Cell Communication and Signaling最新文献

{"title":"TRIM24 regulates chromatin remodeling and calcium dynamics in cardiomyocytes.","authors":"Marco Neu, Anushka Deshpande, Ankush Borlepawar, Elke Hammer, Ahmed Alameldeen, Phillipp Vöcking, Timon Seeger, Michael Hausmann, Norbert Frey, Ashraf Yusuf Rangrez","doi":"10.1186/s12964-025-02323-8","DOIUrl":"10.1186/s12964-025-02323-8","url":null,"abstract":"<p><strong>Background: </strong>Cardiomyocyte proteostasis and calcium homeostasis are critical for maintaining cardiac function, with their dysregulation contributing to cardiac hypertrophy and heart failure. The Tripartite Motif Protein 24 (TRIM24), a well-characterized chromatin reader and transcriptional regulator in cancer, has recently emerged as a potential player in cardiac biology. However, its precise role in cardiomyocytes remains unclear. Using molecular, structural and functional approaches, this study investigates the impact of TRIM24 on cardiomyocyte function and gene regulation.</p><p><strong>Methods: </strong>To dissect the molecular and functional role of TRIM24, we conducted RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) in neonatal rat ventricular cardiomyocytes (NRVCMs) to identify TRIM24-regulated pathways and transcriptional targets. Super-resolution microscopy and proteomics analysis were employed to examine its influence on chromatin organization and calcium-handling protein distribution. Calcium imaging and cardiomyocyte contractility assays were performed in both NRVCMs and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess functional effects. Additionally, NFAT activity was assessed to investigate its role in TRIM24-mediated hypertrophic signaling.</p><p><strong>Results: </strong>Through RNA-seq and ChIP-seq, we identified TRIM24 as a bidirectional transcriptional regulator, predominantly acting as a repressor but also exhibiting context-dependent activation of genes involved in e.g. cytoskeletal organization and calcium signaling. ChIP-seq identified TRIM24 binding at the NFATc4 locus, validated by motif analysis, while functional studies revealed that TRIM24 regulates NFATc4 protein levels and activity, enhancing upon overexpression and reducing upon knockdown. Furthermore, TRIM24 overexpression altered the expression and organization of Ryanodine Receptor 2 (RyR2), Sarcoplasmic/endoplasmic Reticulum Ca²⁺ ATPase 2a (SERCA2a), and Calsequestrin 1 (CASQ1), leading to calcium-handling defects. Super-resolution microscopy revealed a loss of chromatin organization and altered clustering of calcium-handling proteins. Despite a reduction in SERCA2a levels, TRIM24 activated the PI3K-AKT/PLN pathway, increasing phospholamban phosphorylation and compensatory calcium reuptake. In functional assays, TRIM24 overexpression increased beating frequency and calcium cycling in both NRVCMs and iPSC-CMs.</p><p><strong>Conclusion: </strong>Our findings establish TRIM24 as a novel regulator of chromatin remodeling and cardiomyocyte transcription, directly influencing calcium homeostasis and contractility, with potential implications for cardiac disease.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"312"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546243","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":"Peritoneal cavity-derived small extracellular vesicles from aged tumor-naïve hosts promote ovarian cancer adhesion and invasion.","authors":"Reihaneh Safavi-Sohi, Jeff Johnson, Yueying Liu, Jing Yang, Tyvette S Hilliard, Zhikun Wang, Christopher Barile, Josh Mijares, Ceming Wang, Hsueh-Chia Chang, Rebecca J Whelan, M Sharon Stack","doi":"10.1186/s12964-025-02273-1","DOIUrl":"10.1186/s12964-025-02273-1","url":null,"abstract":"<p><strong>Background: </strong>Epithelial ovarian cancer (OvCa) remains a leading cause of mortality among gynecological cancers. Metastasis to the peritoneum, characterized by tumor cell adhesion to and invasion of the mesothelial lining of the abdominal cavity, represents a critical early event in OvCa metastatic progression. The median age of diagnosis is 63 and there exists a strong correlation between advanced age, OvCa incidence and disease stage. Moreover, the aged peritoneal cavity represents a permissive niche for metastatic dissemination.