Cell Communication and Signaling最新文献

{"title":"Intracellular Staphylococcus aureus triggers isolate-specific host transcriptional responses alongside TNF-R1 regulated cell fate decisions.","authors":"Annika Walter, Thorsten Bischler, Marvin Jungblut, Leonhard F Breitsprecher, Filip Vilotic, Johanna Beck, Lucia Hofmann, Nicole Schäfer, Tanja Ziesmann, Rico Franzkoch, Silke Härteis, Iana Gadjalova, Ute Distler, Gerti Beliu, Olympia-Ekaterini Psathaki, Michael Hensel, Wulf Schneider-Brachert, Tom Gräfenhan, Thomas Stempfl, Bärbel Kieninger, Sabrina Mühlen, Volker Alt, Gopala-Krishna Mannala, Jürgen Fritsch","doi":"10.1186/s12964-026-03246-8","DOIUrl":"10.1186/s12964-026-03246-8","url":null,"abstract":"<p><strong>Background: </strong>Staphylococcus aureus (S. aureus) is an increasingly recognized intracellular pathogen, yet infection outcomes vary with bacterial isolate and host cell type. Many mechanisms underlying these differences remain poorly understood. This study investigated how distinct intracellular S. aureus isolates influence host signaling programs and infection outcomes by modulating cell death pathways and TNF-R1 dependent regulation of host cell fates across different human cell lines.</p><p><strong>Methods: </strong>The intracellular localization of four S. aureus isolates was analyzed via transmission electron microscopy (TEM), structured illumination microscopy (SIM), serial block-face scanning electron microscopy (SBF-SEM), and imaging flow cytometry. The transcriptional reprogramming of infected U937 monocytes was examined via mRNA sequencing. Infection outcomes and early TNF-R1 surface expression were characterized and compared with those of A549 and SaOS-2 cell lines employing flow cytometry and Western blot analysis, characterizing host cell death mechanisms in both wild-type and TNF-R1‒deficient backgrounds.</p><p><strong>Results: </strong>All S. aureus isolates localized to the endo-lysosomal and cytosolic compartments but were also frequently detected in nucleo-proximal regions. In U937 monocytes, infection induced a conserved stress signature alongside isolate‑specific transcriptional programs divergently affecting inflammation, metabolism, and cell fate, which was markedly attenuated in response to the chronic‑infection isolate EDCC 5464. Similarly, cell death outcomes were isolate‑ and cell type-dependent, involved caspase activation consistent with intrinsic and extrinsic apoptosis signaling, and caspase-1 activation at distinct temporal dynamics. TNF‑R1 loss initially delayed but later increased later isolate-independent cytotoxicity. Higher TNF-R1 surface expression was triggered in U937 monocytes by all viable isolates, but only by EDCC 5464 in SaOS-2 and A549 cells. Viability of the latter was only marginally influenced by isolate or TNF-R1 loss.</p><p><strong>Conclusions: </strong>These results highlight the multilayered determinants governing intracellular S. aureus survival, host cell susceptibility, and noncanonical intracellular localization that warrants further investigation. The TNF/TNF-R1 axis appears to critically influence regulated host defenses during early infection stages in a tissue-specific manner, though its mechanistic contribution remains to be fully elucidated. Together with distinct isolate-driven gene expression profiles of U937 monocytes, infection risks under TNF-targeted therapies and the contribution of S. aureus heterogeneity should be considered in the design of future host-directed treatment strategies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Orphan Nuclear Receptors expression and function in breast cancer cells: oncogenic action of the NR2F6 receptor.","authors":"Maria Azzurra Caricasulo, Gabriela Paroni, Adriana Zanetti, Laura Brunelli, Mami Kurosaki, Andrea Vincenzo Cavallaro, Marika Foglia, Gabriella Remoli, Luca Guarrera, Marco Bolis, Mineko Terao, Enrico Garattini","doi":"10.1186/s12964-026-03226-y","DOIUrl":"10.1186/s12964-026-03226-y","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149066138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targetome-defined miR-181c signaling from extracellular vesicles governs periodontal MSC fate via RNF150-MAP3K5.","authors":"Jingyi Gao, Anhao Liu, Ye Yint Kaung Myint, Masahiro Hatasa, Supreda Suphanantachat Srithanyarat, Takanori Iwata","doi":"10.1186/s12964-026-03153-y","DOIUrl":"10.1186/s12964-026-03153-y","url":null,"abstract":"<p><strong>Background: </strong>In regenerative settings, robust differentiation of human mesenchymal stromal cells (hMSCs) requires precise coupling between post-transcriptional regulation and kinase-driven pathways to achieve optimal therapeutic efficacy. miRNA-mediated regulation is widely implicated in stem cell fate control, yet its mechanistic contribution to lineage commitment remains incompletely defined.