Cell Communication and Signaling最新文献

{"title":"Cullin-RING ligase BioE3 reveals molecular-glue-induced neosubstrates and rewiring of the endogenous Cereblon ubiquitome.","authors":"Laura Merino-Cacho, Orhi Barroso-Gomila, Mónica Pozo-Rodríguez, Veronica Muratore, Claudia Guinea-Pérez, Álvaro Serrano, Coralia Pérez, Sandra Cano-López, Ainhoa Urcullu, Mikel Azkargorta, Ibon Iloro, Carles Galdeano, Jordi Juárez-Jiménez, Ugo Mayor, Felix Elortza, Rosa Barrio, James D Sutherland","doi":"10.1186/s12964-025-02091-5","DOIUrl":"10.1186/s12964-025-02091-5","url":null,"abstract":"<p><strong>Background: </strong>The specificity of the ubiquitination process is mediated by the E3 ligases. Discriminating genuine substrates of E3s from mere interacting proteins is one of the major challenges in the field. We previously developed BioE3, a biotin-based approach that uses BirA-E3 fusions together with ubiquitin fused to a low-affinity AviTag to obtain a site-specific and proximity-dependent biotinylation of the substrates. We proved the suitability of BioE3 to identify targets of RING and HECT-type E3 ligases.</p><p><strong>Methods: </strong>BioE3 experiments were performed in HEK293FT and U2OS stable cell lines expressing TRIPZ-bio^GEFUb transiently transfected with BirA-cereblon (CRBN). Cells were seeded using biotin-free media, followed later by a short-biotin pulse. We evaluated the applicability of the BioE3 system to CRBN and molecular glues by Western blot and confocal microscopy, blocking the proteasome with bortezomib, inhibiting NEDDylation with MLN4924 and treating the cells with pomalidomide. For the identification of endogenous substrates and neosubstrates we analyzed the eluates of streptavidin pull-downs of BioE3 experiments by LC-MS/MS. Analysis of targets for which ubiquitination changes significantly upon treatment was done using two-sided Student's t-test. Orthogonal validations were performed by histidine pull-down, GFP-trap and computational modelling.</p><p><strong>Results: </strong>Here we demonstrate that BioE3 is suitable for the multi-protein complex Cullin-RING E3s ligases (CRLs), the most utilized E3-type for targeted protein degradation (TPD) strategies. Using CRBN as proof of concept, one of the substrate receptors of CRL4 E3 ligase, we identified both endogenous substrates and novel neosubstrates upon pomalidomide treatment, including CSDE1 which contains a G-loop motif potentially involved in the binding to CRBN in presence of pomalidomide. Importantly, we observed a major rearrangement of the endogenous ubiquitination landscape upon treatment with this molecular glue.</p><p><strong>Conclusions: </strong>The ability of BioE3 to detect and compare both substrates and neosubstrates, as well as how substrates change in response to treatments, will facilitate both on-target and off-target identifications and offer a broader characterization and validation of TPD compounds, like molecular glues and PROTACs.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"101"},"PeriodicalIF":8.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460871","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":"Functions of the Muscleblind-like protein family and their role in disease.","authors":"Hui Zhou, Jiachi Xu, Liusheng Pan","doi":"10.1186/s12964-025-02102-5","DOIUrl":"10.1186/s12964-025-02102-5","url":null,"abstract":"<p><p>Conserved proteins are characterized by their functions remaining nearly constant throughout evolutionary history, both vertically through time and horizontally across species. In this review, we focus on a class of conserved proteins known as the Muscleblind-like (MBNL) family. As RNA-binding proteins, MBNL family members interact with pre-mRNAs through evolutionarily conserved tandem zinc finger domains and play critical roles in various RNA metabolic processes, including alternative splicing, mRNA stability, trafficking, regulation of subcellular localization, and alternative polyadenylation. Dysregulation of MBNL proteins can lead to severe consequences. Initially, research primarily associated MBNL proteins with myotonic dystrophy. However, recent studies have revealed their involvement in a broad spectrum of physiological and pathological processes, such as embryonic tissue differentiation and circulatory disorders. Furthermore, the emerging role of MBNL proteins in cancer sheds light on a novel aspect of these evolutionarily ancient proteins. This review provides a comprehensive overview of the MBNL