Search Results (31)

SASH1 (SAM [sterile alpha motif] and SH3 [SRC-homology-3] domain-containing protein 1) is a multidomain scaffold implicated in pigmentation, innate immunity, receptor signaling, cytoskeletal dynamics, vascular biology, and tumor suppression. Although genetic and expression studies link SASH1 dysfunction to diverse diseases, a unifying mechanistic framework has remained elusive. Here, we synthesize current knowledge of SASH1 structure, interaction networks, and biological functions across cell types and disease contexts. SASH1 contains an intrinsically disordered SPIDER (SLy Proteins Associated Disordered Region), an SH3 domain, two SAM domains, and multiple linear motifs; together, these elements mediate interactions with EphA8 (ephrin type-A receptor 8), β-arrestin 1, TRAF6 (TNF receptor-associated factor 6), CRKL (CRK-like proto-oncogene), IQGAP1 (IQ-motif-containing GTPase-activating protein 1), cortactin, and TNKS2 (tankyrase-2). We propose that SASH1 functions as a context-dependent multi-docking scaffold that organizes signaling architecture. Its modular domains, intrinsically disordered regions, and dual SAM domains enable flexible, multivalent interactions with partners that can be grouped into three functional modules: receptor regulation, intracellular signaling, and cytoskeletal organization. Notably, many SASH1 partners are themselves scaffold or adaptor proteins, allowing integration into pre-existing networks in a hierarchical ‘scaffold-of-scaffolds’ manner. Through selective partner recruitment, SASH1 links cell-surface receptor inputs to downstream signaling pathways and cytoskeletal remodeling. This model provides a mechanistic framework for how SASH1 drives diverse, cell-type-specific outputs across physiology and disease, while revealing broader principles by which multidomain scaffolds encode cellular behavior. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; β-transducin repeat-containing protein, β-TrCP; HMG-CoA reductase degradation protein 1/synoviolin 1, Hrd1/SYVN1; WD repeat-containing protein 23/DDB1- and CUL4-associated factor 11, WDR23/DCAF11); a cytoplasmic scaffold module (p62/sequestosome 1, p62/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase γ/heat shock protein 27, PIPKIγ–HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A/cyclophilin A, PPIA); a nuclear coactivator module at Neh4/5 (CREB-binding protein/p300, CBP/p300; receptor-associated coactivator 3/steroid receptor coactivator 3, RAC3/SRC-3; protein arginine methyltransferase 1/coactivator-associated arginine methyltransferase 1, PRMT1/CARM1; Mediator complex subunit 16, MED16); and a DNA/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target. Full article

The senescence-associated secretory phenotype (SASP) contributes to various age-related pathologies. Methyl caffeate exhibits strong SASP-inhibitory activity; however, its molecular targets and the precise mechanisms underlying its effects remain unclear. Therefore, in this study, we performed affinity chromatography using methyl caffeate-immobilized beads to identify its intracellular binding proteins. The functional roles of the identified target were validated via knockdown experiments, assessment of SASP factor (interleukin [IL]-6 and IL-8) expression at the mRNA and secretion levels, and analysis of nuclear factor-κB and p38 mitogen-activated protein kinase signaling pathways. IQ motif-containing GTPase-activating protein 1 (IQGAP1) was identified as a methyl caffeate-binding partner. IQGAP1 knockdown significantly reduced IL-6 and IL-8 expression levels, mimicking the effects of methyl caffeate treatment. Furthermore, IQGAP1 depletion suppressed nuclear factor-κB activation and p38 phosphorylation. Overall, this study identified IQGAP1 as a critical scaffold protein essential for SASP induction and a target of methyl caffeate. Our findings provide key insights into SASP regulation, facilitating the development of SASP-modulating therapeutics targeting specific IQGAP1 domains. Full article

