{"gene":"HNRNPC","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2018,"finding":"HNRNPC repression in breast cancer cells (MCF7, T47D) leads to accumulation of endogenous double-stranded RNA enriched in Alu sequences, predominantly originating from pre-mRNA introns containing HNRNPC binding sites; these dsRNAs activate the RIG-I-mediated interferon response, inhibiting cell proliferation and tumor growth. This establishes HNRNPC's mechanistic role in suppressing endogenous dsRNA formation.","method":"siRNA knockdown, RNA-seq, dsRNA immunoprecipitation, RIG-I pathway reporter assays, in vitro and in vivo tumor growth assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, sequencing, pathway reporters, in vivo), replicated across two cell lines, mechanistic link from dsRNA accumulation to RIG-I signaling clearly established","pmids":["30158112"],"is_preprint":false},{"year":2019,"finding":"hnRNPC regulates alternative cleavage and polyadenylation (APA) site selection; overexpression of hnRNPC establishes APA profiles characteristic of metastatic colon cancer cells, including regulation of MTHFD1L poly(A) site choice. This was determined by subcellular fractionation to measure nuclear and cytoplasmic APA profiles.","method":"Subcellular fractionation, APA profiling by RNA-seq, hnRNPC overexpression in colon cancer cell line model","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean overexpression system with direct APA readout, single lab but two orthogonal approaches (fractionation + sequencing)","pmids":["31147722"],"is_preprint":false},{"year":2017,"finding":"hnRNPC directly binds p53 protein, destabilizes it, and prevents its activation under normal conditions. Upon doxorubicin treatment, nuclear-retained lncRNA SNHG1 competes with p53 for hnRNPC binding, releasing p53 and promoting p53-dependent apoptosis.","method":"Co-immunoprecipitation, RNA immunoprecipitation, RNA pull-down, siRNA knockdown, apoptosis assays, doxorubicin treatment","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, competition assay, functional apoptosis readout; single lab with multiple orthogonal methods","pmids":["28264987"],"is_preprint":false},{"year":2021,"finding":"HNRNPC antagonizes the anti-metastatic isoform of TAF8 (TAF8L) and promotes the pro-metastatic alternative splicing isoform TAF8S in an m6A-dependent manner; mutation of the m6A site on TAF8 pre-mRNA attenuates HNRNPC-TAF8 interaction, reducing TAF8S production.","method":"RNA immunoprecipitation, m6A site mutagenesis, alternative splicing assays, in vitro invasion assays, in vivo metastasis models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A site mutagenesis combined with RIP and functional metastasis readout; single lab, multiple orthogonal methods","pmids":["34271104"],"is_preprint":false},{"year":2021,"finding":"HNRNPC deficiency, synergizing with ADAR loss, leads to dysregulation of Alu-containing introns through unmasked cryptic splice sites, generating putative MDA5 ligands with reduced A-to-I editing, thereby synergistically inducing MDA5-dependent type I IFN responses.","method":"Candidate screen in THP-1 monocytes, RNA-seq, ADAR/hnRNPC double knockdown, IFN response assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via double knockdown, RNA-seq, functional IFN assay; single lab","pmids":["34297039"],"is_preprint":false},{"year":2022,"finding":"hnRNPC is upregulated and relocates to the sarcomeric Z-disc in cardiomyocytes upon pathological extracellular matrix remodeling; at this site it associates with the translation machinery. Changes in hnRNPC expression, phosphorylation, and localization (mechanically determined) affect alternative splicing of mRNAs involved in mechanotransduction, including the Hippo pathway effector YAP1.","method":"Subcellular fractionation, immunofluorescence/live imaging, FRAP, hnRNPC overexpression/knockdown, ribosome association assays, alternative splicing analysis, mechanical stimulation of cardiomyocytes","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, imaging, FRAP, splicing assays, translational machinery co-localization), direct functional consequences of localization established","pmids":["36417487"],"is_preprint":false},{"year":2021,"finding":"hnRNPC binds poly-uridine (U-tract) sequences in introns 9 and 10 of Tau pre-mRNA; knockdown of hnRNPC induces Tau exon 10 skipping whereas overexpression promotes Tau exon 10 inclusion. Mutation of U-tract motifs abolishes hnRNPC binding and blocks its effect on exon 10 inclusion.","method":"RNA Antisense Purification with Mass Spectrometry (RAP-MS), RIP, mutagenesis of U-tract motifs, splicing reporter assays, siRNA knockdown and overexpression","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — RAP-MS identification, mutagenesis of binding motifs, functional splicing assay; multiple orthogonal methods in single study","pmids":["34965173"],"is_preprint":false},{"year":2023,"finding":"hnRNPC haploinsufficiency results in altered alternative splicing of multiple intellectual disability-associated genes; a meta-analysis of RNA-seq datasets from three cell lines identified a ubiquitous hnRNPC-dependent alternative splicing signature, confirmed in patient fibroblasts. Either decreased or increased HNRNPC levels impair neuronal arborization and migration.","method":"iPSC and fibroblast analysis from individuals with HNRNPC variants, RNA-seq meta-analysis, neuronal arborization and migration assays","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells, meta-analysis of multiple RNA-seq datasets, functional neuronal assays; single study but multiple cell types","pmids":["37541189"],"is_preprint":false},{"year":2025,"finding":"hnRNPC works cooperatively with HuR to directly bind and modulate alternative splicing of meiotic-related genes (Sycp1, Brca1, Smc5) in an m6A-dependent manner during spermatogenesis; germ cell-specific knockout of Hnrnpc causes meiotic arrest at the pachytene stage in both male and female mice.","method":"Germ cell-specific conditional knockout mice, RNA-seq, RIP, m6A-dependent splicing assays, histological analysis of testes","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with defined cellular phenotype, RIP demonstrating direct binding, m6A-dependent mechanism, multiple orthogonal methods","pmids":["39921484"],"is_preprint":false},{"year":2022,"finding":"hnRNPC induces production of the cancer-specific isomiR-21-5p|±1 in liver cancer by binding upstream of pre-miR-21 via a poly-(U) motif and influencing Drosha processing; this isomiR has a shifted seed sequence that suppresses growth hormone receptor (GHR).","method":"High-throughput sequencing analysis, hnRNPC knockdown, antagomir treatment, in vitro tumorigenesis assays, mouse model of spontaneous liver cancer","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — hnRNPC knockdown with direct miRNA processing readout, in vivo validation; single lab","pmids":["35729324"],"is_preprint":false},{"year":2024,"finding":"HNRNPC mediates m6A-dependent alternative splicing of FOXM1 pre-mRNA by binding its m6A-modified motif; mutation of the m6A site on FOXM1 weakens HNRNPC-FOXM1 pre-RNA interaction and reduces the metastasis-promoting FOXM1-S isoform, contributing to lymphatic metastasis in cervical cancer.","method":"RIP, m6A site mutagenesis, alternative splicing assays, HNRNPC knockdown/overexpression, migration/invasion assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of m6A site with RIP and functional splicing readout; single lab, multiple orthogonal methods","pmids":["39375330"],"is_preprint":false},{"year":2022,"finding":"CUL9 binds p53 and together ubiquitinates HNRNPC for proteasomal degradation; this CUL9-p53-mediated HNRNPC degradation increases resistance to erastin-induced ferroptosis through a CUL9-HNRNPC-MATE1 negative loop in colorectal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays, CUL9 overexpression, siRNA knockdown, ferroptosis assays (erastin treatment), whole genome sequencing","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional ferroptosis readout; single lab","pmids":["35505093"],"is_preprint":false},{"year":2024,"finding":"DUSP3 dephosphorylates HNRNPC; DUSP3 knockdown results in tyrosine hyperphosphorylation of HNRNPC, increasing its RNA-binding ability and association with IRES trans-acting factor (ITAF) complexes in the cytoplasm, facilitating translation of IRES-containing mRNAs (c-MYC, XIAP) under genotoxic stress. Hyperphosphorylated HNRNPC also reduces HNRNPC-p53 binding in the presence of RNA.","method":"DUSP3 knockdown, phosphorylation assays, polysome profiling, RIP, protein level measurement by western blot, cell synchronization","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown of phosphatase with direct phosphorylation and translational readout, multiple orthogonal assays; single lab","pmids":["38538536"],"is_preprint":false},{"year":2012,"finding":"The C-terminal self-assembly domain of hnRNP-C enables it to form tetrameric complexes; this domain is structurally homologous to the yeast Nab3 self-assembly domain. A stretch of 16 