Alternative splicing of MAPT exon 10 generates 4R- and 3R-Tau isoforms, and its dysregulation is associated with tauopathies including Alzheimer’s disease (AD), for which effective treatments remain lacking. Here, we identify HuR as a novel repressor of MAPT exon 10 alternative splicing. Mechanistically, the RRM1 domain of HuR is critical for mediating its splicing inhibitory effect. HuR binds to the U-rich region downstream of intron 9 in MAPT together with FUBP1, KHSRP, hnRNPD, hnRNPAB, hnRNPDL, and TIAL1. The expression of HuR shows a negative association with that of FUBP1, KHSRP, hnRNPD, and TIAL1. Finally, we demonstrate that HuR regulates the expression and alternative splicing of genes involved in autophagy and apoptosis, pathways dysregulated in AD. Collectively, these findings establish HuR as a regulator of AD-relevant transcriptomic networks and provide a mechanistic basis for exploring HuR-targeted strategies in AD.
Inducing cuproptosis is considered a novel strategy to impede non-small cell lung cancer (NSCLC) progression. ATOX1 suppressed cuproptosis by chelating free copper ions. This study seeks to elucidate the pathways that regulate ATOX1 upstream and thereby pinpoint molecular targets for activating cuproptosis in NSCLC. Cuproptosis was induced with ES-Cu. Malignant phenotypes were assessed using CCK-8, clonogenic, and Transwell assays. RNA immunoprecipitation, RNA pull-down, and actinomycin D chase were used to examine IGF2BP2-ATOX1 mRNA interaction and mRNA stability. Protein-protein interactions and ubiquitination were examined by co-immunoprecipitation. The co-localization of USP11 and IGF2BP2 was visualized by immunofluorescence. IGF2BP2 protein stability was assessed following cycloheximide treatment. Copper content was quantified using a commercial kit. Gene and protein levels were evaluated by RT-qPCR and Western blot. RNA-binding domain mutant rescue experiments were conducted to determine the functional requirement of IGF2BP2 KH domains. A subcutaneous xenograft model was established to validate the regulatory axis in vivo. ATOX1 suppressed cuproptosis to support NSCLC proliferation. IGF2BP2 bound to the CDS of ATOX1 mRNA via the m6A site at position 261, thereby enhancing ATOX1 mRNA stability. The KH3-4 domains of IGF2BP2 were indispensable for this regulation. Upregulation of ATOX1 by IGF2BP2 inhibited cuproptosis and consequently drove NSCLC proliferation. USP11 maintained IGF2BP2 protein stability via deubiquitination, leading to suppression of cuproptosis and promotion of NSCLC progression through the IGF2BP2/ATOX1 axis in vitro. In vivo, the USP11-IGF2BP2-ATOX1 axis might promote NSCLC tumor growth by suppressing cuproptosis. USP11‑dependent deubiquitination stabilized IGF2BP2, which subsequently increased ATOX1 mRNA stability in an m6A‑dependent manner. Elevated ATOX1 expression inhibited cuproptosis and thereby accelerated NSCLC progression.
Entomopathogenic fungi of the genus Beauveria are widely used biological control agents that infect diverse insect hosts and can also associate with plants as rhizosphere colonizers and endophytes. Within this genus, Beauveria bassiana is a cosmopolitan generalist, whereas Beauveria brongniartii exhibits a narrower host range, primarily targeting soil-dwelling coleopteran larvae with limited evidence of plant colonization. To explore genomic differentiation associated with this ecological divergence, the commercially exploited B. brongniartii strain BIPESCO2 and B. bassiana ATHUM 4946 were sequenced using Oxford Nanopore technology, followed by comparative genomic analyses across multiple strains. Orthology identified species-specific gene families, although overall genome architecture and core gene content were highly conserved. The CAZyme repertoires were nearly identical, indicating retention of a versatile enzymatic toolkit supporting plant association, saprotrophy, and insect pathogenicity. In contrast, biosynthetic gene clusters displayed substantial variation, including structural remodeling of Beauveria-specific virulence-associated clusters and expansion of type I polyketide synthase clusters in B. brongniartii. Effector prediction revealed a conserved core of largely uncharacterized proteins alongside species-specific orthogroups enriched in adhesion-, immunity-, and cuticle-interaction domains. Together, these findings indicate that host-range divergence in Beauveria is associated with compartmentalized genomic differentiation, particularly in secondary metabolism and a limited subset of lineage-specific virulence factors, rather than in the conserved core infection machinery.
Recessive liguleless1 (lg1) gene significantly reduces leaf angle in maize and has become the choice in breeding for high plant density. Here, we sequenced the entire lg1 gene (5560 bp) among seven wild-type (Lg1) and one mutant (lg1) inbreds. The analysis revealed a total of 229 SNPs and 155 InDels within the Lg1 gene. The study also revealed the existence of three exons, with lg1-mutant having two exons. The lg1-mutant harboured an insertion of 130 bp Tourist MITE transposable element in exon-2 at 1663rd base, which deleted 157 amino acids of C-terminal region of the mutant LG1 protein. The mutant LG1 protein was 247 amino acids in length, in contrast to 399–404 amino acids in wild-type protein. The analysis with 26 paralogues and 66 orthologues of Lg1 revealed conservation of the squamosa promoter-binding (SBP) domain. A PCR-based co-dominant InDel marker (MGU-lg1-Tourist) specific to insertion of 130 bp was developed that differentiated the mutant allele (lg1) from the wild-type allele (Lg1). The marker was validated in two F2 populations, which showed a 1:2:1 ratio. F2 plants showed a 3 (wide angle: 41.58°) :1 (narrow angle: 5.88°) segregation for leaf angle. A set of 11 gene-based InDel markers (MGU-InDel1 to MGU-InDel11) specific to Lg1 was also developed, and along with MGU-lg1-Tourist, they classified a diverse set of 48 inbreds into 35 distinct haplotypes (hap1 to hap35) with lg1-based inbreds possessing hap1. This is the first report of the development and validation of a co-dominant gene-based marker specific to lg1, and information generated assumes great significance in maize breeding aimed to tailor the plant architecture suitable for high plant density. .