Tieguanyin (Camellia sinensis cv. Tieguanyin) is an important oolong tea cultivar in China, and heat stress has become a major environmental constraint affecting its growth and productivity. Calmodulin-binding transcription activators (CAMTAs) are important transcription factors involved in calcium/calmodulin-mediated signaling and plant responses to environmental stresses. However, systematic knowledge of the CAMTA gene family in Tieguanyin remains limited. In this study, 20 CsCAMTA genes were identified from the Tieguanyin genome and characterized based on their physicochemical properties, phylogenetic relationships, conserved motifs, gene structures, chromosomal distribution, collinearity, promoter cis-acting elements, and functional annotation. The 20 CsCAMTA genes were unevenly distributed across eight chromosomes, and collinearity analysis suggested that segmental duplication may have contributed to the expansion of this gene family. Conserved motif and domain analyses indicated that CsCAMTA proteins retained typical structural features of CAMTA transcription factors, including CG-1, ANKYR, TIG, and CaMBD/IQ-related regions. Promoter analysis showed that CsCAMTA genes harbored multiple cis-acting elements related to hormone responsiveness, stress response, light response, and growth regulation. Furthermore, qRT-PCR analysis of 18 representative CsCAMTA genes under 40 °C heat treatment revealed distinct temporal expression patterns, suggesting that different CsCAMTA members may respond to heat stress at different stages. Several genes, such as CsCAMTA2, CsCAMTA10, and CsCAMTA16, showed marked transcriptional changes and may represent candidate heat-responsive genes in Tieguanyin. These results provide a systematic overview of the CsCAMTA gene family and lay a foundation for further functional studies of heat stress responses in Tieguanyin. Full article

IQ67-domain (IQD) proteins are plant-specific calmodulin (CaM)/calmodulin-like (CML) targets implicated in the spatial organization of Ca²⁺ signaling, yet their roles in tartary buckwheat (Fagopyrum tataricum) remain largely unexplored. Here, we identified 24 FtIQD genes and classified them into six phylogenetic subfamilies. FtIQDs show uneven chromosomal distribution and mainly arise from segmental duplication under purifying selection. Promoter analysis revealed the enrichment of MYB-, light-, and ABA-related cis-elements. To link FtIQDs with rutin variation, we performed an FtIQD-focused association analysis using whole-genome resequencing data from altitude-stratified panels of up to 220 accessions. Under additive, dominant, and recessive models, multiple significant SNPs (p < 1 × 10⁻⁵) were detected near a subset of FtIQD loci, showing clear model- and environment-dependent patterns. Recurrent loci included FtIQD22, FtIQD02, FtIQD16, and FtIQD19. RNA-seq under PEG-induced drought stress, tissue expression patterns, pathway co-expression, and qRT–PCR further prioritized FtIQD19. FtIQD19–GFP showed predominant nuclear localization with additional filamentous/peripheral signals, and yeast two-hybrid assays identified FtCaM7.2 as the strongest interactor among representative CaMs. Structural modeling of the FtIQD19–FtCaM7.2 complex suggested testable residue-level interaction features. Collectively, this work provides a foundational FtIQD resource and highlights candidate Ca²⁺/CaM–IQD modules potentially associated with altitude-dependent rutin variation in tartary buckwheat. Full article

Calcium signaling is essential for coordinating plant responses to diverse stimuli and regulating growth and development. Among calcium sensors, calmodulin (CaM) and CaM-like proteins (CMLs) represent a class that, despite increasing research, remains incompletely characterized in wheat, with many interacting partners and biological functions remaining largely elusive. This study conducted bioinformatics analyses of subgroup II CaM/CMLs, characterizing their phylogenetic relationships, conserved motifs, sequence features, and cis-elements. Expression analysis revealed that TaCML49-B was significantly upregulated in roots under salt stress. Moreover, TaCML49-B was localized to nucleus, cytoplasm, and membrane. Function characterization demonstrated that overexpression of TaCML49-B in Arabidopsis enhanced salt tolerance, whereas the BSMV-VIGS silencing of TaCML49-B reduced salt resistance in wheat. Furthermore, STRING database prediction analysis and bimolecular fluorescence complementation (BiFC) assay confirmed that TaCML49-B can physically interact with TaIQD23, which encodes an IQ67 domain protein, suggesting its potential involvement in the salt stress signaling pathway. Collectively, our findings indicate that TaCML49-B functions as a positive role in wheat salt stress response, thereby providing novel insights into the functions of TaCML genes and calcium signaling in wheat. Full article