glutamines adjacent to a putative α-helix potentiates self-assembly. Self-assembly is independent of RNA binding but acts in concert with RNA interactions.","method":"Biochemical self-assembly assays, in vitro tetramerization, domain mutagenesis, yeast functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with mutagenesis in yeast ortholog; single study with direct biochemical evidence but focused on yeast Nab3 with relevance to human hnRNP-C domain","pmids":["23192344"],"is_preprint":false},{"year":2022,"finding":"hnRNPC promotes Sertoli cell function in mice: conditional knockout of hnRNPC in Sertoli cells leads to aberrant proliferation, disrupted cytoskeleton, compromised blood-testis barrier function, and ultimately defective spermiogenesis, establishing an essential role in supporting germ cell development.","method":"Conditional knockout mice (Sertoli cell-specific), RNA-seq, histological analysis, blood-testis barrier assays","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with specific cellular and spermatogenic phenotype; single study","pmids":["38590182"],"is_preprint":false},{"year":2022,"finding":"HNRNPC regulates RhoA as a downstream target; HNRNPC overexpression promotes radiation resistance in pancreatic cancer, and this resistance is attenuated by RhoA silencing. The mechanism involves the RhoA/ROCK2-YAP/TAZ pathway for DNA damage repair and cancer-associated fibroblast activation.","method":"siRNA knockdown, HNRNPC overexpression, RhoA inhibition, in vitro radiation resistance assays, in vivo xenograft model","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by epistasis via siRNA, single lab, limited mechanistic detail on direct binding","pmids":["35277915"],"is_preprint":false},{"year":2024,"finding":"HNRNPC stabilizes HIF1A mRNA by directly binding it; HNRNPC downregulation decreases HIF1A expression by destabilizing HIF1A mRNA. Additionally, IL-6/STAT3 signaling upregulates HNRNPC expression in HCC cells.","method":"RNA-seq, mRNA stability assays (actinomycin D), HNRNPC knockdown, HIF1A overexpression rescue, IL-6 treatment and STAT3 inhibition","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay with actinomycin D, rescue experiment, upstream pathway identification; single lab","pmids":["35848884"],"is_preprint":false},{"year":2024,"finding":"The m6A reader HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the MAPK signaling pathway and malignant behavior in glioma. Integrative RNA-seq and MeRIP-seq identified IRAK1 as a downstream target.","method":"RNA-seq, MeRIP-seq, RIP, mRNA stability assays, HNRNPC knockdown/overexpression, IRAK1 knockdown, in vivo glioma models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP and mRNA stability assays identifying m6A-dependent target; single lab, multiple orthogonal methods","pmids":["38830885"],"is_preprint":false},{"year":2024,"finding":"HNRNPC modulates PKM alternative splicing via m6A methylation, upregulating PKM2 expression to promote aerobic glycolysis in papillary thyroid carcinoma. HNRNPC promotes the PKM2 isoform over PKM1 through m6A-dependent splicing regulation.","method":"Alternative splicing assays, m6A modification analysis, HNRNPC knockdown, metabolic assays (glycolysis), overexpression studies","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — splicing and metabolic assays in single lab with limited mechanistic detail on direct m6A binding","pmids":["39380010"],"is_preprint":false},{"year":2022,"finding":"hnRNPC interaction with influenza A virus nucleoprotein (NP) is mediated via the C-terminal auxiliary domain of hnRNPC; hnRNPC acts as a negative regulator of influenza viral growth and its interaction with NP promotes host cell apoptosis during viral infection.","method":"Co-immunoprecipitation across multiple influenza subtypes, domain mapping (C-terminal auxiliary domain), viral growth assays, apoptosis assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, functional viral growth and apoptosis readout; single lab","pmids":["36362400"],"is_preprint":false},{"year":2025,"finding":"HNRNPC crotonylation at lysine 189 (HNRNPCK189Cr) promotes colorectal cancer cell proliferation by stabilizing CCND1 and MCM3 mRNAs; HDAC3 acts as the specific decrotonylase of HNRNPCK189Cr through the MDM2/HDAC3 axis. Activating (K189Q) and inactivating (K189R) mutations confirmed the functional role of K189 crotonylation.","method":"Crotonylome mass spectrometry, HNRNPCK189Q/K189R mutagenesis, HDAC3 agonist treatment, siRNA knockdown, mRNA stability assays, in vivo colorectal cancer models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-specific mutagenesis confirming PTM function, identification of decrotonylase, mRNA stability readout; single lab but multiple orthogonal methods","pmids":["40482911"],"is_preprint":false},{"year":2025,"finding":"HNRNPC lactylation at lysine 176 (K176la) strengthens binding to poly-U motifs in PAK6 pre-mRNA, facilitating expression of the oncogenic isoform PAK6S in pancreatic cancer. Blocking K176la inhibits pancreatic cancer growth and metastasis.","method":"Lactylome analysis, HNRNPC K176 mutagenesis, RIP with PAK6 pre-mRNA, alternative splicing assays, in vivo tumor growth models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-specific PTM with mutagenesis and direct RNA binding readout; single lab","pmids":["41435694"],"is_preprint":false},{"year":2026,"finding":"During mitosis, hnRNPC undergoes a density shift forming low- and high-density complexes; mitotic hnRNPC acquires prevalent binding to exons, predominantly within 3' UTRs of mature mRNAs (rather than introns as in interphase), acting as a stabilizer of pre-mRNA and mRNA. Downregulation of hnRNPC causes a global negative effect on the abundance of its mitotic targets.","method":"Cell cycle synchronization, fCLIP (fluorescent crosslinking immunoprecipitation), RNA-seq, density gradient fractionation, hnRNPC knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct fCLIP mapping of binding sites, density gradient fractionation, knockdown with global mRNA abundance readout; multiple orthogonal methods in single study","pmids":["42049236"],"is_preprint":false},{"year":2025,"finding":"hnRNPC promotes MITA (STING) degradation via K48-linked ubiquitination through its C-terminal domain interaction with MITA, suppressing the type I IFN response. This mechanism is evolutionarily conserved: human hnRNPC similarly interacts with MITA and decreases MITA protein levels in HEK293 cells.","method":"Co-immunoprecipitation, ubiquitination assays (K48-linked), hnRNPC overexpression in HEK293 cells, zebrafish model viral infection, IFN production assays","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain identification, K48 ubiquitination assay, functional IFN readout in both zebrafish and human cells; single lab","pmids":["39994817"],"is_preprint":false},{"year":2025,"finding":"HNRNPC stabilizes TRAF6 transcripts in an m6A-dependent manner, thereby activating autophagy and driving gemcitabine resistance in pancreatic cancer. Additionally, HNRNPC stabilizes ALDH1A3 mRNA, enhancing glycolysis and H3K18 lactylation, establishing a positive feedback loop where H3K18la drives HNRNPC overexpression.","method":"Multi-omics (transcriptomics + epigenomics), mRNA stability assays, m6A-RIP, HNRNPC knockdown, autophagy assays, gemcitabine resistance assays, patient-derived xenograft models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assays, m6A-RIP, functional autophagy and resistance readout, PDX validation; single lab with multiple orthogonal methods","pmids":["41309519"],"is_preprint":false},{"year":2025,"finding":"FBXW11 acts as the E3 ubiquitin ligase for HNRNPC, ubiquitinating and degrading HNRNPC in preeclampsia placenta. HNRNPC binds ACSL3 RNA and promotes exon 10 skipping in an m6A-dependent manner; m6A site mutation reduces HNRNPC binding and reduces the ACSL3-S isoform.","method":"Co-IP, in vitro ubiquitination assays, western blot, RT-PCR, m6A site mutagenesis, mouse preeclampsia model","journal":"Journal of hypertension","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination assay identifying E3 ligase, m6A mutagenesis with splicing readout; single lab, multiple orthogonal methods","pmids":["41037014"],"is_preprint":false},{"year":2025,"finding":"HNRNPC m6A reader function regulates the expression of CELF2 through m6A modification; increased HNRNPC in drug-resistant AML cells decreases CELF2 expression, leading to upregulated glycolysis, enhanced glucose consumption, lactate production, and mitochondrial dysfunction. CELF2 knockdown reverses the metabolic effects of HNRNPC knockdown.","method":"m6A modification analysis, HNRNPC knockdown/overexpression, CELF2 knockdown/overexpression, metabolic assays (Seahorse XF), glycolysis assays","journal":"Cell & bioscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis via knockdown, single lab, limited mechanistic detail on direct m6A-dependent CELF2 regulation","pmids":["40380235"],"is_preprint":false},{"year":2024,"finding":"HNRNPC circASAP1 interaction occurs through amino acids 16-87 of HNRNPC (mapped