation studies broadened the protein's recognized scope—RNA localization in oocytes and caspase cleavage—hinting at regulated turnover and developmental roles.\",\n      \"evidence\": \"Xenopus VgRBP71 RNA-binding and Prrp co-IP; in vitro caspase-3/-7 cleavage mapping of KSRP/FBP2\",\n      \"pmids\": [\"12421702\", \"12553859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of caspase cleavage in cells not defined\", \"Ortholog localization role not connected to mammalian decay function\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined KSRP as an essential ARE-mediated decay factor that couples RNA binding to recruitment of the exosome and PARN, establishing its core post-transcriptional mechanism.\",\n      \"evidence\": \"In vitro mRNA decay assays, KH domain mutagenesis, and co-IP of KSRP with exosome and PARN\",\n      \"pmids\": [\"15175153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which KH domains contact ARE versus decay enzymes structurally\", \"In vitro decay not yet linked to endogenous target half-lives\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed signaling kinases gate decay activity and that KSRP competes with stabilizing factors, framing it as a regulated, antagonistic node in mRNA turnover.\",\n      \"evidence\": \"In vitro p38 kinase assay with ARE-binding comparison in myoblasts; iNOS ARE decay with HuR competition and TTP co-IP\",\n      \"pmids\": [\"16364914\", \"16126846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"p38 phosphorylation site(s) not mapped\", \"Mechanism by which phospho-KSRP retains decay-enzyme binding but loses RNA binding unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that KSRP acts by recruiting decay machinery to transcripts and that AKT signaling inactivates this via 14-3-3, establishing a kinase-controlled decay switch.\",\n      \"evidence\": \"Rev-KSRP tethering decay assay; in vitro AKT kinase assay, 14-3-3 and exosome co-IP, and mRNA half-life measurements with phospho-site mutants\",\n      \"pmids\": [\"16648466\", \"17177604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tethering relied on heterologous RNA targeting\", \"Single AKT serine not yet structurally explained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the structural logic of RNA recognition—KH3 highest-affinity G-rich binding, KH4 decay-critical element—and mapped the endogenous target repertoire.\",\n      \"evidence\": \"NMR structures of KH3/KH4 with ITC binding and mutagenesis; siRNA knockdown with IL-8 decay/deadenylation readouts and RNA pulldown-microarray\",\n      \"pmids\": [\"17437720\", \"17908789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length four-domain RNA complex not resolved\", \"How individual domains combine on a single transcript not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Systematically defined the sequence selectivity of all four KH domains, explaining how one protein binds a broad but biased target range.\",\n      \"evidence\": \"Scaffold-independent NMR/ITC binding analysis of all four KH domains with selectivity assays\",\n      \"pmids\": [\"18684992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity measured per isolated domain, not in full-length context\", \"In vivo target preference not directly tested here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded KSRP from a decay factor into a miRNA biogenesis factor, showing it is part of Drosha and Dicer complexes and selectively promotes maturation of G-rich-loop precursors.\",\n      \"evidence\": \"Reciprocal co-IP with Drosha/Dicer, RIP, in vitro processing assays, KSRP knockdown miRNA profiling, and NMR binding\",\n      \"pmids\": [\"19458619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same protein partitions between decay and processing complexes not resolved\", \"Determinants of precursor selectivity awaited later structural work\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the structural mechanism of AKT-driven nuclear sequestration, showing KH1 phosphorylation triggers unfolding and 14-3-3ζ-dependent relocalization, and confirmed exosome dependence for additional endoribonucleolytic targets.\",\n      \"evidence\": \"NMR of phospho/unphospho KH1 with 14-3-3ζ binding and localization assays; KSRP/PMR1/exosome co-IP and siRNA for PTH mRNA cleavage\",\n      \"pmids\": [\"19198587\", \"19775426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of nuclear-cytoplasmic shuttling in vivo not quantified\", \"PMR1-KSRP findings from single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established antagonistic and architectural controls on KSRP function: hnRNP A1 competes for let-7 terminal loops while the KH2–KH3 linker organizes the central RNA-binding unit, and KSRP destabilizes beta-catenin mRNA downstream of Dishevelled.\",\n      \"evidence\": \"In vitro Drosha processing with binding competition; NMR interdomain orientation analysis; Dvl affinity-MS, co-IP, and beta-catenin mRNA stability assays\",\n      \"pmids\": [\"20639884\", \"20385598\", \"20332102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How signaling redirects KSRP versus hnRNP A1 occupancy not fully defined\", \"Dvl-KSRP interaction from a single study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic and functional studies tied KSRP to antiviral IFN control, translational silencing, and a dual decay/miRNA switch in myogenesis, revealing how one protein executes opposing post-transcriptional outcomes.\",\n      \"evidence\": \"Ksrp-/- MEFs with viral infection and IFN mRNA decay; polysome profiling for IL-6/IL-1α silencing; C2C12 and Ksrp-/- mice with PI3K/AKT manipulation of decay versus miRNA maturation\",\n      \"pmids\": [\"21690298\", \"21795706\", \"21886180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis distinguishing decay-competent from processing-competent KSRP pools not resolved\", \"Translational silencing mechanism vs. decay not separated mechanistically\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the structural basis of let-7 precursor selectivity and showed signaling transducers (R-SMADs) and partner complexes (HuR) physically reconfigure KSRP activity in differentiation.