The calmodulin-binding transcriptional activator (CAMTA) is a small, conserved gene family in plants that plays a crucial role in regulating growth, development, and responses to various abiotic stress. Given the significance of the CAMTA gene family, various studies have been dedicated to uncovering its functional characteristics. In this study, genome-wide identification and bioinformatics analysis were conducted to explore CAMTAs in Phoebe bournei. A total of 17 CAMTA genes, each containing at least one domain from CG-1, TIG, ANK, or IQ, were identified in the P. bournei genome. The diversity of PbCAMTAs could be varied depending on their subcellular localization. An analysis of protein motifs, domains, and gene structure revealed that members within the same subgroup exhibited similar organization, supporting the results of the phylogenetic analysis. Gene duplications occurred among members of the PbCAMTA gene family. According to the cis-regulatory element prediction and protein–protein interaction network analysis, eight genes were subjected to qRT-PCR under drought, heat, and light stresses. The expression profiles indicated that PbCAMTAs, particularly PbCAMTA2, PbCAMTA12, and PbCAMTA16, were induced by abiotic stress. This study provides profound insights into the functions of CAMTAs in P. bournei. Full article

Microtubules undergo dynamic remodeling in response to diverse abiotic stress in plants. The plant-specific IQ67 DOMAIN (IQD) family proteins serve as microtubule-associated proteins, playing multifaceted roles in plant development and response to abiotic stress. However, the biological function of IQD genes in apple remains unclear. In this study, we conducted a comprehensive analysis of the Malus domestica genome, identifying 42 IQD genes distributed across 17 chromosomes and categorized them into four subgroups. Promoter analysis revealed the presence of stress-responsive elements. Subsequent expression analysis highlighted the significant upregulation of MdIQD17 and MdIQD28 in response to cold treatments, prompting their selection for further functional investigation. Subcellular localization studies confirmed the association of MdIQD17 and MdIQD28 with microtubules. Crucially, confocal microscopy and quantification revealed diminished microtubule depolymerization in cells transiently overexpressing MdIQD17 and MdIQD28 compared to wild-type cells during cold conditions. In conclusion, this study provides a comprehensive analysis of IQD genes in apple, elucidating their molecular mechanism in response to cold stress. Full article

Expression of microRNAs, such as miR-365, is known to be dysregulated in many tumors, including oral cancers, although little is known about their role or functions. The objective of this project is to evaluate the downstream targets of miR-365 to determine any potential pathways or effects. Downstream targets for miR-365 (miRdatabase target scores > 90) were used for qPCR screening of oral cancer cell lines (SCC4, SCC9, SCC15, SCC25, CAL27). Each oral cancer cell line expressed miR-365 downstream targets molybdenum cofactor synthesis-2 (MOCS2), erythropoietin receptor (EPOR), IQ motif containing-K (IQCK), carboxypeptidase A3 (CPA3), solute carrier family 24 member-3 (SLC24A3), and coiled-coil domain containing 47 (CCDC47)—although the expression levels varied somewhat. However, differential results were observed with ubiquitin protein ligase E3 component n-recognin-3 (UBR3), nudix hydrolase-12 (NUDT12), zinc finger CCHC-type containing-14 (ZCCHC14), and homeobox and leucine zipper encoding (HOMEZ). These data suggest that many of the miR-365 targets are expressed in the oral cancers screened, with the differential expression of UBR3, ZCCHC14, HOMEZ, and NUDT12, which may be correlated with chemoresistance among two specific oral cancer cell lines (SCC25, SCC9). These results suggest this differential expression may signal potential targets for patient treatment with tumors exhibiting miR-365 and chemotherapeutic resistance. Full article