by truncated isoform experiments); HNRNPC binding to circASAP1 influences GPX4-regulated ferroptosis in clear cell renal cell carcinoma.","method":"RNA pull-down, RIP, mass spectrometry, truncated HNRNPC isoform binding assays, FISH, GPX4 expression analysis, in vivo tumor models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by truncation plus RIP and mass spectrometry; single lab, direct binding domain identified","pmids":["39748364"],"is_preprint":false},{"year":2024,"finding":"EGF induces recruitment of UPF1 adjacent to HNRNPC on RNA to effect splicing surveillance of cell proliferation mRNAs; simultaneous HNRNPC and UPF1 co-binding was confirmed on RND3 and DDX3X mRNAs by sequential immunoprecipitation.","method":"irCLIP-RNP (UV crosslinking IP combined with mass spectrometry), Re-CLIP (sequential immunoprecipitation), EGF stimulation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel method (irCLIP-RNP + Re-CLIP) with direct protein-RNA co-binding demonstration; preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"HNRNPA1 and HNRNPC are key repressors of TARDBP exitron splicing; ASOs blocking their binding sites restored exitron splicing, suppressed TDP-43 pathology and neurodegeneration in neuronal cell models and a mouse model of TDP-43 proteinopathy.","method":"ASO-mediated blockade of HNRNPC binding sites, splicing reporter assays, in vitro and in vivo neurodegeneration models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ASO blockade with direct splicing and neurodegeneration readout in vivo; preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"HNRNPC is an abundant nuclear RNA-binding protein that binds U-rich/poly-U motifs on pre-mRNAs to regulate intron retention, alternative splicing, alternative polyadenylation, and mRNA stability; it functions as an m6A reader to stabilize target mRNAs; during mitosis it redistributes to bind mature mRNA 3' UTRs to globally stabilize the transcriptome; its activity is regulated by post-translational modifications including tyrosine phosphorylation (dephosphorylated by DUSP3), lysine crotonylation (K189, erased by HDAC3), lysine lactylation (K176), and ubiquitination (by FBXW11/CUL9-p53); it suppresses endogenous Alu-derived dsRNA accumulation to prevent RIG-I/MDA5-mediated interferon responses; it interacts with p53 to destabilize it under basal conditions, and with the IFN pathway mediator MITA/STING to promote its K48-ubiquitination and degradation; and it is essential for meiosis and Sertoli cell function in the male germline."},"narrative":{"mechanistic_narrative":"HNRNPC is an abundant nuclear RNA-binding protein that recognizes U-rich/poly-uridine tracts in pre-mRNA to govern alternative splicing, alternative cleavage and polyadenylation, miRNA processing, and mRNA stability across diverse cellular programs [PMID:31147722, PMID:34965173, PMID:35729324]. It directly binds poly-U motifs in target introns and exons—for example dictating Tau exon 10 inclusion through U-tract recognition that is abolished by motif mutation [PMID:34965173]—and additionally functions as an m6A reader, binding m6A-modified motifs to direct splice-isoform choice and to stabilize target transcripts in a methylation-dependent manner [PMID:34271104, PMID:39921484, PMID:39375330, PMID:38830885]. A central biological role is the suppression of endogenous double-stranded RNA: loss of HNRNPC permits accumulation of Alu-derived dsRNA from pre-mRNA introns and unmasking of cryptic splice sites, generating ligands that activate RIG-I and MDA5 type I interferon responses, an effect that synergizes with loss of ADAR-mediated A-to-I editing [PMID:30158112, PMID:34297039]. Beyond RNA, HNRNPC restrains innate immune and stress signaling at the protein level by binding and destabilizing p53 under basal conditions and by promoting K48-linked ubiquitination and degradation of the STING/MITA adaptor [PMID:28264987, PMID:39994817]. Its abundance and activity are tuned by post-translational modifications—tyrosine phosphorylation reversed by the phosphatase DUSP3, which controls RNA-binding and cytoplasmic IRES-dependent translation [PMID:38538536]; lysine 189 crotonylation erased by HDAC3 [PMID:40482911]; lysine 176 lactylation that strengthens poly-U binding [PMID:41435694]; and ubiquitination by E3 ligases including FBXW11 and a CUL9–p53 complex [PMID:35505093, PMID:41037014]. The protein self-assembles into tetramers via a C-terminal domain independent of RNA binding [PMID:23192344]. HNRNPC is essential in the male and female germline, where germ-cell-specific knockout causes pachytene meiotic arrest and Sertoli-cell-specific loss disrupts the blood-testis barrier and spermiogenesis [PMID:39921484, PMID:38590182], and HNRNPC dosage controls a neuronal alternative-splicing program required for normal neuronal arborization and migration, with haploinsufficiency linked to a neurodevelopmental/intellectual-disability phenotype [PMID:37541189].","teleology":[{"year":2012,"claim":"Established that hnRNP-C is not merely a monomeric RNA binder but oligomerizes, defining a C-terminal self-assembly module that organizes its activity.","evidence":"in vitro tetramerization and domain mutagenesis with yeast Nab3 functional assays","pmids":["23192344"],"confidence":"Medium","gaps":["self-assembly characterized largely via the yeast Nab3 ortholog","functional consequence of tetramerization for human pre-mRNA targeting not directly tested","no structure of the assembled human complex"]},{"year":2017,"claim":"Showed HNRNPC acts beyond RNA by directly binding and destabilizing p53, positioning it as a basal brake on the apoptotic checkpoint that a competing lncRNA can release.","evidence":"reciprocal Co-IP, RNA pull-down, SNHG1 competition and apoptosis assays after doxorubicin","pmids":["28264987"],"confidence":"Medium","gaps":["whether p53 destabilization is direct or RNA-bridged not fully resolved","single lab","physiological contexts of SNHG1 competition undefined"]},{"year":2018,"claim":"Identified the key cellular role of HNRNPC in masking intronic Alu-derived dsRNA, preventing aberrant RIG-I interferon activation.","evidence":"siRNA knockdown, dsRNA-IP, RNA-seq and RIG-I reporter assays in two breast cancer lines plus in vivo tumor growth","pmids":["30158112"],"confidence":"High","gaps":["mechanism by which HNRNPC binding prevents duplex formation not structurally defined","extent of overlap with other dsRNA-masking factors unclear"]},{"year":2019,"claim":"Demonstrated HNRNPC regulates alternative polyadenylation site choice, linking its dosage to cancer-associated 3'-end processing programs.","evidence":"subcellular fractionation and APA profiling by RNA-seq in a colon cancer overexpression model","pmids":["31147722"],"confidence":"Medium","gaps":["direct binding at regulated poly(A) sites not mapped","single overexpression model"]},{"year":2021,"claim":"Extended the dsRNA-suppression model by showing HNRNPC and ADAR act epistatically: their combined loss unmasks cryptic Alu splice sites generating under-edited MDA5 ligands.","evidence":"ADAR/hnRNPC double knockdown, RNA-seq and IFN response assays in THP-1 monocytes","pmids":["34297039"],"confidence":"Medium","gaps":["relative contribution of editing vs splicing masking to ligand load not quantified","single cell system"]},{"year":2021,"claim":"Defined the sequence basis of HNRNPC splicing control by mapping poly-U binding to specific Tau introns and showing dose-dependent exon 10 inclusion.","evidence":"RAP-MS, RIP, U-tract mutagenesis and splicing reporter assays","pmids":["34965173"],"confidence":"High","gaps":["splicing mechanism (spliceosome interplay) not detailed","relevance to tauopathy in vivo not tested here"]},{"year":2021,"claim":"Introduced HNRNPC as an m6A-coupled splicing regulator, showing its interaction with target pre-mRNA depends on the m6A mark to bias pro-metastatic isoforms.","evidence":"RIP, m6A-site mutagenesis, splicing and invasion/metastasis assays for TAF8","pmids":["34271104"],"confidence":"Medium","gaps":["whether HNRNPC reads m6A directly or via an indirect structural switch unresolved","single target studied"]},{"year":2022,"claim":"Revealed mechanosensitive relocalization of hnRNPC to the sarcomeric Z-disc where it couples to translation and mechanotransduction splicing (YAP1).","evidence":"fractionation, FRAP/live imaging, ribosome association and splicing analysis in mechanically stimulated cardiomyocytes","pmids":["36417487"],"confidence":"High","gaps":["signal driving cytoplasmic Z-disc targeting unknown","direct cytoplasmic RNA targets not exhaustively mapped"]},{"year":2022,"claim":"Established HNRNPC as essential for germ cell support, with Sertoli-cell knockout disrupting cytoskeleton, blood-testis barrier and spermiogenesis.","evidence":"Sertoli-cell conditional knockout mice, RNA-seq, histology, barrier assays","pmids":["38590182"],"confidence":"Medium","gaps":["RNA targets responsible for barrier/cytoskeleton defects not pinpointed","single study"]},{"year":2022,"claim":"Showed HNRNPC protein level is controlled by a CUL9–p53 