</p><p><strong>Methods: </strong>Multi-conditioned periodontal ligament-derived hMSCs were developed as the regenerative model for alveolar bone. Extracellular vesicle (EV)-encapsulated miRNAs were delineated through microarrays. AGO2 RNA-immunoprecipitation sequencing with transcriptome profiling was integrated to establish the miRISC-associated targetome. Protein-protein interactions and signaling hierarchy were examined by Co-IP, WB, and IFC under knockdown/overexpression with pharmacological interventions. The translational efficacy of EV and miRNA was validated using a mouse ligature-induced periodontitis model, followed by µCT and histological analyses.</p><p><strong>Results: </strong>EVs produced by hMSCs with higher intrinsic osteogenic capacity exhibited enhanced osteo-inductivity, traced to the enrichment of miR-181c. miR-181c was consistently upregulated during osteogenesis, with gain- and loss-of-function producing concordant effects. Mechanistically, the E3 ubiquitin ligase RNF150 emerged as the main target, whose repression reduced MAP3K5 ubiquitin-mediated proteolysis and enabled p38 activation. Local administration of EVs and miR-181c both promoted alveolar bone regeneration process in vivo.</p><p><strong>Conclusion: </strong>Collectively, EV-miR-181c-RNF150-MAP3K5-p38 axis was proposed linking miRNA-mediated repression to kinase activation and lineage commitment. This work provides the framework for how EV-delivered miRNAs gate hMSCs' fate decision, with significance for acellular therapeutic modalities in periodontal and skeletal tissues.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149032052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NheABC is a pH-dependent cytotoxin that targets mitochondria and contributes to the virulence of Bacillus cereus in wound infections.","authors":"Naeem Ullah, Abdelbasset Yabrag, Anne Yska, Raswati Pant, Vignesh Ramnath, Toril Lindbäck, Laura M Carroll, Manoj Puthia, Aftab Nadeem","doi":"10.1186/s12964-026-03235-x","DOIUrl":"10.1186/s12964-026-03235-x","url":null,"abstract":"<p><p>Members of the Bacillus cereus group are Gram-positive, spore-forming, facultative anaerobic bacteria widely distributed in the environment. Pathogenic B. cereus group strains have been linked to a range of illnesses and infections, including severe non-gastrointestinal infections, such as wound infections. In the present study, we show that, among the pore-forming toxin (PFT)-producing bacterial strains tested, B. cereus group strain 75/95 induced pronounced membrane permeabilization in epithelial cells, prompting us to investigate the contribution of its tripartite NheABC toxin to host cell damage. NheABC exhibited potent cell membrane permeability in 2D epithelial cell cultures as well as in 3D spheroids and intestinal organoids, with prominent effects on the cell membrane and mitochondria. Functional analysis using liposome leakage assays demonstrated that cardiolipin (CL) and phosphatidylethanolamine (PE) promote NheABC-mediated membrane permeabilization, suggesting that membrane lipid composition contributes to NheABC activity and mitochondrial damage. Moreover, using erythrocytes and epithelial cells as model systems, we further demonstrated that the cytolytic activity of NheABC is pH-dependent and is markedly reduced under acidic conditions (pH 5.5). This pH dependence was independently confirmed using liposome leakage assays. Importantly, NheABC enhanced bacterial colonization and the local inflammatory response in a murine model of wound infection. Overall, our study highlights the critical role of mitochondria and pH in regulating NheABC-mediated cytolytic activity in mammalian cells, which may lead to the development of novel therapeutic strategies for managing B. cereus group-related gastrointestinal and non-gastrointestinal infections.