family, emphasizing its structure, the mechanisms underlying its biological functions, and its roles in various diseases.Subject terms: Muscleblind-like-like protein, RNA-binding proteins, Alternative splicing, Tumor, Myotonic dystrophy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"97"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450401","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":"On the road: extracellular vesicles in intercellular communication.","authors":"Silja Wessler, Nicole Meisner-Kober","doi":"10.1186/s12964-024-01999-8","DOIUrl":"10.1186/s12964-024-01999-8","url":null,"abstract":"<p><p>Cells from organisms across all kingdoms of life continuously release a diverse repertoire of extracellular vesicles (EVs) into their extracellular environment as an elegant strategy for both, cellular homeostasis and communication with other cells. Through different biogenesis routes within the donor cell, nanosized vesicles are generated either from endomembranes or the plasma membrane, and loaded and decorated with macromolecular cargo in a controlled manner through molecular sorting machineries. Since they can affect a recipient cell in the same tissue, distant organs or even other organisms, EVs have been increasingly recognized as essential mediators orchestrating intercellular communication in health and disease. In the last 15 years, research on the fundamental biology of EVs as well as their potential for biomedical applications has been greatly intensified. Time to present new advances on EV biogenesis, their intercellular communication competencies as well as technical and biomedical applications in a special thematic series of Cell Communication and Signaling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"95"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450853","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":"REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling.","authors":"Xiaojing Ren, Yunfei Teng, Kunxin Xie, Xiao He, Gang Chen, Kaini Zhang, Qingyi Liao, Jia Zhang, Xiaohang Zhou, Yating Zhu, Wenyu Song, Yuege Lin, Yi Zhang, Zhijian Xu, Noriaki Maeshige, Xiubin Liang, Dongming Su, Peng Sun, Ying Ding","doi":"10.1186/s12964-025-02103-4","DOIUrl":"10.1186/s12964-025-02103-4","url":null,"abstract":"<p><strong>Background: </strong>Regenerating family member 3A (REG3A) is involved in the development of multiple malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). However, any role of REG3A in PDAC remains controversial due to its unclear tissue localization or direct receptors, and complex downstream signal transductions.</p><p><strong>Methods: </strong>Morphological analysis and public multi-omics data retrieval were was utilized to elucidate the tissue localization of REG3A in PDAC. To ascertain the pro-oncogenic role of secreted REG3A, experiments were conducted using in vitro PDAC cell lines and in vivo tumor formation assays in nude mice. A battery of investigative techniques, including RNA sequencing, phospho-kinase arrays, western blot analyses, in silico docking simulations, gene truncation strategies, and co-immunoprecipitation, were employed to delve into the downstream signaling transduction pathways induced by REG3A.</p><p><strong>Results: </strong>In this study, we confirmed an association between increased serum levels of REG3A and poor prognosis in patients with PDAC. Morphological staining and bioinformatic analysis showed that REG3A was mainly expressed in peritumoral acinar cells that were spatially close to tumor region, while it was almost negative in PDAC tumor cells. Peritumoral REG3A expression levels, but not tumoral REG3A, were highly correlated with PDAC progression. Further in vitro experiments including RNA sequencing and molecular biological assays revealed that secreted REG3A could directly bind to the epidermal growth factor receptor (EGFR), an important pro-oncogene involved in cellular proliferation, and subsequently activate the downstream mitogen-activated protein kinase (MAPK) signals to promote PDAC tumor cell growth.