ubiquitination axis that tunes ferroptosis sensitivity.","evidence":"Co-IP, ubiquitination assays, CUL9 overexpression and erastin ferroptosis assays in colorectal cells","pmids":["35505093"],"confidence":"Medium","gaps":["ubiquitination site on HNRNPC not mapped","single lab"]},{"year":2022,"claim":"Broadened HNRNPC's RNA-processing repertoire to miRNA biogenesis, showing poly-U binding near pre-miR-21 reshapes Drosha processing into a cancer-specific isomiR.","evidence":"knockdown, high-throughput sequencing, antagomir and spontaneous liver cancer mouse model","pmids":["35729324"],"confidence":"Medium","gaps":["direct interaction with Drosha machinery not shown","single lab"]},{"year":2022,"claim":"Identified HNRNPC as a host restriction factor for influenza A, binding the viral NP via its C-terminal auxiliary domain and promoting apoptosis.","evidence":"reciprocal Co-IP across subtypes, domain mapping, viral growth and apoptosis assays","pmids":["36362400"],"confidence":"Medium","gaps":["mechanism linking NP binding to restriction unclear","single lab"]},{"year":2022,"claim":"Linked HNRNPC to HIF1A mRNA stabilization downstream of IL-6/STAT3, embedding it in a hypoxia/inflammation signaling axis.","evidence":"actinomycin D stability assays, knockdown, rescue and IL-6/STAT3 modulation in HCC cells","pmids":["35848884"],"confidence":"Medium","gaps":["binding site on HIF1A mRNA not mapped","single lab"]},{"year":2023,"claim":"Established HNRNPC dosage as a determinant of a conserved neuronal splicing program and a neurodevelopmental disease, with both loss and excess impairing neuronal arborization and migration.","evidence":"patient iPSC/fibroblast analysis, RNA-seq meta-analysis across three lines, neuronal assays","pmids":["37541189"],"confidence":"Medium","gaps":["individual splicing events driving the neuronal phenotype not isolated","haploinsufficiency mechanism vs gain-of-function not separated"]},{"year":2024,"claim":"Defined PTM control of HNRNPC by DUSP3, showing tyrosine dephosphorylation tunes RNA-binding and cytoplasmic IRES-dependent translation of c-MYC and XIAP.","evidence":"DUSP3 knockdown, phosphorylation/polysome profiling, RIP under genotoxic stress","pmids":["38538536"],"confidence":"Medium","gaps":["kinase responsible for HNRNPC phosphorylation not identified","single lab"]},{"year":2024,"claim":"Consolidated the m6A-reader splicing/stability model across cancers, showing HNRNPC binds m6A-marked FOXM1 and IRAK1 to drive metastatic isoforms and MAPK signaling.","evidence":"RIP, MeRIP-seq, m6A-site mutagenesis and mRNA stability assays in cervical cancer and glioma","pmids":["39375330","38830885"],"confidence":"Medium","gaps":["direct m6A recognition vs cooperating reader not resolved","each target studied in a single context"]},{"year":2024,"claim":"Mapped a discrete circRNA interaction interface (residues 16–87) on HNRNPC linked to GPX4/ferroptosis regulation, refining its protein-RNA contact map.","evidence":"RNA pull-down, RIP, mass spectrometry, truncation binding assays in renal cell carcinoma","pmids":["39748364"],"confidence":"Medium","gaps":["functional contribution of circASAP1 binding to splicing vs sequestration unclear","single lab"]},{"year":2024,"claim":"Showed HNRNPC and UPF1 co-occupy target mRNAs to perform EGF-induced splicing surveillance of proliferation transcripts.","evidence":"irCLIP-RNP and Re-CLIP sequential IP after EGF stimulation (preprint)","pmids":[],"confidence":"Medium","gaps":["preprint, not peer-reviewed","functional outcome of co-binding on target stability not fully defined"]},{"year":2024,"claim":"Implicated HNRNPC (with HNRNPA1) as a repressor of TARDBP exitron splicing relevant to TDP-43 proteinopathy, with ASO blockade rescuing neurodegeneration.","evidence":"ASO blockade of binding sites, splicing reporters and TDP-43 mouse model (preprint)","pmids":[],"confidence":"Medium","gaps":["preprint, not peer-reviewed","relative contributions of HNRNPC vs HNRNPA1 not separated"]},{"year":2025,"claim":"Demonstrated that distinct acyl-lysine modifications act as functional switches: K189 crotonylation (erased by HDAC3) and K176 lactylation reprogram HNRNPC mRNA stabilization and poly-U binding to drive cancer phenotypes.","evidence":"crotonylome/lactylome MS, site-specific K-to-Q/R mutagenesis, RIP and mRNA stability assays in colorectal and pancreatic cancer","pmids":["40482911","41435694"],"confidence":"Medium","gaps":["writers of these acyl marks not all defined","interplay between distinct lysine PTMs unexplored"]},{"year":2025,"claim":"Defined HNRNPC's in vivo meiotic requirement, showing it cooperates with HuR for m6A-dependent splicing of meiotic genes and that germ-cell knockout arrests meiosis at pachytene in both sexes.","evidence":"germ-cell conditional knockout mice, RIP, m6A-dependent splicing assays, testis histology","pmids":["39921484"],"confidence":"High","gaps":["which specific splicing targets are rate-limiting for meiotic progression not isolated","molecular basis of HuR cooperation undefined"]},{"year":2025,"claim":"Showed HNRNPC suppresses innate antiviral immunity at the protein level by driving K48-ubiquitination and degradation of STING/MITA via its C-terminal domain, an evolutionarily conserved function.","evidence":"Co-IP, K48-ubiquitination assays, zebrafish infection and human HEK293 cells","pmids":["39994817"],"confidence":"Medium","gaps":["whether HNRNPC recruits an E3 ligase or acts as adaptor not resolved","single lab"]},{"year":2025,"claim":"Identified FBXW11 as an E3 ligase degrading HNRNPC and linked HNRNPC m6A-dependent ACSL3 splicing to placental pathology in preeclampsia.","evidence":"Co-IP, in vitro ubiquitination, m6A-site mutagenesis and mouse preeclampsia model","pmids":["41037014"],"confidence":"Medium","gaps":["ubiquitination site and degron on HNRNPC not mapped","single lab"]},{"year":2026,"claim":"Revealed a cell-cycle-regulated rewiring of HNRNPC: during mitosis it shifts density and relocates from introns to 3'UTRs of mature mRNAs to act as a global transcriptome stabilizer.","evidence":"cell-cycle synchronization, fCLIP binding-site mapping, density gradient fractionation and knockdown with global mRNA abundance readout","pmids":["42049236"],"confidence":"High","gaps":["trigger for the mitotic density/binding shift unknown","machinery mediating 3'UTR stabilization undefined"]},{"year":null,"claim":"It remains unresolved how HNRNPC integrates its many inputs—poly-U recognition, m6A reading, self-assembly state, and a layered PTM code—into context-specific decisions between splicing, polyadenylation, stability, and protein-level regulation of partners like p53 and STING.","evidence":"no single study in the corpus reconciles the sequence-, modification-, and cell-cycle-dependent modes into a unified regulatory logic","pmids":[],"confidence":"Low","gaps":["no integrated structural model of m6A vs poly-U recognition","writers/erasers of all PTMs not fully mapped","rules governing nuclear splicing vs cytoplasmic translation/stability roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6,9,21,22,27]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,6,9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,16,17,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,12]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,22]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,6,9,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,23]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[8,14]}],"complexes":[],"partners":["P53","STING/MITA","CUL9","FBXW11","DUSP3","HUR","UPF1","INFLUENZA NP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07910","full_name":"Heterogeneous nuclear ribonucleoproteins 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Interacts with poly-U tracts in the 3'-UTR or 5'-UTR of mRNA and modulates the stability and the level of translation of bound mRNA molecules (PubMed:12509468, PubMed:16010978, PubMed:7567451, PubMed:8264621). Single HNRNPC tetramers bind 230-240 nucleotides. Trimers of HNRNPC tetramers bind 700 nucleotides (PubMed:8264621). May play a role in the early steps of spliceosome assembly and pre-mRNA splicing. N6-methyladenosine (m6A) has been shown to alter the local structure in mRNAs and long non-coding RNAs (lncRNAs) via a mechanism named 'm(6)A-switch', facilitating binding of HNRNPC, leading to regulation of mRNA splicing (PubMed:25719671)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P07910/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPC","classification":"Common 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PROTEIN; RALY","url":"https://www.omim.org/entry/614663"},{"mim_id":"614648","title":"RALY-LIKE PROTEIN; RALYL","url":"https://www.omim.org/entry/614648"},{"mim_id":"610640","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 2; YTHDF2","url":"https://www.omim.org/entry/610640"},{"mim_id":"300841","title":"COAGULATION FACTOR VIII; F8","url":"https://www.omim.org/entry/300841"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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accumulation of endogenous double-stranded RNA enriched in Alu sequences, predominantly originating from pre-mRNA introns containing HNRNPC binding sites; these dsRNAs activate the RIG-I-mediated interferon response, inhibiting cell proliferation and tumor growth. This establishes HNRNPC's mechanistic role in suppressing endogenous dsRNA formation.