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KDM6B inhibition modulates monocyte activation and alleviates IMQ-induced psoriasis-like skin inflammation.","authors":"Aman Damara, Najla Abassi, Delia Mihoc, Mahsa Nastaranpour, Pauline Kraft, Tina Sarkar, Tanja Kübelbeck, Daniela Kramer, Carsten Deppermann, Johannes U Mayer, Stephan Grabbe, Michael Delacher, Federico Marini, Fatemeh Shahneh","doi":"10.1186/s12964-026-03220-4","DOIUrl":"10.1186/s12964-026-03220-4","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory monocytes are increasingly recognized as key amplifiers of psoriasis, yet the epigenetic drivers of their pathogenic signature remain unclear. The mechanisms linking epigenetic regulation to metabolic reprogramming in monocyte-driven inflammation in psoriasis are poorly defined.</p><p><strong>Methods: </strong>We examined the expression and activity of the histone demethylase KDM6B in classical monocytes in the imiquimod (IMQ)-induced psoriasis model. Epigenetic changes were assessed by measuring H3K27me3 levels at inflammatory and metabolic gene promoters. Pharmacological inhibition of KDM6-family H3K27 demethylase activity after disease onset was performed using GSK-J4, a cell-permeable prodrug that is intracellularly converted to the active inhibitor GSK-J1. In parallel, inflammatory and metabolic transcriptional programs, bioenergetic profiles, immune cell recruitment to inflamed skin, and single-cell transcriptomic changes in myeloid populations were analyzed.</p><p><strong>Results: </strong>KDM6B expression and KDM6A/B demethylase activity were increased in classical monocytes during IMQ-induced psoriasis-like inflammation. This was associated with reduced levels of the repressive histone mark H3K27me3, an epigenetic modification linked to chromatin compaction and transcriptional silencing, at the Il1b, Tnf, Pgam1, Pgk1, and Aldoa promoters, together with an enhanced inflammatory and glycolytic gene signature. GSK-J4 treatment after disease onset restored H3K27me3 at inflammatory and metabolic loci, suppressed Il1b and Tnf transcription, normalized bioenergetic profiles, and reduced monocyte and neutrophil recruitment to inflamed skin. Single-cell transcriptomic profiling further revealed that GSK-J4 treatment was associated with reduced cytokine-mediated signaling, glycolysis, and chemotaxis pathways in monocytes, while enriching antigen presentation modules, consistent with a shift toward a homeostatic, antigen-presenting surveillance program in myeloid cells and a regulatory T cell (Treg)-supportive milieu.</p><p><strong>Conclusions: </strong>Collectively, our data identify KDM6B-associated epigenetic-metabolic remodeling as a component of inflammatory monocyte activation in IMQ-induced psoriasis-like inflammation. GSK-J4 treatment attenuated ongoing inflammation when initiated after disease onset. These findings support further investigation of KDM6-family demethylases as therapeutic targets in psoriasis-like inflammation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The landscape of peripheral blood RNA modifications and its clinical implications for diagnosis of hepatocellular carcinoma.","authors":"Lichen Ge, Mei Shang, Xia He, Fangfang Cui, Lijun Tao, Shuqin Dai, Hongsheng Wang, Bo Hu","doi":"10.1186/s12964-026-03206-2","DOIUrl":"10.1186/s12964-026-03206-2","url":null,"abstract":"<p><strong>Background: </strong>While over 170 RNA modifications have been identified and implicated in various cancers, their role in hepatocellular carcinoma (HCC) progression is increasingly recognized. Despite this established relevance in tumor biology, the landscape of RNA modifications in the peripheral blood of HCC patients-and their potential diagnostic utility-remains largely unexplored.