</p><p><strong>Conclusion: </strong>Taken together, our data indicated that increased expression of REG3A in peritumoral acinar cells acts as a specific event to indicate PDAC progression, and verified EGFR as a possible target of REG3A, providing mechanistic insights into the role of REG3A, the diagnostic method and therapeutic strategy of PDAC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"96"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450800","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 interplay of cancer-associated fibroblasts and apoptotic cancer cells suppresses lung cancer cell growth through WISP-1-integrin ανβ3-STAT1 signaling pathway.","authors":"Shinyoung Kim, Kyungwon Yang, Kiyoon Kim, Hee Ja Kim, Da Young Kim, Jeesoo Chae, Young-Ho Ahn, Jihee Lee Kang","doi":"10.1186/s12964-025-02094-2","DOIUrl":"10.1186/s12964-025-02094-2","url":null,"abstract":"<p><strong>Background: </strong>Cell death within the tumor microenvironment (TME) plays a crucial role in controlling cancer by influencing the balance of tumor-specific immunity. Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression through paracrine mechanisms. We found that reprogramming of CAFs by apoptotic cancer cells suppresses tumor volume and lung metastasis. Here, we investigated the mechanisms by which the interaction between apoptotic lung cancer cells and CAFs hinders tumor growth.</p><p><strong>Methods: </strong>Experimental methods including CCK assay, colony formation assay, immunoblotting, co-immunoprecipitation, qRT-PCR analysis, qRT-PCR array, apoptosis assay, ELISA, and immunofluorescent staining were used in this study. Additionally, CAFs were isolated from lung tumors of Kras-mutant (KrasLA1) mice and human lung adenocarcinoma samples using magnetic-activated cell sorting. Murine lung cancer cells (344SQ cells) along with various human cancer cell lines (A549, HCT116, and LoVo) were cultured. In animal study, conditioned medium (CM) derived from CAFs (undiluted or 50% diluted) with or without neutralizing anti-WISP-1 antibody was administered into syngeneic mice to study anti-tumoral effects. To confirm the paracrine role of WISP-1, recombinant WISP-1 (rWISP-1) was administered via intratumoral injection.</p><p><strong>Results: </strong>We demonstrate that treatment with CM from lung CAFs exposed to apoptotic cancer cells suppresses proliferation and promotes apoptosis in lung cancer cells through STAT1 signaling. Pharmacologic inhibition of Notch1 activation or siRNA-mediated Notch1 silencing in CAFs reversed the antiproliferative and proapoptotic effects. Similarly, knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs or neutralizing the CM with anti-WISP-1 antibodies reversed the antiproliferative and proapoptotic effects. WISP-1 signaled through integrin ανβ3-STAT1 signaling pathway to inhibit cancer cell growth and promote apoptosis. The in vivo introduction of CM derived from apoptotic 344SQ-exposed CAFs (ApoSQ-CAF CM) potently decelerated tumor growth. This effect was observed alongside the downregulation of proliferative and anti-apoptotic markers, while simultaneously boosting the activation of phosphorylated STAT1 and pro-apoptotic markers in CD326⁺ tumor cells within syngeneic immunocompetent mice. rWISP-1 effectively replicates the in vivo effects of ApoSQ-CAF CM.</p><p><strong>Conclusions: </strong>These findings suggest that CM from apoptotic cancer cell-exposed CAFs may offer a promising therapeutic approach by lung cancer suppression.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"98"},"PeriodicalIF":8.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450801","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":"COVID-19 patient serum-derived extracellular vesicles deliver miR-20b-5p induces neutrophil extracellular traps.","authors":"Yao Liao, Yuheng Liu, Dinghao Li, Shiqi Luo, Yun Huang, Junwei Wu, Jin Su, Yi Yang, Ji Wu, Zifeng Zhu, Mengxi Yanglan, Haiyi Deng, Xinyi Wu, Junhao Xu, Feiyang Cao, Chunmei Cai, Zhen Li, Ruibing Yang, Xiaoyan Deng, Jie Wei, Lifu Wang","doi":"10.1186/s12964-025-02095-1","DOIUrl":"10.1186/s12964-025-02095-1","url":null,"abstract":"<p><strong>Background: </strong>Severe cases of COVID-19 are characterized by an excessive presence of neutrophils. Neutrophil extracellular traps (NETs), released by activated neutrophils due to SARS-CoV-2 infection, contribute to lung epithelial cell death and are key drivers in COVID-19-associated immunothrombosis. However, the mechanism underlying NET formation in COVID-19 remain unclear.</p><p><strong>Methods: </strong>Extracellular vesicles (EVs) were isolated from the serum of COVID-19 patients and healthy volunteers, while neutrophils were isolated from blood samples of healthy volunteers. Neutrophils were treated with EVs, and the formation of NETs was observed. To identify the components responsible for the COVID-19-EVs-induced NET formation, we analyzed the expression profiles of microRNA (miRNAs) in COVID-19-EVs. We identified eight highly expressed miRNAs in COVID-19-EVs and explored their potential roles in COVID-19-EVs-mediated NET formation. Additionally, we explored the role of miR-20b-5p in COVID-19-EVs-induced NET formation.