\",\n      \"method\": \"siRNA knockdown, RNA-seq, dsRNA immunoprecipitation, RIG-I pathway reporter assays, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, sequencing, pathway reporters, in vivo), replicated across two cell lines, mechanistic link from dsRNA accumulation to RIG-I signaling clearly established\",\n      \"pmids\": [\"30158112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPC regulates alternative cleavage and polyadenylation (APA) site selection; overexpression of hnRNPC establishes APA profiles characteristic of metastatic colon cancer cells, including regulation of MTHFD1L poly(A) site choice. This was determined by subcellular fractionation to measure nuclear and cytoplasmic APA profiles.\",\n      \"method\": \"Subcellular fractionation, APA profiling by RNA-seq, hnRNPC overexpression in colon cancer cell line model\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean overexpression system with direct APA readout, single lab but two orthogonal approaches (fractionation + sequencing)\",\n      \"pmids\": [\"31147722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPC directly binds p53 protein, destabilizes it, and prevents its activation under normal conditions. Upon doxorubicin treatment, nuclear-retained lncRNA SNHG1 competes with p53 for hnRNPC binding, releasing p53 and promoting p53-dependent apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, RNA pull-down, siRNA knockdown, apoptosis assays, doxorubicin treatment\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, competition assay, functional apoptosis readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28264987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HNRNPC antagonizes the anti-metastatic isoform of TAF8 (TAF8L) and promotes the pro-metastatic alternative splicing isoform TAF8S in an m6A-dependent manner; mutation of the m6A site on TAF8 pre-mRNA attenuates HNRNPC-TAF8 interaction, reducing TAF8S production.\",\n      \"method\": \"RNA immunoprecipitation, m6A site mutagenesis, alternative splicing assays, in vitro invasion assays, in vivo metastasis models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A site mutagenesis combined with RIP and functional metastasis readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34271104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HNRNPC deficiency, synergizing with ADAR loss, leads to dysregulation of Alu-containing introns through unmasked cryptic splice sites, generating putative MDA5 ligands with reduced A-to-I editing, thereby synergistically inducing MDA5-dependent type I IFN responses.\",\n      \"method\": \"Candidate screen in THP-1 monocytes, RNA-seq, ADAR/hnRNPC double knockdown, IFN response assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via double knockdown, RNA-seq, functional IFN assay; single lab\",\n      \"pmids\": [\"34297039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPC is upregulated and relocates to the sarcomeric Z-disc in cardiomyocytes upon pathological extracellular matrix remodeling; at this site it associates with the translation machinery. Changes in hnRNPC expression, phosphorylation, and localization (mechanically determined) affect alternative splicing of mRNAs involved in mechanotransduction, including the Hippo pathway effector YAP1.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence/live imaging, FRAP, hnRNPC overexpression/knockdown, ribosome association assays, alternative splicing analysis, mechanical stimulation of cardiomyocytes\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, imaging, FRAP, splicing assays, translational machinery co-localization), direct functional consequences of localization established\",\n      \"pmids\": [\"36417487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPC binds poly-uridine (U-tract) sequences in introns 9 and 10 of Tau pre-mRNA; knockdown of hnRNPC induces Tau exon 10 skipping whereas overexpression promotes Tau exon 10 inclusion. Mutation of U-tract motifs abolishes hnRNPC binding and blocks its effect on exon 10 inclusion.\",\n      \"method\": \"RNA Antisense Purification with Mass Spectrometry (RAP-MS), RIP, mutagenesis of U-tract motifs, splicing reporter assays, siRNA knockdown and overexpression\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — RAP-MS identification, mutagenesis of binding motifs, functional splicing assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34965173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"hnRNPC haploinsufficiency results in altered alternative splicing of multiple intellectual disability-associated genes; a meta-analysis of RNA-seq datasets from three cell lines identified a ubiquitous hnRNPC-dependent alternative splicing signature, confirmed in patient fibroblasts. Either decreased or increased HNRNPC levels impair neuronal arborization and migration.\",\n      \"method\": \"iPSC and fibroblast analysis from individuals with HNRNPC variants, RNA-seq meta-analysis, neuronal arborization and migration assays\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells, meta-analysis of multiple RNA-seq datasets, functional neuronal assays; single study but multiple cell types\",\n      \"pmids\": [\"37541189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPC works cooperatively with HuR to directly bind and modulate alternative splicing of meiotic-related genes (Sycp1, Brca1, Smc5) in an m6A-dependent manner during spermatogenesis; germ cell-specific knockout of Hnrnpc causes meiotic arrest at the pachytene stage in both male and female mice.\",\n      \"method\": \"Germ cell-specific conditional knockout mice, RNA-seq, RIP, m6A-dependent splicing assays, histological analysis of testes\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with defined cellular phenotype, RIP demonstrating direct binding, m6A-dependent mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"39921484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPC induces production of the cancer-specific isomiR-21-5p|±1 in liver cancer by binding upstream of pre-miR-21 via a poly-(U) motif and influencing Drosha processing; this isomiR has a shifted seed sequence that suppresses growth hormone receptor (GHR).\",\n      \"method\": \"High-throughput sequencing analysis, hnRNPC knockdown, antagomir treatment, in vitro tumorigenesis assays, mouse model of spontaneous liver cancer\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — hnRNPC knockdown with direct miRNA processing readout, in vivo validation; single lab\",\n      \"pmids\": [\"35729324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPC mediates m6A-dependent alternative splicing of FOXM1 pre-mRNA by binding its m6A-modified motif; mutation of the m6A site on FOXM1 weakens HNRNPC-FOXM1 pre-RNA interaction and reduces the metastasis-promoting FOXM1-S isoform, contributing to lymphatic metastasis in cervical cancer.\",\n      \"method\": \"RIP, m6A site mutagenesis, alternative splicing assays, HNRNPC knockdown/overexpression, migration/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of m6A site with RIP and functional splicing readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39375330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CUL9 binds p53 and together ubiquitinates HNRNPC for proteasomal degradation; this CUL9-p53-mediated HNRNPC degradation increases resistance to erastin-induced ferroptosis through a CUL9-HNRNPC-MATE1 negative loop in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, CUL9 overexpression, siRNA knockdown, ferroptosis assays (erastin treatment), whole genome sequencing\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional ferroptosis readout; single lab\",\n      \"pmids\": [\"35505093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUSP3 dephosphorylates HNRNPC; DUSP3 knockdown results in tyrosine hyperphosphorylation of HNRNPC, increasing its RNA-binding ability and association with IRES trans-acting factor (ITAF) complexes in the cytoplasm, facilitating translation of IRES-containing mRNAs (c-MYC, XIAP) under genotoxic stress. Hyperphosphorylated HNRNPC also reduces HNRNPC-p53 binding in the presence of RNA.\",\n      \"method\": \"DUSP3 knockdown, phosphorylation assays, polysome profiling, RIP, protein level measurement by western blot, cell synchronization\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown of phosphatase with direct phosphorylation and translational readout, multiple orthogonal assays; single lab\",\n      \"pmids\": [\"38538536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The C-terminal self-assembly domain of hnRNP-C enables it to form tetrameric complexes; this domain is structurally homologous to the yeast Nab3 self-assembly domain. A stretch of 16 glutamines adjacent to a putative α-helix potentiates self-assembly. Self-assembly is independent of RNA binding but acts in concert with RNA interactions.