</p><p><strong>Methods: </strong>Peripheral blood samples from patients with HCC, liver cirrhosis (LC), and normal healthy (NH) controls were collected. The abundances of 55 RNA modifications were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess their diagnostic potential for HCC, particularly at early stages. Correlations among these modifications and their associations with clinical parameters were analyzed. Simultaneously, differentially expressed genes, including those encoding RNA-modifying enzymes, were screened in peripheral blood. The biological relevance of the identified signatures was subsequently validated using in vitro co-culture and in vivo syngeneic HCC mouse models.</p><p><strong>Results: </strong>Compared to the combined non-HCC group (NH and LC), the abundances of 11 RNA modifications were significantly altered in both overall and stage I HCC groups, with N²,N²-dimethylguanosine (m^2,2G) emerging as a key component exhibiting the most pronounced dysregulation. A diagnostic model centered on an m^2,2G-based modification panel achieved area under the curves (AUCs) of 0.901 and 0.891 for detecting HCC and stage I HCC, respectively, demonstrating promising diagnostic potential. Notably, the incorporation of two upregulated genes in peripheral blood-IFI27 and CCR2-significantly enhanced the model's performance, yielding improved AUCs of 0.972 and 0.968, respectively. Further analysis revealed distinct correlation patterns among RNA modifications, as well as between RNA modifications and clinical laboratory parameters, exhibiting both shared and HCC-specific features that suggest systemic reprogramming of RNA modification network in HCC. This biological relevance was confirmed by elevated m^2,2G abundances in human lymphocytes co-cultured with HCC cells and blood from a syngeneic HCC mouse model.</p><p><strong>Conclusions: </strong>This study systematically profiled peripheral blood RNA modifications and provided preliminary evidence supporting their potential as diagnostic biomarkers for HCC. By integrating key modifications (m^2,2G, m^2,2,7G, m^6,6A) with two mRNA markers (IFI27 and CCR2), we developed a multi-omics signature that demonstrated promising diagnostic performance, particularly for early-stage HCC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virobiome-mediated regulation of microbiota-gut-brain axis signaling and neuroimmune homeostasis.","authors":"Alireza Afkhamian, Abolfazl Saffari Natanzi, Mahin Jafaridarabjerdi, Sara Aghaei, Ali Haghjou, Mohammadreza Shafiei, Aysa Hasanzade Bashkandi, Sajjad Shahraki, Russel J Reiter, Hamed Haddad Kashani, Yanchao Yang","doi":"10.1186/s12964-026-03067-9","DOIUrl":"10.1186/s12964-026-03067-9","url":null,"abstract":"<p><p>The human gut-brain axis (GBA) is increasingly recognized as a complex bidirectional communication system integrating microbial, neural, endocrine, and immune networks that shape neurological health. While bacterial contributions to this dialogue have been extensively characterized, the viral component of the gut ecosystem, the virome, has emerged as an important component associated with host physiological regulation. This review synthesizes evidence suggesting that bacteriophages and eukaryotic viruses may contribute to microbial and immune homeostasis and may influence signaling along the microbiota-gut-brain axis. In experimental studies, Bacteriophages have been shown to influence microbial community structure through lytic and lysogenic cycles, horizontal gene transfer, and metabolic modulation, indirectly regulating production of neuroactive metabolites such as short-chain fatty acids and tryptophan derivatives which in turn have been linked to blood brain barrier integrity and modulate microglial activation. In observational human studies and experimental models, eukaryotic viruses including Epstein Barr virus and cytomegalovirus have been associated with systemic inflammation, molecular mimicry, and cytokine dysregulation, amplifying neuroimmune cascades implicated in Alzheimer's disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD), and major depressive disorder (MDD). The convergence of viral-bacterial interactions highlights a transkingdom signaling network shaping neuroinflammatory tone and influencing disease susceptibility. Emerging experimental strategies, including precision phage therapy, engineered probiotics incorporating CRISPR-based