</p><p><strong>Methods: </strong>To investigate age-related factors that influence host-tumor communication in metastatic progression, the current study isolated small extracellular vesicles (sEVs) from the peritoneal lavage of healthy tumor-naïve young (3-6 month) and aged (20-22 month) mice. sEVs were analyzed using LC-MS/MS to identify sEV protein cargoes and incubated with murine and human OvCa cells to evaluate effect on pro-metastatic behaviors.</p><p><strong>Results: </strong>Treatment of human or murine OvCa cells with sEVs from healthy aged hosts significantly enhanced adhesion to peritoneal mesothelial cells in a three-dimensional in vitro meso-mimetic culture assay and to the intact omentum in a short-term in vivo adhesion assay relative to OvCa cells treated with sEVs from young hosts. OvCa cell invasion of collagen gels was also enhanced by aged host-derived sEVs. Proteomic analysis of sEV protein cargos identified differentially expressed proteins in sEVs obtained from aged vs. young hosts that may play a significant role in regulation of adhesion. This was confirmed using meso-mimetic adhesion assays with function blocking antibodies or small molecule inhibitors, supporting a potential role for several proteins in promoting intra-peritoneal dissemination in the aged host.</p><p><strong>Conclusions: </strong>Results suggest that sEVs derived from the aged peritoneal microenvironment can contribute significantly to disease progression, highlighting sEV-mediated host: tumor communication as a potential therapeutic target for intervention in OvCa progression or recurrence in the aged host.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"308"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546195","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":"Progress on multifunctional transmembrane protein ATG9A.","authors":"Xi Lin, Lin Liang, Shan Liao, Yanling Li, Yanhong Zhou","doi":"10.1186/s12964-025-02317-6","DOIUrl":"10.1186/s12964-025-02317-6","url":null,"abstract":"<p><p>ATG9A is the only transmembrane protein among the components required for autophagosome formation and participates in multiple cellular biological processes. ATG9A undergoes intracellular transport via microtubules and actin. As a lipid scramblase, ATG9A facilitates the random movement of lipid molecules between the inner and outer leaflets of lipid bilayers. Additionally, it can influence the homeostasis of the plasma membrane and membranous organelles. In autophagy, ATG9A is recruited to autophagic initiation sites to initiate cellular autophagy and subsequently participates in the process by promoting lipid transfer. Moreover, ATG9A also plays roles in maintaining neuronal homeostasis and is involved in embryonic development, infection, and immune responses. In this review, we comprehensively and systematically summarize the roles and mechanisms of ATG9A, aiming to provide a new perspective for understanding its functions.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"314"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546197","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 Drosophila histone variant H2Av facilitates Notch signaling activity in a two-tier regulatory fashion.","authors":"Yao Chen, Xinyue Zhang, Yu Song, Jie Shen, Junzheng Zhang","doi":"10.1186/s12964-025-02333-6","DOIUrl":"10.1186/s12964-025-02333-6","url":null,"abstract":"<p><strong>Background: </strong>H2Av is an evolutionarily conserved H2A variant protein involved in the regulation of transcription. The Tip60 complex is recruited by different transcription factors to facilitate the incorporation and acetylation of H2Av, thereby influencing target gene expression. The Tip60-H2Av axis is involved in various developmental processes, though its precise roles are not yet fully understood.</p><p><strong>Methods: </strong>RNA interference and gene mutation technology were used to screen essential genes in regulating Notch signaling pathway. Immunostaining was used to detect the protein level of H2Av, Tip60 complex as well as Notch signaling pathway components. Chromatin immunoprecipitation assays were performed to detect the specific binding site of H2Av in E(spl)-Complex and Su(H) genes.