\",\n      \"evidence\": \"NMR of KH3 bound to pre-let-7 G-rich loop with mutagenesis; phospho-SMAD/phospho-KSRP co-IP and SMAD knockdown rescue; HuR-KSRP-PARN-exosome co-IP for NPM mRNA\",\n      \"pmids\": [\"23142982\", \"23177623\", \"24969639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SMAD and HuR studies each from single labs\", \"How phosphorylation enables SMAD binding to KSRP not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended KSRP decay control to neuronal, circadian/metabolic, and muscle physiology and identified DDX1 as a competing localization regulator, establishing broad in vivo phenotypes.\",\n      \"evidence\": \"Ksrp-/- neurons and embryos with GAP-43/HuD competition and axon length; Ksrp-/- liver with Per2 decay and circadian/lipogenic readouts; utrophin A p38/ARE in mdx muscle; DDX1 affinity-MS, co-IP, and fractionation\",\n      \"pmids\": [\"24244461\", \"25514904\", \"23575223\", \"24023901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Several metabolic and muscle studies from single labs\", \"How DDX1 and 14-3-3 mutually exclusive binding is regulated unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the H19 lncRNA as a scaffold for an AKT-regulated post-transcriptional switch and established direct KSRP→miRNA→target axes controlling adipose biology.\",\n      \"evidence\": \"RIP and in vitro binding for H19 scaffold with AKT-dependent dismissal in C2C12; Ksrp-/- adipose with miR-150→PRDM16/PPARGC1A and miR-145→FOXO1/CGI58 processing, reporter validation, and mimic rescue\",\n      \"pmids\": [\"25385579\", \"24722250\", \"24732799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H19 scaffolding mechanism from single lab\", \"Whether scaffolding generalizes beyond myogenic context unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed ubiquitin and miRNA-mediated control of KSRP and its role as a negative ITAF in IRES translation and an EMT-associated splicing/miRNA regulator.\",\n      \"evidence\": \"KLHL12 ubiquitination at K109/K121/K122 with site mutagenesis and IRES reporters; miR-27b-3p silencing of KHSRP with RNA-seq, hnRNPA1 co-IP, and splicing of Cd44/Fgfr2\",\n      \"pmids\": [\"27899653\", \"27396342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Consequence of K109/121/122 ubiquitination on stability versus activity not fully separated\", \"EMT splicing study from single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed SUMOylation directs KSRP localization and miRNA processing capacity and uncovered a non-RNA-decay role suppressing RIG-I innate immune sensing.\",\n      \"evidence\": \"SUMO1 modification at K87 with mutagenesis, fractionation, RIP, and miRNA-seq plus xenografts; co-IP of KHSRP with RIG-I regulatory domain and antiviral signaling assays\",\n      \"pmids\": [\"29020972\", \"28248290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between SUMO, AKT-phospho, and ubiquitin marks not integrated\", \"RIG-I suppression mechanism from single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established axonal local translation and decay of KSRP targets as a brake on nerve regeneration and revealed direct chromatin occupancy linking KSRP to transcriptional control.\",\n      \"evidence\": \"Axoplasm proteomics, Ksrp-/- nerve injury with regeneration phenotype, axonal RIP/decay for Gap43/Snap25/Fubp1; ChIP-seq/RNA-seq/CLIP-seq in CD34+ monocytic differentiation\",\n      \"pmids\": [\"35556128\", \"36518592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of KSRP genomic recruitment to promoters/enhancers not defined\", \"Direct versus indirect transcriptional effects not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified new molecular modalities—m6A reading, SF3B1-dependent branch-site splicing enhancement, and SIRT7-opposed acetylation—linking KHSRP to cancer and tissue injury.\",\n      \"evidence\": \"m6A-RIP and stability assays for MET/ITGAV/ITGB1 with FAK signaling in PDAC; KHSRP-SF3B1 co-IP with intron-retention RNA-seq in liver failure; SIRT7-KHSRP co-IP with DDR mRNA decay in prostate cancer\",\n      \"pmids\": [\"39120596\", \"39187547\", \"38501452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A-reader activity not structurally defined relative to KH domains\", \"How acetylation, SUMO, and phosphorylation are coordinated unresolved\", \"Each modality from a single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dense network of post-translational modifications and competing partners is integrated to partition a single KHSRP molecule among decay, miRNA processing, splicing, m6A reading, and chromatin functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM combinations to functional outcome\", \"No full-length structure showing domain coordination on physiological targets\", \"Hierarchy and crosstalk among AKT, p38, SUMO, ubiquitin, and acetylation marks undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 6, 8, 9, 18]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5, 25]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [16, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 24, 25, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 30, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 9, 36]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 21, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 35, 36]}\n    ],\n    \"complexes\": [\n      \"Drosha/DGCR8 microprocessor\",\n      \"Dicer complex\",\n      \"exosome\"\n    ],\n    \"partners\": [\n      \"PARN\",\n      \"hnRNP A1\",\n      \"SF3B1\",\n      \"14-3-3 (YWHAZ)\",\n      \"DDX1\",\n      \"HuR (ELAVL1)\",\n      \"KLHL12\",\n      \"RIG-I (DDX58)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}