antiviral systems, and fecal virome transplantation (FVT), are being explored as potential approaches to modulate virome-microbiome interactions. Integration of multiomics platforms with artificial intelligence-driven modeling will be critical for clarifying the temporal and mechanistic relationships between virome dynamics and neurological function. Collectively, these insights highlight the gut virobiome as a potentially important contributor to neuroimmune equilibrium and illuminate avenues for microbiome-informed diagnostics and interventions in neurodegenerative and neuropsychiatric disorders. This review therefore highlights the often underappreciated role of the gut virobiome and proposes an integrative conceptual model linking virome dynamics with microbiota-gut-brain axis signaling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148931974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Avobenzone induces intestinal injury by targeting ATG14 and impairing mitophagy.","authors":"Zi-Kang Gui, Zi-Jia Huang, Xiao-Yu Qi, Bao-Peng Wang, Jian-Rui Zhong, Yu-Jie Zeng, Yi-Ping Zhou, Qing-Yu He, Jing Zhang, Yang Wang","doi":"10.1186/s12964-026-03211-5","DOIUrl":"10.1186/s12964-026-03211-5","url":null,"abstract":"<p><strong>Background: </strong>Avobenzone (Avo) is a widely used ultraviolet filter in sunscreens and facial skincare products. In addition to dermal exposure, chronic oral intake may also occur through daily-use products. However, the potential intestinal toxicity of Avo and its underlying mechanisms remain poorly understood.</p><p><strong>Methods: </strong>We investigated the intestinal effects of Avo using repeated oral exposure mouse models, the Caco-2 intestinal epithelial cell line, human intestinal organoids, proteomic analysis, and mechanistic assays examining autophagy, mitophagy, mitochondrial stress responses, and Wnt/β-catenin signaling.</p><p><strong>Results: </strong>Administration of Avo (10-40 mg/kg) for two months induced intestinal epithelial injury in mice, as evidenced by reduced crypt number, shortened villi, impaired intestinal epithelial barrier, and decreased intestinal stem cell abundance. Avo also caused mitochondrial dysfunction, oxidative stress, and lipid accumulation. Mechanistically, Avo interacted with ATG14, a key component of the autophagy initiation complex, and promoted CUL3-mediated ubiquitination and proteasomal degradation of ATG14. Loss of ATG14 impaired mitophagy, leading to the accumulation of damaged mitochondria and activation of eIF2α-ATF5-associated mitochondrial unfolded protein response (UPR^mt). This mitochondrial stress suppressed Wnt/β-catenin signaling, reduced maintenance of LGR5-positive intestinal stem cells, and ultimately disrupted epithelial regeneration. Importantly, pharmacological induction of autophagy with rapamycin or inhibition of stress signaling with ISRIB alleviated Avo-induced intestinal injury in mice. Similar effects were observed in human intestinal organoids.</p><p><strong>Conclusions: </strong>These findings identify a previously unrecognized intestinal toxicity associated with Avo exposure and suggest that disruption of ATG14-dependent mitophagy and mitochondrial quality control is a key mechanism underlying this effect.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hemifusomes and proteolipid nanodroplets: a critical synthesis of an emerging model for endosomal membrane remodeling.","authors":"Mohammed A Abdel-Rasol, Wael M El-Sayed","doi":"10.1186/s12964-026-03182-7","DOIUrl":"10.1186/s12964-026-03182-7","url":null,"abstract":"<p><p>Vesicular membrane trafficking is central to eukaryotic homeostasis, governing receptor downregulation, lysosomal degradation, and intercellular communication via exosomes. These processes are classically explained by SNARE-mediated fusion and ESCRT-dependent membrane remodeling, which together define current models of vesicle biogenesis and multivesicular body (MVB) formation. Recent high-resolution cryo-electron tomography of intact mammalian cells has identified a structurally distinct membrane-associated assembly termed the hemifusome. Hemifusomes consist of two heterotypic vesicles connected by a persistent hemifusion