\",\n      \"method\": \"Biochemical self-assembly assays, in vitro tetramerization, domain mutagenesis, yeast functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with mutagenesis in yeast ortholog; single study with direct biochemical evidence but focused on yeast Nab3 with relevance to human hnRNP-C domain\",\n      \"pmids\": [\"23192344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPC promotes Sertoli cell function in mice: conditional knockout of hnRNPC in Sertoli cells leads to aberrant proliferation, disrupted cytoskeleton, compromised blood-testis barrier function, and ultimately defective spermiogenesis, establishing an essential role in supporting germ cell development.\",\n      \"method\": \"Conditional knockout mice (Sertoli cell-specific), RNA-seq, histological analysis, blood-testis barrier assays\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with specific cellular and spermatogenic phenotype; single study\",\n      \"pmids\": [\"38590182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HNRNPC regulates RhoA as a downstream target; HNRNPC overexpression promotes radiation resistance in pancreatic cancer, and this resistance is attenuated by RhoA silencing. The mechanism involves the RhoA/ROCK2-YAP/TAZ pathway for DNA damage repair and cancer-associated fibroblast activation.\",\n      \"method\": \"siRNA knockdown, HNRNPC overexpression, RhoA inhibition, in vitro radiation resistance assays, in vivo xenograft model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by epistasis via siRNA, single lab, limited mechanistic detail on direct binding\",\n      \"pmids\": [\"35277915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPC stabilizes HIF1A mRNA by directly binding it; HNRNPC downregulation decreases HIF1A expression by destabilizing HIF1A mRNA. Additionally, IL-6/STAT3 signaling upregulates HNRNPC expression in HCC cells.\",\n      \"method\": \"RNA-seq, mRNA stability assays (actinomycin D), HNRNPC knockdown, HIF1A overexpression rescue, IL-6 treatment and STAT3 inhibition\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay with actinomycin D, rescue experiment, upstream pathway identification; single lab\",\n      \"pmids\": [\"35848884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The m6A reader HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the MAPK signaling pathway and malignant behavior in glioma. Integrative RNA-seq and MeRIP-seq identified IRAK1 as a downstream target.\",\n      \"method\": \"RNA-seq, MeRIP-seq, RIP, mRNA stability assays, HNRNPC knockdown/overexpression, IRAK1 knockdown, in vivo glioma models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP and mRNA stability assays identifying m6A-dependent target; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38830885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPC modulates PKM alternative splicing via m6A methylation, upregulating PKM2 expression to promote aerobic glycolysis in papillary thyroid carcinoma. HNRNPC promotes the PKM2 isoform over PKM1 through m6A-dependent splicing regulation.\",\n      \"method\": \"Alternative splicing assays, m6A modification analysis, HNRNPC knockdown, metabolic assays (glycolysis), overexpression studies\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — splicing and metabolic assays in single lab with limited mechanistic detail on direct m6A binding\",\n      \"pmids\": [\"39380010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPC interaction with influenza A virus nucleoprotein (NP) is mediated via the C-terminal auxiliary domain of hnRNPC; hnRNPC acts as a negative regulator of influenza viral growth and its interaction with NP promotes host cell apoptosis during viral infection.\",\n      \"method\": \"Co-immunoprecipitation across multiple influenza subtypes, domain mapping (C-terminal auxiliary domain), viral growth assays, apoptosis assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, functional viral growth and apoptosis readout; single lab\",\n      \"pmids\": [\"36362400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPC crotonylation at lysine 189 (HNRNPCK189Cr) promotes colorectal cancer cell proliferation by stabilizing CCND1 and MCM3 mRNAs; HDAC3 acts as the specific decrotonylase of HNRNPCK189Cr through the MDM2/HDAC3 axis. Activating (K189Q) and inactivating (K189R) mutations confirmed the functional role of K189 crotonylation.\",\n      \"method\": \"Crotonylome mass spectrometry, HNRNPCK189Q/K189R mutagenesis, HDAC3 agonist treatment, siRNA knockdown, mRNA stability assays, in vivo colorectal cancer models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific mutagenesis confirming PTM function, identification of decrotonylase, mRNA stability readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40482911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPC lactylation at lysine 176 (K176la) strengthens binding to poly-U motifs in PAK6 pre-mRNA, facilitating expression of the oncogenic isoform PAK6S in pancreatic cancer. Blocking K176la inhibits pancreatic cancer growth and metastasis.\",\n      \"method\": \"Lactylome analysis, HNRNPC K176 mutagenesis, RIP with PAK6 pre-mRNA, alternative splicing assays, in vivo tumor growth models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific PTM with mutagenesis and direct RNA binding readout; single lab\",\n      \"pmids\": [\"41435694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"During mitosis, hnRNPC undergoes a density shift forming low- and high-density complexes; mitotic hnRNPC acquires prevalent binding to exons, predominantly within 3' UTRs of mature mRNAs (rather than introns as in interphase), acting as a stabilizer of pre-mRNA and mRNA. Downregulation of hnRNPC causes a global negative effect on the abundance of its mitotic targets.\",\n      \"method\": \"Cell cycle synchronization, fCLIP (fluorescent crosslinking immunoprecipitation), RNA-seq, density gradient fractionation, hnRNPC knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct fCLIP mapping of binding sites, density gradient fractionation, knockdown with global mRNA abundance readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"42049236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPC promotes MITA (STING) degradation via K48-linked ubiquitination through its C-terminal domain interaction with MITA, suppressing the type I IFN response. This mechanism is evolutionarily conserved: human hnRNPC similarly interacts with MITA and decreases MITA protein levels in HEK293 cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48-linked), hnRNPC overexpression in HEK293 cells, zebrafish model viral infection, IFN production assays\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain identification, K48 ubiquitination assay, functional IFN readout in both zebrafish and human cells; single lab\",\n      \"pmids\": [\"39994817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPC stabilizes TRAF6 transcripts in an m6A-dependent manner, thereby activating autophagy and driving gemcitabine resistance in pancreatic cancer. Additionally, HNRNPC stabilizes ALDH1A3 mRNA, enhancing glycolysis and H3K18 lactylation, establishing a positive feedback loop where H3K18la drives HNRNPC overexpression.\",\n      \"method\": \"Multi-omics (transcriptomics + epigenomics), mRNA stability assays, m6A-RIP, HNRNPC knockdown, autophagy assays, gemcitabine resistance assays, patient-derived xenograft models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assays, m6A-RIP, functional autophagy and resistance readout, PDX validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41309519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW11 acts as the E3 ubiquitin ligase for HNRNPC, ubiquitinating and degrading HNRNPC in preeclampsia placenta. HNRNPC binds ACSL3 RNA and promotes exon 10 skipping in an m6A-dependent manner; m6A site mutation reduces HNRNPC binding and reduces the ACSL3-S isoform.\",\n      \"method\": \"Co-IP, in vitro ubiquitination assays, western blot, RT-PCR, m6A site mutagenesis, mouse preeclampsia model\",\n      \"journal\": \"Journal of hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination assay identifying E3 ligase, m6A mutagenesis with splicing readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41037014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPC m6A reader function regulates the expression of CELF2 through m6A modification; increased HNRNPC in drug-resistant AML cells decreases CELF2 expression, leading to upregulated glycolysis, enhanced glucose consumption, lactate production, and mitochondrial dysfunction. CELF2 knockdown reverses the metabolic effects of HNRNPC knockdown.