Aim: This study systematically explored the biological effects and mechanisms of PGC on gastric cancer (GC) cells in vitro and in vivo. Method: The critical biological roles of PGC in GC were assessed via EdU staining, Hoechst staining, flow cytometry, mouse models, CCK-8, wound healing, transwell, and sphere-forming assays. The interaction study with IQ-domain GTPase-activating protein 1 (IQGAP1) was used by Liquid chromatography-mass spectrometry co-immunoprecipitation, immunofluorescence staining, CHX-chase assay, MG132 assay, and qRT-PCR. Results: PGC inhibited the proliferation, viability, epithelial–mesenchymal transition, migration, invasion, and stemness of GC cells and promoted GC cell differentiation. PGC suppressed subcutaneous tumor growth and peritoneal dissemination in vivo. The interaction study found PGC inhibits GC cell migration and invasion by downregulating IQGAP1 protein and IQGAP1-mediated Rho-GTPase signaling suppression. In addition, PGC disrupts the stability of the IQGAP1 protein, promoting its degradation and significantly shortening its half-life. Moreover, the expression levels of PGC and IQGAP1 in GC tissues were significantly negatively correlated. Conclusion: PGC may act as a tumor suppressor in the development and metastasis of GC. PGC can downregulate its interacting protein IQGAP1 and inhibit the Rho-GTPase pathway, thereby participating in the inhibition of GC cell migration and invasion. Full article

Background: Sotos syndrome is a genetic disorder caused by NSD1 gene (nuclear receptor binding SET domain containing protein 1) variants and characterized by overgrowth, macrocephaly, learning disabilities, and co-occurring neuropsychiatric symptoms. Methods: Literature sources published in 2002–2023 were selected and analyzed from PubMed and Google Scholar databases. Results: Neuropsychiatric symptoms are observed among children and adolescents with Sotos syndrome. The majority have intellectual disabilities or borderline intellect. Verbal IQ is higher than performance IQ. Individuals display difficulties in expressing language. Aggression is reported by parents. Children express autistic behavior, ADHD, anxiety based on phobias, and early bedtime-wake times. Conclusions: Sotos syndrome is associated with neuropsychiatric disorders in children. Slow intellectual and language development, aggressive outbursts, anxiety, autism spectrum disorder, and hyperactivity are present in the newest studies. Comprehensive assistance is needed for Sotos syndrome patients in responding to areas of difficulty. There is still a lack of research on the developmental characteristics of these children and the possibilities of improving psychosocial adaptation by providing multidisciplinary long-term medical, educational, and social care. Full article

Reperfusion after ischemia would cause massive myocardial injury, which leads to oxidative stress (OS). Calcium homeostasis imbalance plays an essential role in myocardial OS injury. Ca_V1.2 calcium channel mediates calcium influx into cardiomyocytes, and its activity is modulated by a region of calpastatin (CAST) domain L, CS_L54-64. In this study, the effect of Ahf-caltide, derived from CS_L54-64, on myocardial OS injury was investigated. Ahf-caltide decreased the levels of LDH, MDA and ROS and increased heart rate, coronary flow, cell survival and SOD activity during OS. In addition, Ahf-caltide permeated into H9c2 cells and increased Ca_V1.2, Ca_Vβ2 and CAST levels by inhibiting protein degradation. At different Ca²⁺ concentrations (25 nM, 10 μM, 1 mM), the binding of CS_L to the IQ motif in the C terminus of the Ca_V1.2 channel was increased in a H₂O₂ concentration-dependent manner. CS_L54-64 was predicted to be responsible for the binding of CS_L to Ca_V1.2. In conclusion, Ahf-caltide exerted a cardioprotective effect on myocardial OS injury by stabilizing Ca_V1.2 protein expression. Our study, for the first time, proposed that restoring calcium homeostasis by targeting the Ca_V1.2 calcium channel and its regulating factor CAST could be a novel treatment for myocardial OS injury. Full article