</p><p><strong>Result: </strong>Here we report that H2Av is required for Notch signaling activation during Drosophila wing development. H2Av depletion disrupts the expression of Notch target genes, resulting in wing marginal defects. Unexpectedly, we find that H2Av regulates the expression of the Su(H) gene which encodes for the transcription factor of the Notch signaling cascade. We further demonstrate that the Tip60 complex modulates the transcription of both Notch targets and Su(H) likely through H2Av. Based on these observations, we propose a model that the Tip60-H2Av axis facilitates Notch pathway activation by simultaneously promoting the expression of both the target genes and the transcription factor.</p><p><strong>Conclusion: </strong>This study offers insights into the diverse roles of the Tip60-H2Av axis in Notch pathway activation by identifying a novel two-tier regulatory mechanism which may also be utilized by other chromatin remodeling factors.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"322"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546201","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":"Behavioral assessment and gene expression changes in a mouse model with dysfunctional STAT1 signaling.","authors":"Luca Büschgens, Nina Hempel, Aditi Methi, Andre Fischer, Nele Siering, Lars Piepkorn, Olaf Jahn, Thomas Meyer, Oliver Wirths","doi":"10.1186/s12964-025-02313-w","DOIUrl":"10.1186/s12964-025-02313-w","url":null,"abstract":"<p><strong>Background: </strong>Signal transduction via the Signal Transducer and Activator of Transcription 1 (STAT1) pathway is indispensable for mediating the intracellular effects of interferon-α (IFN-α), interferon-γ (IFN-γ) and other cytokines in the brain and, thereby, crucial for antiviral and antibacterial responses during potential life-threatening CNS infections. However, the role of STAT1 signaling beyond the known IFN-α and IFN-γ effects in immediate antimicrobial defense is highly context-dependent, and studies in the existing literature using STAT1-targeted mouse models under normal physiological conditions remain scarce.</p><p><strong>Methods: </strong>Here, we characterized a STAT1 targeted-disruption mouse model in the absence of infectious stimuli by employing established behavioral testing paradigms and immunohistochemical stainings, as well as bulk hippocampal transcriptomic and proteomic analyses.</p><p><strong>Results: </strong>While we found neither overt behavioral alterations nor immunohistochemical changes with respect to microglial phagocytosis or proliferation, significant alterations were detected in gene and protein expression profiles implicated in neuroinflammatory processes and neuroprotection.</p><p><strong>Conclusion: </strong>In summary, this study highlights the complex and context-dependent role of STAT1-mediated signaling even in the absence of any detectable behavioral and neuropathological changes.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"305"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546188","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":"A novel mechanism of sperm midpiece epididymal maturation and the role of CCDC112 in sperm midpiece formation and establishing an optimal flagella waveform.","authors":"Maddison L Graffeo, Joseph Nguyen, Farin Yazdan Parast, Jessica E M Dunleavy, Denis Korneev, Hongyi Yang, Hidenobu Okuda, Anne E O'Connor, Donald F Conrad, Reza Nosrati, Brendan J Houston, Moira K O'Bryan","doi":"10.1186/s12964-025-02320-x","DOIUrl":"10.1186/s12964-025-02320-x","url":null,"abstract":"<p><strong>Background: </strong>The mitochondrial sheath is a defining feature of mammalian sperm with proposed functions in structural support and energy production for flagella movement. Recently, coiled coil domain containing (CCDC) protein 112 (CCDC112) was suggested to play a role in the regulation of ciliogenesis. CCDC112 is a poorly characterised protein and there is virtually no knowledge of its in vivo function.</p><p><strong>Methods: </strong>Here, we define CCDC112 as crucial for male fertility using a Ccdc112 loss-of-function mouse line. To characterize and analyze male fertility, and to identify a novel process of epididymal midpiece maturation, we utilized a range of assays including fertility testing, scanning electron microscopy, high-resolution sperm motility and power output analysis, in vitro fertilization, intracytoplasmic sperm injection, mitochondria stress test assays and glycolytic flux assays. Localization of CCDC112 in cilia was assessed via the transfection of IMCD-3 cells with a CCDC112-eGFP vector and subsequent immunofluorescent staining.