Pub Date : 2025-11-20DOI: 10.1038/s44318-025-00629-4
Diego Ulisse Pizzagalli,Pau Carrillo-Barberà,Himanshu Bansal,Elisa Palladino,Kevin Ceni,Benedikt Thelen,Alain Pulfer,Enrico Moscatello,Raffaella Fiamma Cabini,Johannes Textor,Inge M N Wortel, ,Rolf Krause,Santiago Fernandez Gonzalez
Understanding the spatiotemporal dynamics of immune cells in living organisms is a major goal in bioimaging. Intravital microscopy enables direct observation of cellular behavior over time with tissue-to-subcellular resolution, making it essential for investigating immune responses across tissues, conditions, and disease contexts. However, most intravital microscopy data remain siloed in individual labs, limiting reuse, standardization, and large-scale analysis. To address these limitations, we present Immunemap, an open-data platform and interactive atlas of immune cell motility. Immunemap currently provides access to over 58,000 curated single-cell tracks and more than 1,049,000 cell-centroid annotations from 400 intravital microscopy videos in murine models, spanning diverse tissues and conditions. The platform supports both exploratory and quantitative research. We show here how unsupervised learning identifies distinct motility patterns, and how large-scale mapping enables comparisons across stimuli, imaging setups, and organs. Its cloud-based architecture offers an interactive web interface and public APIs for integration with computational pipelines. By adhering to FAIR principles (Findability, Accessibility, Interoperability, and Reuse) and fostering cross-disciplinary studies, Immunemap supports reproducible research and provides a benchmark for bioimage analysis and tool development in intravital imaging.
{"title":"Systematic analysis of immune cell motility leveraging the open intravital microscopy database Immunemap.","authors":"Diego Ulisse Pizzagalli,Pau Carrillo-Barberà,Himanshu Bansal,Elisa Palladino,Kevin Ceni,Benedikt Thelen,Alain Pulfer,Enrico Moscatello,Raffaella Fiamma Cabini,Johannes Textor,Inge M N Wortel, ,Rolf Krause,Santiago Fernandez Gonzalez","doi":"10.1038/s44318-025-00629-4","DOIUrl":"https://doi.org/10.1038/s44318-025-00629-4","url":null,"abstract":"Understanding the spatiotemporal dynamics of immune cells in living organisms is a major goal in bioimaging. Intravital microscopy enables direct observation of cellular behavior over time with tissue-to-subcellular resolution, making it essential for investigating immune responses across tissues, conditions, and disease contexts. However, most intravital microscopy data remain siloed in individual labs, limiting reuse, standardization, and large-scale analysis. To address these limitations, we present Immunemap, an open-data platform and interactive atlas of immune cell motility. Immunemap currently provides access to over 58,000 curated single-cell tracks and more than 1,049,000 cell-centroid annotations from 400 intravital microscopy videos in murine models, spanning diverse tissues and conditions. The platform supports both exploratory and quantitative research. We show here how unsupervised learning identifies distinct motility patterns, and how large-scale mapping enables comparisons across stimuli, imaging setups, and organs. Its cloud-based architecture offers an interactive web interface and public APIs for integration with computational pipelines. By adhering to FAIR principles (Findability, Accessibility, Interoperability, and Reuse) and fostering cross-disciplinary studies, Immunemap supports reproducible research and provides a benchmark for bioimage analysis and tool development in intravital imaging.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s44318-025-00637-4
Alexandra Boegli,Elliott M Bernard,Louise Lacante,Gaël Majeux,Ella Hartenian,Vanessa Mack,Petr Broz
The cytosolic innate immune sensor NLRP6 controls host defense against bacteria and viruses in the gastrointestinal tract, but the underlying mechanism is poorly understood. Here, we report that NLRP6 forms an inflammasome following endolysosomal damage caused by sterile triggers or bacterial pathogens such as Listeria monocytogenes in human intestinal epithelial cells (IECs). NLRP6 activation requires Listeriolysin O-dependent cytosolic invasion of L. monocytogenes and triggers IEC pyroptosis and IL-1β release via ASC/caspase-1-mediated GSDMD cleavage. NLRP6 activation requires its NACHT domain and ATP binding, whereas inflammasome formation is independent of bacterial pathogen-associated molecular patterns (PAMPs), such as lipoteichoic acid or dsRNA, which were previously reported to activate NLRP6. L. monocytogenes mutants deficient in cell-to-cell spread or escape from secondary vacuoles induce lower levels of cell death, linking bacteria-induced endolysosomal damage to NLRP6 activation. Finally, sterile endolysosomal damage recapitulates pathogen-induced NLRP6 activation and induces IEC pyroptosis. In summary, our study reveals that NLRP6 enables intestinal epithelial cells to detect endolysosomal damage, thereby mediating their response not only to pathogens but more generally to wide-ranging sources of pathological endolysosomal damage.