Pathogenic loss-of-function variants in the IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause intellectual disability with Rett syndrome (RTT)-like features. The aim of this study was to obtain systematic information on the natural history and extra-central nervous system (CNS) manifestations for the Italian IQSEC2 population (>90%) by using structured family interviews and semi-quantitative questionnaires. IQSEC2 encephalopathy prevalence estimate was 7.0 to 7.9 × 10⁻⁷. Criteria for typical RTT were met in 42.1% of the cases, although psychomotor regression was occasionally evidenced. Genetic diagnosis was occasionally achieved in infancy despite a clinical onset before the first 24 months of life. High severity in both the CNS and extra-CNS manifestations for the IQSEC2 patients was documented and related to a consistently adverse quality of life. Neurodevelopmental delay was diagnosed before the onset of epilepsy by 1.8 to 2.4 years. An earlier age at menarche in IQSEC2 female patients was reported. Sleep disturbance was highly prevalent (60 to 77.8%), with mandatory co-sleeping behavior (50% of the female patients) being related to de novo variant origin, younger age, taller height with underweight, better social interaction, and lower life quality impact for the family and friends area. In conclusion, the IQSEC2 encephalopathy is a rare and likely underdiagnosed developmental encephalopathy leading to an adverse life quality impact. Full article

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with a global prevalence of 25%. However, the medicines approved by the FDA or EMA are still not commercially available for the treatment of NAFLD. The NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome plays a crucial role in inflammatory responses, and the mechanisms related to steatohepatitis have been sufficiently clarified. NLRP3 has been widely evaluated as a potential target for multiple active agents in treating NAFLD. As a quercetin glycoside, isoquercitrin (IQ) has a broad inhibitory effect on oxidative stress, cancers, cardiovascular diseases, diabetes, and allergic reactions in vitro and in vivo. This study aimed to investigate the undercover mechanism of IQ in the treatment of NAFLD, particularly in anti-steatohepatitis, by suppressing the NLRP3 inflammasome. In this study, a methionine-choline-deficient induced steatohepatitis mice model was used to explore the effect of IQ on NAFLD treatment. Further mechanism exploration based on transcriptomics and molecular biology revealed that IQ inhibited the activated NLRP3 inflammasome by down-regulating the expression of heat shock protein 90 (HSP90) and suppressor of G-two allele of Skp1 (SGT1). In conclusion, IQ could alleviate NAFLD by inhibiting the activated NLRP3 inflammasome by suppressing the expression of HSP90. Full article

Sortilin-related vacuolar protein sorting 10 (VPS10) domain containing receptor 3 (SORCS3) is a neuron-specific transmembrane protein involved in the trafficking of proteins between intracellular vesicles and the plasma membrane. Genetic variation at SORCS3 is associated with multiple neuropsychiatric disorders and behavioural phenotypes. Here, we undertake a systematic search of published genome-wide association studies to identify and catalogue associations between SORCS3 and brain-related disorders and traits. We also generate a SORCS3 gene-set based on protein–protein interactions and investigate the contribution of this gene-set to the heritability of these phenotypes and its overlap with synaptic biology. Analysis of association signals at SORSC3 showed individual SNPs to be associated with multiple neuropsychiatric and neurodevelopmental brain-related disorders and traits that have an impact on the experience of feeling, emotion or mood or cognitive function, while multiple LD-independent SNPs were associated with the same phenotypes. Across these SNPs, alleles associated with the more favourable outcomes for each phenotype (e.g., decreased risk of neuropsychiatric illness) were associated with increased expression of the SORCS3 gene. The SORCS3 gene-set was enriched for heritability contributing to schizophrenia (SCZ), bipolar disorder (BPD), intelligence (IQ) and education attainment (EA). Eleven genes from the SORCS3 gene-set were associated with more than one of these phenotypes at the genome-wide level, with RBFOX1 associated with SCZ, IQ and EA. Functional annotation revealed that the SORCS3 gene-set is enriched for multiple ontologies related to the structure and function of synapses. Overall, we find many independent association signals at SORCS3 with brain-related disorders and traits, with the effect possibly mediated by reduced gene expression, resulting in a negative impact on synaptic function. Full article