</p><p><strong>Results: </strong>Results reveal CCDC112 as a requirement for male fertility in the mouse with an essential role in mitochondrial sheath formation. Our data reveal the critical role of CCDC112 in mitochondrial morphogenesis during midpiece formation, with the lack of CCDC112 leading to significantly reduced respiration capacity, irregular flagellar waveforms, diminished progressive motility and ultimately male sterility. In the absence of CCDC112, sperm are unable to traverse the female reproductive tract to the site of fertilization and in vitro have a poor capacity to penetrate the zonae pellucidae of oocytes or fuse with the oocyte. We further unveil a previously unrecognized process of epididymal mitochondrial sheath maturation. We show the sperm midpiece is structurally immature upon exiting the testis and maturation continues during transit from the caput to the cauda epididymis. Finally, we identify CCDC112 as a component of the distal appendages of the mother centriole in IMCD-3 cells suggestive of a facilitative role for CCDC112 in protein entry into the ciliary compartment within germ cells.</p><p><strong>Conclusion: </strong>Collectively, we establish CCDC112 as a key regulator of sperm midpiece assembly and function while further expanding our understanding on functional sperm production, energy generation and flagella kinematics.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"319"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546184","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":"TRIM21 functions as an oncogene in glioblastoma by transactivating FOSL1 and promoting the ubiquitination of p27.","authors":"Vanajothi Ramar, Rajveer Singh Sidhu, Osei Pako, Cheyenne R Cisse, Alyssa A Guo, Jason Li, Kelcey Stapleton, Shanchun Guo, Guangdi Wang, Mingli Liu","doi":"10.1186/s12964-025-02325-6","DOIUrl":"10.1186/s12964-025-02325-6","url":null,"abstract":"<p><p>Our previous studies demonstrated that FOSL1 promotes glioblastoma (GBM) progression and stemness through pathways such as STAT3 and NF-κB signaling. Recently, we identified that FOSL1 physically interacts with the nuclear E3 ligase TRIM21. This study investigates the role of TRIM21 in GBM, including its interaction with FOSL1, its regulation of FOSL1 transactivation, and its ubiquitination-mediated degradation of tumor suppressor p27. Immunoprecipitation assays were used to evaluate the interactions between TRIM21, FOSL1, and p27. TRIM21 expression was manipulated through overexpression and siRNA-mediated knockdown to assess its effects on p27 levels and ubiquitination. TCGA and CGGA datasets were analyzed to explore correlations between TRIM21 expression, glioma subtypes, and patient survival. Glioma cell proliferation (MTT and colony formation) and invasion (transwell assays) were evaluated following TRIM21 manipulation. Immunohistochemistry on glioma patient tissue microarray (TMA) assessed TRIM21 expression and its association with FOSL1, IDH status, and glioma grade. The role of nuclear TRIM21 in FOSL1 promoter transactivation was analyzed via AP-1 binding sites. TCGA and CGGA revealed that TRIM21 is highly expressed in GBM, particularly in the mesenchymal subtypes, and correlates with poor survival outcomes. Functional assays demonstrated that TRIM21 enhances glioma cell proliferation and invasion. Immunohistochemistry confirmed elevated TRIM21 levels in gliomas, positively correlating with FOSL1 expression and glioma grade, and inversely correlating with IDH1 wild-type status. Mechanistically, TRIM21 physically interacts with FOSL1 and p27, driving tumorigenesis by transactivating FOSL1 via AP-1 binding sites and promoting p27 ubiquitination and degradation. These functions are mediated through TRIM21's RING domain for p27 degradation and its PRYSPRY domain for FOSL1 regulation. TRIM21 functions as an oncogene in GBM by degrading the tumor suppressor p27 and promoting FOSL1 transactivation. These findings highlight TRIM21 as a promising therapeutic target in GBM.