diaphragm (~ 160 nm in diameter) and feature a ~ 42 nm proteolipid nanodroplet (PND) localized at the diaphragm rim. This architecture expands current views of hemifusion intermediates and raises the possibility of an alternative mode of endosomal membrane organization distinct from canonical ESCRT-mediated processes. However, the molecular composition, biogenesis, and regulatory mechanisms of this system remain undefined. Here, we provide the first integrated synthesis of hemifusome and PND biology, consolidating structural, biophysical, and mechanistic observations within the context of endosomal trafficking. We compare this emerging framework with ESCRT-mediated intraluminal vesicle formation, highlighting both shared features and key mechanistic gaps. We further examine preliminary and largely correlative links to neurodegenerative and lysosomal storage disorders, while emphasizing the absence of direct causal evidence. Given that this field currently rests on a single primary research report, we deliberately separate this evidence-based structural synthesis from more speculative functional, disease-related, and translational extensions, which are presented as explicit future perspectives rather than established conclusions. Finally, we outline unresolved questions, including PND molecular identity, determinants of hemifusion diaphragm organization and stability, and the temporal sequence of hemifusome assembly and remodeling. Together, these findings position hemifusomes as a potentially distinct structural state within the endosomal network, warranting systematic molecular and functional investigation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13555894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network integration of neocortical Cajal-Retzius neurons shapes early cortical dynamics and contributes to their transient nature.","authors":"Federico De Rosa, Werner Kilb, Heiko J Luhmann, Anne Sinning","doi":"10.1186/s12964-026-03210-6","DOIUrl":"10.1186/s12964-026-03210-6","url":null,"abstract":"<p><p>Cajal-Retzius neurons (CRN) represent an early-born transient neuronal population in the mammalian neocortex. They are best known for secreting reelin, which is essential for neuronal migration and layer formation in the developing cortex. However, their functional integration into developing cortical circuits and their contribution to early network dynamics have been poorly understood. In this study, we investigated the structural and functional integration of CRN into developing neocortical networks with immunohistochemistry, three-dimensional reconstruction of GABAergic inputs, extracellular electrophysiology and calcium imaging. In addition, multiplexed FISH was used to determine the expression levels of the chloride transporters NKCC1 and KCC2 in CRN at different postnatal stages. Finally, we employed optogenetic stimulation to assess the functional and developmental consequences of CRN activation. We found that CRN receive dense dendritic GABAergic synaptic inputs at early postnatal stages. Functional analyses revealed that a substantial fraction of CRN is spontaneously active, and that their activity is synchronized with both CRN and non-CRN neurons. At the molecular level, they display a persistent NKCC1-dominant expression profile. This profile can contribute to the excitatory GABA responses, but also affect their cell death, as chronic blockade of NKCC1 was associated with reduced CRN loss in vitro. Acute optogenetic activation of CRN at early stages increased network excitability in organotypic neocortical cultures and induced stimulus-evoked field responses, while chronic activation at later time points accelerated CRN loss. Overall, these findings demonstrate that, during development, dense GABAergic input connectivity, coupled with the putative excitatory action of GABA, can engage CRN in early network activity. Furthermore, not only do CRN actively participate in early immature circuits, but their activity also amplifies spontaneous network dynamics and contributes to their own transience, highlighting a potential novel functional role of CRN during neocortical development.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}