\",\n      \"method\": \"m6A modification analysis, HNRNPC knockdown/overexpression, CELF2 knockdown/overexpression, metabolic assays (Seahorse XF), glycolysis assays\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis via knockdown, single lab, limited mechanistic detail on direct m6A-dependent CELF2 regulation\",\n      \"pmids\": [\"40380235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPC circASAP1 interaction occurs through amino acids 16-87 of HNRNPC (mapped by truncated isoform experiments); HNRNPC binding to circASAP1 influences GPX4-regulated ferroptosis in clear cell renal cell carcinoma.\",\n      \"method\": \"RNA pull-down, RIP, mass spectrometry, truncated HNRNPC isoform binding assays, FISH, GPX4 expression analysis, in vivo tumor models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by truncation plus RIP and mass spectrometry; single lab, direct binding domain identified\",\n      \"pmids\": [\"39748364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EGF induces recruitment of UPF1 adjacent to HNRNPC on RNA to effect splicing surveillance of cell proliferation mRNAs; simultaneous HNRNPC and UPF1 co-binding was confirmed on RND3 and DDX3X mRNAs by sequential immunoprecipitation.\",\n      \"method\": \"irCLIP-RNP (UV crosslinking IP combined with mass spectrometry), Re-CLIP (sequential immunoprecipitation), EGF stimulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel method (irCLIP-RNP + Re-CLIP) with direct protein-RNA co-binding demonstration; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HNRNPA1 and HNRNPC are key repressors of TARDBP exitron splicing; ASOs blocking their binding sites restored exitron splicing, suppressed TDP-43 pathology and neurodegeneration in neuronal cell models and a mouse model of TDP-43 proteinopathy.\",\n      \"method\": \"ASO-mediated blockade of HNRNPC binding sites, splicing reporter assays, in vitro and in vivo neurodegeneration models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ASO blockade with direct splicing and neurodegeneration readout in vivo; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"HNRNPC is an abundant nuclear RNA-binding protein that binds U-rich/poly-U motifs on pre-mRNAs to regulate intron retention, alternative splicing, alternative polyadenylation, and mRNA stability; it functions as an m6A reader to stabilize target mRNAs; during mitosis it redistributes to bind mature mRNA 3' UTRs to globally stabilize the transcriptome; its activity is regulated by post-translational modifications including tyrosine phosphorylation (dephosphorylated by DUSP3), lysine crotonylation (K189, erased by HDAC3), lysine lactylation (K176), and ubiquitination (by FBXW11/CUL9-p53); it suppresses endogenous Alu-derived dsRNA accumulation to prevent RIG-I/MDA5-mediated interferon responses; it interacts with p53 to destabilize it under basal conditions, and with the IFN pathway mediator MITA/STING to promote its K48-ubiquitination and degradation; and it is essential for meiosis and Sertoli cell function in the male germline.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HNRNPC is an abundant nuclear RNA-binding protein that recognizes U-rich/poly-uridine tracts in pre-mRNA to govern alternative splicing, alternative cleavage and polyadenylation, miRNA processing, and mRNA stability across diverse cellular programs [#1, #6, #9]. It directly binds poly-U motifs in target introns and exons—for example dictating Tau exon 10 inclusion through U-tract recognition that is abolished by motif mutation [#6]—and additionally functions as an m6A reader, binding m6A-modified motifs to direct splice-isoform choice and to stabilize target transcripts in a methylation-dependent manner [#3, #8, #10, #17]. A central biological role is the suppression of endogenous double-stranded RNA: loss of HNRNPC permits accumulation of Alu-derived dsRNA from pre-mRNA introns and unmasking of cryptic splice sites, generating ligands that activate RIG-I and MDA5 type I interferon responses, an effect that synergizes with loss of ADAR-mediated A-to-I editing [#0, #4]. Beyond RNA, HNRNPC restrains innate immune and stress signaling at the protein level by binding and destabilizing p53 under basal conditions and by promoting K48-linked ubiquitination and degradation of the STING/MITA adaptor [#2, #23]. Its abundance and activity are tuned by post-translational modifications—tyrosine phosphorylation reversed by the phosphatase DUSP3, which controls RNA-binding and cytoplasmic IRES-dependent translation [#12]; lysine 189 crotonylation erased by HDAC3 [#20]; lysine 176 lactylation that strengthens poly-U binding [#21]; and ubiquitination by E3 ligases including FBXW11 and a CUL9–p53 complex [#11, #25]. The protein self-assembles into tetramers via a C-terminal domain independent of RNA binding [#13]. HNRNPC is essential in the male and female germline, where germ-cell-specific knockout causes pachytene meiotic arrest and Sertoli-cell-specific loss disrupts the blood-testis barrier and spermiogenesis [#8, #14], and HNRNPC dosage controls a neuronal alternative-splicing program required for normal neuronal arborization and migration, with haploinsufficiency linked to a neurodevelopmental/intellectual-disability phenotype [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that hnRNP-C is not merely a monomeric RNA binder but oligomerizes, defining a C-terminal self-assembly module that organizes its activity.\",\n      \"evidence\": \"in vitro tetramerization and domain mutagenesis with yeast Nab3 functional assays\",\n      \"pmids\": [\"23192344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"self-assembly characterized largely via the yeast Nab3 ortholog\", \"functional consequence of tetramerization for human pre-mRNA targeting not directly tested\", \"no structure of the assembled human complex\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed HNRNPC acts beyond RNA by directly binding and destabilizing p53, positioning it as a basal brake on the apoptotic checkpoint that a competing lncRNA can release.\",\n      \"evidence\": \"reciprocal Co-IP, RNA pull-down, SNHG1 competition and apoptosis assays after doxorubicin\",\n      \"pmids\": [\"28264987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether p53 destabilization is direct or RNA-bridged not fully resolved\", \"single lab\", \"physiological contexts of SNHG1 competition undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the key cellular role of HNRNPC in masking intronic Alu-derived dsRNA, preventing aberrant RIG-I interferon activation.\",\n      \"evidence\": \"siRNA knockdown, dsRNA-IP, RNA-seq and RIG-I reporter assays in two breast cancer lines plus in vivo tumor growth\",\n      \"pmids\": [\"30158112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism by which HNRNPC binding prevents duplex formation not structurally defined\", \"extent of overlap with other dsRNA-masking factors unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated HNRNPC regulates alternative polyadenylation site choice, linking its dosage to cancer-associated 3'-end processing programs.\",\n      \"evidence\": \"subcellular fractionation and APA profiling by RNA-seq in a colon cancer overexpression model\",\n      \"pmids\": [\"31147722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct binding at regulated poly(A) sites not mapped\", \"single overexpression model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the dsRNA-suppression model by showing HNRNPC and ADAR act epistatically: their combined loss unmasks cryptic Alu splice sites generating under-edited MDA5 ligands.\",\n      \"evidence\": \"ADAR/hnRNPC double knockdown, RNA-seq and IFN response assays in THP-1 monocytes\",\n      \"pmids\": [\"34297039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"relative contribution of editing vs splicing masking to ligand load not quantified\", \"single cell system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the sequence basis of HNRNPC splicing control by mapping poly-U binding to specific Tau introns and showing dose-dependent exon 10 inclusion.\",\n      \"evidence\": \"RAP-MS, RIP, U-tract mutagenesis and splicing reporter assays\",\n      \"pmids\": [\"34965173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"splicing mechanism (spliceosome interplay) not detailed\", \"relevance to tauopathy in vivo not tested here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Introduced HNRNPC as an m6A-coupled splicing regulator, showing its interaction with target pre-mRNA depends on the m6A mark to bias pro-metastatic isoforms.\",\n      \"evidence\": \"RIP, m6A-site mutagenesis, splicing and invasion/metastasis assays for TAF8\",\n      \"pmids\": [\"34271104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether HNRNPC reads m6A directly or via an indirect structural switch unresolved\", \"single target studied\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed mechanosensitive relocalization of hnRNPC to the sarcomeric Z-disc where it couples to translation and mechanotransduction splicing (YAP1).