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"313"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546242","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":"AIM2 activation mediated by RIPK1/3-dependent mitochondrial DNA release drives Aβ_1-40-Induced retinal pigment epithelium injury.","authors":"Xiaoxu Huang, Tongqi Li, Guanran Zhang, Jieqiong Chen, Tong Li, Shiqi Yang, Qiyu Bo, Xiaohuan Zhao, Xiaoling Wan, Xinyue Zhu, Bo Yu, Xiaodong Sun, Junran Sun","doi":"10.1186/s12964-025-02294-w","DOIUrl":"10.1186/s12964-025-02294-w","url":null,"abstract":"<p><strong>Background: </strong>The retinal pigment epithelium (RPE) degeneration and subsequent retinal atrophy are hallmarks of age-related macular degeneration (AMD). Amyloid-beta (Aβ), the primary component of amyloid plaques in Alzheimer's disease (AD), is also present within drusen and is considered a critical factor contributing to RPE degeneration in AMD. Recent findings indicate that Aβ-induced inflammation plays a role in RPE degeneration. The aim of this study was to explore the molecular players and the precise mechanisms involved in this process, particularly the potential role of the absent in melanoma 2 (AIM2)-like receptors (ALRs) inflammasome.</p><p><strong>Methods: </strong>An animal model of Aβ_1-40-induced RPE injury was established. Fundus photography, electrophysiology and hematoxylin-eosin staining were used to evaluate the morphological and functional RPE damage. Transcriptome sequencing was used to detect the differentially expressed genes between Aβ_1-40 group and control group. The transcriptional and protein expression levels of AIM2 pathway and RIPK family members were detected. Adeno-associated virus vector 2/2 (AAV2/2)-shAIM2 was constructed to knockdown AIM2 expression in mice RPE cells. Aβ_1-40-treated ARPE-19 cells and hRPE cells were employed to analyze the regulatory effects of RIPK family on mitochondrial DNA (mtDNA) release and AIM2 pathway activation.</p><p><strong>Results: </strong>Aβ induces RPE damage through stimulation of AIM2 inflammasome and augmentation of caspase-1 and interleukin-1β (IL-1β). Knocking down AIM2 inhibits the release of inflammatory cytokines and alleviates the degeneration of the retina and RPE. Simultaneously, Aβ triggers the activation of RIPK1/RIPK3 kinases, as manifested by heightened protein expression and phosphorylation. Inhibiting RIPK1/RIPK3 phosphorylation dampens AIM2 inflammasome activity and curtails IL-1β secretion. Mechanistically, RIPK1/RIPK3 inhibition attenuates Aβ-induced Drp1(S616) hyperphosphorylation, consequently reducing mitochondrial fission and the efflux of mitochondrial DNA (mtDNA) into the cytosol. The diminished mtDNA release is responsible for attenuated AIM2 activation and subsequent inactivation of the stimulator of interferon genes (STING)/nuclear factor-kappa-B (NF-κB) signaling cascade.</p><p><strong>Conclusions: </strong>Our study is the first to validate AIM2's contribution in Aβ-induced RPE pathology and underscore the significance of the RIPK1/RIPK3-induced mtDNA release in modulating inflammatory responses, shedding light on the underlying mechanisms and potential therapeutics of AMD.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"301"},"PeriodicalIF":8.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340670","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":"STING-ΔN, a novel splice isoform of STING, modulates innate immunity and autophagy in response to DNA virus infection.","authors":"Jian Deng, Sheng-Nan Zheng, Jing Zhang, Cheng-Hao Li, Tao Li, Pei-Hui Wang","doi":"10.1186/s12964-025-02305-w","DOIUrl":"10.1186/s12964-025-02305-w","url":null,"abstract":"<p><strong>Background: </strong>Stimulator of interferon (IFN) genes (STING) is a central adaptor protein in the cGAS-STING signaling pathway, orchestrating the production of type I interferons (IFNs) in response to cytosolic DNA detection, a crucial mechanism in antiviral defense. However, further investigation is needed to understand how post-transcriptional regulation, particularly alternative splicing, modulates STING activity.