</p><p><strong>Results: </strong>In this study, we demonstrate that patients with COVID-19 have a higher concentration of serum EVs (COVID-19-EVs) than healthy controls (Normal-EVs). We also found that COVID-19-EVs are internalized by neutrophils to induced NET formation. Through comprehensive miRNA profiling of COVID-19-EVs versus Normal-EVs, we identified 78 differentially expressed miRNAs, with 27 of these being upregulated and 51 being downregulated. Subsequently, we discovered that COVID-19-EVs that were highly abundant with certain miRNAs promote NET formation. Specifically, miR-20b-5p was found to be the strongest inducer of NET formation of the identified miRNAs. Inhibition of miR-20b-5p resulted in a significant decrease in COVID-19-EVs-mediated induction of NET formation.</p><p><strong>Conclusion: </strong>Herein, we reveal a previously unknown role of COVID-19-EVs in NET formation, which contributes to COVID-19 progression. This study suggests that miR-20b-5p may serve as a potential therapeutic target for COVID-19 treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"93"},"PeriodicalIF":8.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442989","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":"Cooperative Hedgehog/GLI and JAK/STAT signaling drives immunosuppressive tryptophan/kynurenine metabolism via synergistic induction of IDO1 in skin cancer.","authors":"Dominik P Elmer, Georg Stockmaier, Sandra Grund-Gröschke, Victoria Strobl, Hieu-Hoa Dang, Markus Wiederstein, David Licha, Anna Strobl, Anna Eglseer, Christina Sternberg, Suzana Tesanovic, Wolfgang Gruber, Florian Wolff, Richard Moriggl, Angela Risch, Roland Reischl, Christian G Huber, Peter W Krenn, Nikolaus Fortelny, Jutta Horejs-Hoeck, Fritz Aberger","doi":"10.1186/s12964-025-02101-6","DOIUrl":"10.1186/s12964-025-02101-6","url":null,"abstract":"<p><strong>Background: </strong>Pharmacological targeting of Hedgehog (HH)/GLI has proven effective for certain blood, brain and skin cancers including basal cell carcinoma (BCC). However, limited response rates and the development of drug resistance call for improved anti-HH therapies that take synergistic crosstalk mechanisms and immune evasion strategies into account. In previous work, we demonstrated that cooperation of HH/GLI and Interleukin 6 (IL6)/STAT3 signaling drives BCC growth. Whether synergistic HH-IL6 signaling promotes BCC via the activation of immune evasion mechanisms remained unclear.</p><p><strong>Methods: </strong>HH-IL6 regulated immunosuppressive genes such as indoleamine 2,3-dioxygenase 1 (IDO1) were identified by gene expression profiling. IDO1 expression was evaluated in human BCC and melanoma models by qPCR and Western blot analyses. The cis-regulatory region of IDO1 was interrogated for HH-IL6-regulated GLI and STAT transcription factor binding and epigenetic modifications by targeted chromatin-immunoprecipitation and bisulfite pyrosequencing. Functional analyses of the immunosuppressive effects of IDO1 involved HPLC-MS measurements of its metabolites and the assessment of T cell proliferation via flow cytometry. Bioinformatic analyses of GLI-STAT cooperation were conducted on published bulk and single-cell RNA-seq data of human BCC and melanoma patients.</p><p><strong>Results: </strong>We identified IDO1 as a target gene of cooperative GLI-STAT activity in BCC and melanoma. GLI1 and STAT3 transcription factors synergistically enhanced IDO1 expression by jointly binding to the cis-regulatory region of IDO1 and by increasing active chromatin marks at the histone level. In human melanoma cells, inhibition of GLI1 expression prevented the induction of IDO1 expression in response to IL6/STAT3 and IFNγ/STAT1 signaling. Pharmacological targeting of HH/GLI signaling reduced IDO1 expression, resulting in decreased production of the immunosuppressive metabolite kynurenine. Further, inhibition of GLI1 enhanced the efficacy of the selective IDO1 inhibitor epacadostat and rescued T cell proliferation by attenuating IDO1/kynurenine-mediated immunosuppression. Elevated expression of IDO1 correlated with active HH/GLI and JAK/STAT signaling in skin cancer patients supporting the clinical relevance of the mechanistic data presented.