\",\n      \"evidence\": \"fractionation, FRAP/live imaging, ribosome association and splicing analysis in mechanically stimulated cardiomyocytes\",\n      \"pmids\": [\"36417487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"signal driving cytoplasmic Z-disc targeting unknown\", \"direct cytoplasmic RNA targets not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established HNRNPC as essential for germ cell support, with Sertoli-cell knockout disrupting cytoskeleton, blood-testis barrier and spermiogenesis.\",\n      \"evidence\": \"Sertoli-cell conditional knockout mice, RNA-seq, histology, barrier assays\",\n      \"pmids\": [\"38590182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets responsible for barrier/cytoskeleton defects not pinpointed\", \"single study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed HNRNPC protein level is controlled by a CUL9–p53 ubiquitination axis that tunes ferroptosis sensitivity.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, CUL9 overexpression and erastin ferroptosis assays in colorectal cells\",\n      \"pmids\": [\"35505093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ubiquitination site on HNRNPC not mapped\", \"single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Broadened HNRNPC's RNA-processing repertoire to miRNA biogenesis, showing poly-U binding near pre-miR-21 reshapes Drosha processing into a cancer-specific isomiR.\",\n      \"evidence\": \"knockdown, high-throughput sequencing, antagomir and spontaneous liver cancer mouse model\",\n      \"pmids\": [\"35729324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct interaction with Drosha machinery not shown\", \"single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified HNRNPC as a host restriction factor for influenza A, binding the viral NP via its C-terminal auxiliary domain and promoting apoptosis.\",\n      \"evidence\": \"reciprocal Co-IP across subtypes, domain mapping, viral growth and apoptosis assays\",\n      \"pmids\": [\"36362400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking NP binding to restriction unclear\", \"single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked HNRNPC to HIF1A mRNA stabilization downstream of IL-6/STAT3, embedding it in a hypoxia/inflammation signaling axis.\",\n      \"evidence\": \"actinomycin D stability assays, knockdown, rescue and IL-6/STAT3 modulation in HCC cells\",\n      \"pmids\": [\"35848884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"binding site on HIF1A mRNA not mapped\", \"single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established HNRNPC dosage as a determinant of a conserved neuronal splicing program and a neurodevelopmental disease, with both loss and excess impairing neuronal arborization and migration.\",\n      \"evidence\": \"patient iPSC/fibroblast analysis, RNA-seq meta-analysis across three lines, neuronal assays\",\n      \"pmids\": [\"37541189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"individual splicing events driving the neuronal phenotype not isolated\", \"haploinsufficiency mechanism vs gain-of-function not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined PTM control of HNRNPC by DUSP3, showing tyrosine dephosphorylation tunes RNA-binding and cytoplasmic IRES-dependent translation of c-MYC and XIAP.\",\n      \"evidence\": \"DUSP3 knockdown, phosphorylation/polysome profiling, RIP under genotoxic stress\",\n      \"pmids\": [\"38538536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"kinase responsible for HNRNPC phosphorylation not identified\", \"single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated the m6A-reader splicing/stability model across cancers, showing HNRNPC binds m6A-marked FOXM1 and IRAK1 to drive metastatic isoforms and MAPK signaling.\",\n      \"evidence\": \"RIP, MeRIP-seq, m6A-site mutagenesis and mRNA stability assays in cervical cancer and glioma\",\n      \"pmids\": [\"39375330\", \"38830885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct m6A recognition vs cooperating reader not resolved\", \"each target studied in a single context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped a discrete circRNA interaction interface (residues 16–87) on HNRNPC linked to GPX4/ferroptosis regulation, refining its protein-RNA contact map.\",\n      \"evidence\": \"RNA pull-down, RIP, mass spectrometry, truncation binding assays in renal cell carcinoma\",\n      \"pmids\": [\"39748364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional contribution of circASAP1 binding to splicing vs sequestration unclear\", \"single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed HNRNPC and UPF1 co-occupy target mRNAs to perform EGF-induced splicing surveillance of proliferation transcripts.\",\n      \"evidence\": \"irCLIP-RNP and Re-CLIP sequential IP after EGF stimulation (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"preprint, not peer-reviewed\", \"functional outcome of co-binding on target stability not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated HNRNPC (with HNRNPA1) as a repressor of TARDBP exitron splicing relevant to TDP-43 proteinopathy, with ASO blockade rescuing neurodegeneration.\",\n      \"evidence\": \"ASO blockade of binding sites, splicing reporters and TDP-43 mouse model (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"preprint, not peer-reviewed\", \"relative contributions of HNRNPC vs HNRNPA1 not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that distinct acyl-lysine modifications act as functional switches: K189 crotonylation (erased by HDAC3) and K176 lactylation reprogram HNRNPC mRNA stabilization and poly-U binding to drive cancer phenotypes.\",\n      \"evidence\": \"crotonylome/lactylome MS, site-specific K-to-Q/R mutagenesis, RIP and mRNA stability assays in colorectal and pancreatic cancer\",\n      \"pmids\": [\"40482911\", \"41435694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"writers of these acyl marks not all defined\", \"interplay between distinct lysine PTMs unexplored\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined HNRNPC's in vivo meiotic requirement, showing it cooperates with HuR for m6A-dependent splicing of meiotic genes and that germ-cell knockout arrests meiosis at pachytene in both sexes.\",\n      \"evidence\": \"germ-cell conditional knockout mice, RIP, m6A-dependent splicing assays, testis histology\",\n      \"pmids\": [\"39921484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"which specific splicing targets are rate-limiting for meiotic progression not isolated\", \"molecular basis of HuR cooperation undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed HNRNPC suppresses innate antiviral immunity at the protein level by driving K48-ubiquitination and degradation of STING/MITA via its C-terminal domain, an evolutionarily conserved function.\",\n      \"evidence\": \"Co-IP, K48-ubiquitination assays, zebrafish infection and human HEK293 cells\",\n      \"pmids\": [\"39994817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether HNRNPC recruits an E3 ligase or acts as adaptor not resolved\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FBXW11 as an E3 ligase degrading HNRNPC and linked HNRNPC m6A-dependent ACSL3 splicing to placental pathology in preeclampsia.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, m6A-site mutagenesis and mouse preeclampsia model\",\n      \"pmids\": [\"41037014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ubiquitination site and degron on HNRNPC not mapped\", \"single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a cell-cycle-regulated rewiring of HNRNPC: during mitosis it shifts density and relocates from introns to 3'UTRs of mature mRNAs to act as a global transcriptome stabilizer.\",\n      \"evidence\": \"cell-cycle synchronization, fCLIP binding-site mapping, density gradient fractionation and knockdown with global mRNA abundance readout\",\n      \"pmids\": [\"42049236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"trigger for the mitotic density/binding shift unknown\", \"machinery mediating 3'UTR stabilization undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how HNRNPC integrates its many inputs—poly-U recognition, m6A reading, self-assembly state, and a layered PTM code—into context-specific decisions between splicing, polyadenylation, stability, and protein-level regulation of partners like p53 and STING.\",\n      \"evidence\": \"no single study in the corpus reconciles the sequence-, modification-, and cell-cycle-dependent modes into a unified regulatory logic\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no integrated structural model of m6A vs poly-U recognition\", \"writers/erasers of all PTMs not fully mapped\", \"rules governing nuclear splicing vs cytoplasmic translation/stability roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6, 9, 21, 22, 27]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 6, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 16, 17, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 6, 9, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 23]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"p53\", \"STING/MITA\", \"CUL9\", \"FBXW11\", \"DUSP3\", \"HuR\", \"UPF1\", \"influenza NP\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}