</p><p><strong>Methods: </strong>We identified a novel alternatively spliced isoform of STING, termed STING-∆N, resulting from exon 3 skipping. We examined STING-∆N expression in various human tissues and cell lines and assessed its role in cGAS-STING signaling using RT-qPCR, luciferase reporter assays, SDD-AGE, immunofluorescence, and immunoblot analysis. We evaluated the influence of STING-∆N on HSV-1 proliferation and STING-induced autophagy by viral plaque assay and immunoblotting. To unravel the mechanistic role of STING-∆N, we further investigated its interaction with STING, TBK1, and 2'3'-cGAMP and its effect on the STING-TBK1 complex using co-immunoprecipitation and 2'3'-cGAMP pull-down assay.</p><p><strong>Results: </strong>STING-∆N shares an identical C-terminal sequence (aa 121-379) with STING but lacks a 120-amino acid N-terminal region encoding three conserved transmembrane (TM) domains. STING-∆N is expressed in various human tissues and cell lines. STING-∆N significantly suppressed IFN activation induced by cGAS, 2'3'-cGAMP, and STING. STING-∆N also reduced type I and III IFN induction in response to double-stranded DNA, HPV, and HSV-1. Additionally, STING-∆N promoted HSV-1 replication and inhibited STING-induced autophagy. Mechanistically, STING-∆N interacts with 2'3'-cGAMP, STING, and TBK1, sequestering their binding and disrupting the formation of the 2'3'-cGAMP-STING and STING-TBK1 complexes.</p><p><strong>Conclusions: </strong>STING-∆N acts as a potent negative regulator of the cGAS-STING pathway, revealing a previously unrecognized regulatory mechanism by which alternative splicing modulates immune responses to DNA viruses. These findings suggest that STING-∆N could be a promising therapeutic target for modulating immune responses in viral infections, autoimmune diseases, and cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"299"},"PeriodicalIF":8.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340672","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":"Prevalence and clinical relavance of germline mutations in Chinese patients with pancreatic cancer.","authors":"Yu Jiang, Dan Li, Yang Liu, Jiejie Qin, Hao Chen, Jun Zhang, Yijin Gu, Baiyong Shen, Jiabin Jin","doi":"10.1186/s12964-025-02281-1","DOIUrl":"10.1186/s12964-025-02281-1","url":null,"abstract":"<p><strong>Introduction: </strong>The prevalence and clinical significance of germline sequence variations in unselected Chinese pancreatic cancer (PC) patients remain underexplored.</p><p><strong>Methods: </strong>This retrospective study analyzed PC patients (not selected for age or family history) who underwent germline cancer predisposition gene analysis from January 2019 to December 2023 at Ruijin Hospital. Comparative data were sourced from The Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP) database. Germline P/LP variants were classified using MSK's Precision Oncology Knowledge Base, and their clinical relevance and potential for genotype-directed therapy were evaluated.</p><p><strong>Results: </strong>Sequencing of 1812 unselected Chinese PC cases (1088 [60.0%] male; mean [SD] age, 65.3 [9.5] years) identified 185 pathogenic and Likely pathogenic germline variants (P/LP GVs) in 174 patients (9.3%, 95% CI 8.0%-10.7%), with 43.1% affecting known pancreatic cancer susceptibility genes. Patients with P/LP GVs were diagnosed 2.68 years younger (p < 0.001) than those without. Besides the known PC predisposition genes, DNMT3A emerge as novel potential susceptibility genes for PC. OncoKB classification showed 54.0% had P/LP GVs with therapeutic implications, occurring in 94 out of 1,812 (5.2%) Chinese PC patients. Collectively, P/LP GVs in homologous recombination genes constituted 95.7% (n = 90) of all therapeutically actionable GVs. After adjustment, patients with P/LP GVs exhibited significantly improved overall survival (OS) than those without (HR = 0.7107, 95% CI: 0.5390-0.9373, p = 0.0156). Among patients with P/LP GVs, 119 had de novo metastases. Those with OncoKB level 1 variants had better OS than those without. Additionally, patients received genotype directed chemo or targeted therapies had much better improved survival.</p><p><strong>Conclusion: </strong>In this cohort, 5.2% of PC patients possessed therapeutically relevant P/LPGVs. Germline testing may provide prognostic benefits and is crucial for therapy selection, particularly in metastatic PC patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"300"},"PeriodicalIF":8.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340671","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}