</p><p><strong>Conclusions: </strong>These results identify the immunosuppressive IDO1-kynurenine pathway as a novel pro-tumorigenic target of oncogenic GLI and STAT1/STAT3 cooperation. Our data suggest simultaneous pharmacological targeting of these signaling axes as rational combination therapy in melanoma and non-melanoma skin cancers.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"91"},"PeriodicalIF":8.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442986","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":"Adenosine A_2A receptor-mediated interactions between Th1⁺ T cells and the choroid plexus epithelium via IFN-γ signalling control T-Cell infiltration in experimental autoimmune encephalomyelitis.","authors":"Chenxing Qi, Yuwen Yang, Ping Tang, Cheng Zheng, Xuhang Li, Nan Jiang, Jia Qu, Jiang-Fan Chen, Wu Zheng","doi":"10.1186/s12964-025-02100-7","DOIUrl":"10.1186/s12964-025-02100-7","url":null,"abstract":"<p><strong>Background: </strong>Adenosine A_2A receptor (A_2AR) antagonists have been consistently demonstrated to protect against multiple sclerosis (MS) pathology, but A_2AR knockout (A_2AR^-/-) mice exhibit exacerbated immune injury, raising concerns regarding the use of A_2AR antagonists for MS treatment. Here, we revealed the critical involvement of A_2AR-mediated interactions between Th1⁺ T cells and the choroid plexus (ChP) epithelium in the pathology of experimental autoimmune encephalomyelitis (EAE).</p><p><strong>Methods: </strong>We assessed the effects of A_2AR knockout on ChP gateway activity and the interferon gamma (IFN-γ)-secreting capacity of Th1⁺ T cells in an EAE model by immunofluorescence, qPCR and flow cytometry (FCM). We also investigated the effects of A_2AR-mediated interactions between Th1⁺ T cells and the ChP epithelium on ChP gateway activity in vivo via intracerebroventricular (ICV) injection of Th1⁺ T cells and in vitro via coculture of ChP epithelial cells and splenic Th1⁺ T cells. We further knocked down IFN-γ receptor 1 (IFNGR1) specifically in the ChP of A_2AR^-/- mice via ICV injection of AAV2/5-shRNA (IFNGR1) to disrupt the interactions between Th1⁺ T cells and the ChP epithelium and thus assess the roles of these interactions in the development of EAE pathology.</p><p><strong>Results: </strong>A_2AR knockout disrupted the ChP barrier and increased T-cell infiltration across the ChP in EAE model mice. Coculture of splenic Th1⁺ T cells and ChP epithelial cells revealed that A_2AR knockout in ChP epithelial cells strengthened the ChP barrier and attenuated T-cell migration, whereas A_2AR knockout in Th1⁺ T cells increased the accumulation of Th1⁺ T cells in the ChP via the secretion of IFN-γ. Consistent with the coculture results, ICV injection of activated splenic Th1⁺ T cells from A_2AR^-/- mice increased the accumulation of T cells in the ChP to a greater extent than did injection of Th1⁺ T cells from A_2AR^+/+ mice. This effect was due to the increased secretion of IFN-γ in A_2AR^-/- mice compared with A_2AR^+/+ mice. Finally, ChP-specific knockdown of IFNGR1 attenuated A_2AR knockout-induced T-cell infiltration, brain inflammation and EAE pathology.</p><p><strong>Conclusion: </strong>A_2AR-mediated interactions between Th1⁺ T cells and the ChP epithelium via the secretion of IFN-γ from CD4⁺ T cells and the binding IFN-γ to IFNGR1 in the ChP epithelium control immune cell invasion and the development of EAE pathology in A_2AR^-/- mice.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"94"},"PeriodicalIF":8.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442984","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":"IgA displays site- and subclass-specific glycoform differences despite equal glycoenzyme expression.","authors":"David Falck, Maria V Sokolova, Carolien A M Koeleman, Vanessa Irumva, Philipp Kirchner, Sebastian R Schulz, Katja G Schmidt, Thomas Harrer, Arif B Ekici, Bernd Spriewald, Georg Schett, Manfred Wuhrer, Martin Herrmann, Ulrike Steffen","doi":"10.1186/s12964-025-02088-0","DOIUrl":"10.1186/s12964-025-02088-0","url":null,"abstract":"<p><strong>Background: </strong>Glycosylation is an important posttranslational modification of proteins and in most cases indispensable for proper protein function. Like most soluble proteins, IgA, the second most prevalent antibody in human serum, contains several N- and O-glycosylation sites. While for IgG the impact of Fc glycosylation on effector functions and inflammatory potential has been studied intensively, only little is known for IgA. In addition, only glimpses exist regarding the regulation of IgA glycosylation. We have previously shown that IgA1 and IgA2 differ functionally and also show differences in their glycosylation pattern. The more pro-inflammatory IgA2 which is linked to autoimmune diseases displays decreased sialylation, galactosylation, fucosylation and bisection as compared to IgA1. In the present study, we aimed to investigate these differences in glycosylation in detail and to explore the mechanisms underlying them.</p><p><strong>Methods: </strong>IgA1 and IgA2 was isolated from serum of 12 healthy donors. Site specific glycosylation was analyzed by mass spectrometry. In addition, human bone marrow plasma cells were investigated using single cell mRNA sequencing, flow cytometry and ELISpot.</p><p><strong>Results: </strong>We found that certain glycoforms greatly differ in their abundance between IgA1 and IgA2 while others are equally abundant. Overall, the IgA2 glycans displayed a more immature phenotype with a higher prevalence of oligomannose and fewer fully processed glycans. Of note, these differences can't be explained by differences in the glycosylation enzyme machinery as mRNA sequencing and flow cytometry analysis showed equal enzyme expression in IgA1 and IgA2 producing plasma cells. ELISpot analysis suggested a slightly increased antibody production rate in IgA2 producing plasma cells which might contribute to its lower glycan processing rates. But this difference was only minor, suggesting that further factors such as steric accessibility determine glycan processing. This is supported by the fact that glycans at different positions on the same IgA chain differ dramatically in fucosylation, sialylation and bisection.</p><p><strong>Conclusion: </strong>In summary, our detailed overview of IgA1 and IgA2 glycosylation shows a class, subclass, and site-specific glycosylation fingerprint, most likely due to structural differences of the protein backbones.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"92"},"PeriodicalIF":8.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442991","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":"Microglial depletion decreases Müller cell maturation and inner retinal vascular density.","authors":"Nathaniel Rowthorn-Apel, Naveen Vridhachalam, Kip M Connor, Gracia M Bonilla, Ruslan Sadreyev, Charandeep Singh, Gopalan Gnanaguru","doi":"10.1186/s12964-025-02083-5","DOIUrl":"10.1186/s12964-025-02083-5","url":null,"abstract":"<p><strong>Background: </strong>The neuroretinal vascular system is comprised of three interconnected layers. The initial superficial vascular plexus formation is guided by astrocytes around birth in mice. The formation of the deep and intermediate vascular plexuses occurs in the second postnatal week and is driven by Müller-cell-derived angiogenic signaling. Previously, we reported that microglia play an important role in regulating astrocyte density during superficial vascular plexus formation. Here, we investigated the role of microglia in regulating Müller-cell-dependent inner retinal vascular development.</p><p><strong>Methodology: </strong>In this study, we depleted microglia during retinal development using Csf1R antagonist (PLX5622). We characterized the developmental progression of inner retinal vascular growth, effect of microglial depletion on inner retinal vascular growth and Müller cell marker expressions by immunostaining. Differential expressions of genes in the control and microglia depleted groups were analyzed by mRNA-seq and qPCR. Unpaired t-test was performed to determine the statistical differences between groups.</p><p><strong>Results: </strong>This study show that microglia interact with Müller cells and the growing inner retinal vasculature. Depletion of microglia resulted in reduced inner retinal vascular layers densities and decreased Vegfa isoforms transcript levels. RNA-seq analysis further revealed that microglial depletion significantly reduced specific Müller cell maturation markers including glutamine synthetase, responsible for glutamine biosynthesis, necessary for angiogenesis.</p><p><strong>Conclusions: </strong>Our study reveals an important role for microglia in facilitating inner retinal angiogenesis and Müller cell maturation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"90"},"PeriodicalIF":8.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442993","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}