{"title":"The NLRP6 inflammasome is activated by sterile or pathogen-induced endolysosomal damage.","authors":"Alexandra Boegli,Elliott M Bernard,Louise Lacante,Gaël Majeux,Ella Hartenian,Vanessa Mack,Petr Broz","doi":"10.1038/s44318-025-00637-4","DOIUrl":"https://doi.org/10.1038/s44318-025-00637-4","url":null,"abstract":"The cytosolic innate immune sensor NLRP6 controls host defense against bacteria and viruses in the gastrointestinal tract, but the underlying mechanism is poorly understood. Here, we report that NLRP6 forms an inflammasome following endolysosomal damage caused by sterile triggers or bacterial pathogens such as Listeria monocytogenes in human intestinal epithelial cells (IECs). NLRP6 activation requires Listeriolysin O-dependent cytosolic invasion of L. monocytogenes and triggers IEC pyroptosis and IL-1β release via ASC/caspase-1-mediated GSDMD cleavage. NLRP6 activation requires its NACHT domain and ATP binding, whereas inflammasome formation is independent of bacterial pathogen-associated molecular patterns (PAMPs), such as lipoteichoic acid or dsRNA, which were previously reported to activate NLRP6. L. monocytogenes mutants deficient in cell-to-cell spread or escape from secondary vacuoles induce lower levels of cell death, linking bacteria-induced endolysosomal damage to NLRP6 activation. Finally, sterile endolysosomal damage recapitulates pathogen-induced NLRP6 activation and induces IEC pyroptosis. In summary, our study reveals that NLRP6 enables intestinal epithelial cells to detect endolysosomal damage, thereby mediating their response not only to pathogens but more generally to wide-ranging sources of pathological endolysosomal damage.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s44318-025-00638-3
Alexander N R Weber,Philip Rosenstiel
{"title":"You (bacteria) shall not pass: NLRP6 can sense you!","authors":"Alexander N R Weber,Philip Rosenstiel","doi":"10.1038/s44318-025-00638-3","DOIUrl":"https://doi.org/10.1038/s44318-025-00638-3","url":null,"abstract":"","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s44318-025-00604-z
Julia A Thayer,Jennifer D Petersen,Xiaoping Huang,Luiza M Gruel Budet,James Hawrot,Daniel M Ramos,Shiori Sekine,Yan Li,Michael E Ward,Derek P Narendra
Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.
{"title":"A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.","authors":"Julia A Thayer,Jennifer D Petersen,Xiaoping Huang,Luiza M Gruel Budet,James Hawrot,Daniel M Ramos,Shiori Sekine,Yan Li,Michael E Ward,Derek P Narendra","doi":"10.1038/s44318-025-00604-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00604-z","url":null,"abstract":"Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"149 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The size and complexity of the neocortex are largely determined during brain development by neurogenesis from radial glial progenitor (RGP) cells. Neurogenesis from such cells can be direct (i.e., RGP cells give rise directly to neurons) or indirect (i.e., RGP cells first produce intermediate progenitor cells, which then divide further to produce neurons). How direct and indirect neurogenesis from RGP cells leads to the appropriate neocortical size and cell-type composition remains incompletely understood. In this study, we developed a combined retrovirus- and FlashTag-based labeling technique that allows clonal tracking of sequential RGP divisions and identification of progeny identities in vivo. Using this method, we show that divisions of mouse RGP cells giving rise to neurogenic (N), neurogenic intermediate progenitor (IP), and neurogenic proliferative intermediate progenitor (IPP) cells tend to generate similar numbers of pyramidal neurons. In the early neuronal progeny of RGP cells, the distribution of neurons produced by the N-, IP-, and IPP-producing divisions follows an "inside-out" pattern in the neocortex. Clonal analysis and mathematical modeling indicate that RGP cells initially give rise to neurons, IP, and IPP cells in a stochastic manner, followed by relatively stable transition patterns between direct and indirect neurogenesis across successive generations. These findings provide a comprehensive and novel understanding of the dynamics of cell division during cortical neurogenesis.
{"title":"Direct and indirect neurogenesis from radial glial progenitor cell clones in the mouse neocortex.","authors":"Dan Shen,Xin-Yi Wang,Ruo-Hang Liu,Huan-Huan Deng,Shi-Yuan Tong,Jun-Yang Chen,Zi-Yun Zhai,Yuan-Xin Li,You-Ning Lin,Fu-Wei Yang,Chen-Xi Wang,Lin-Yun Liu,Ying Zhu,Yong-Chun Yu","doi":"10.1038/s44318-025-00624-9","DOIUrl":"https://doi.org/10.1038/s44318-025-00624-9","url":null,"abstract":"The size and complexity of the neocortex are largely determined during brain development by neurogenesis from radial glial progenitor (RGP) cells. Neurogenesis from such cells can be direct (i.e., RGP cells give rise directly to neurons) or indirect (i.e., RGP cells first produce intermediate progenitor cells, which then divide further to produce neurons). How direct and indirect neurogenesis from RGP cells leads to the appropriate neocortical size and cell-type composition remains incompletely understood. In this study, we developed a combined retrovirus- and FlashTag-based labeling technique that allows clonal tracking of sequential RGP divisions and identification of progeny identities in vivo. Using this method, we show that divisions of mouse RGP cells giving rise to neurogenic (N), neurogenic intermediate progenitor (IP), and neurogenic proliferative intermediate progenitor (IPP) cells tend to generate similar numbers of pyramidal neurons. In the early neuronal progeny of RGP cells, the distribution of neurons produced by the N-, IP-, and IPP-producing divisions follows an \"inside-out\" pattern in the neocortex. Clonal analysis and mathematical modeling indicate that RGP cells initially give rise to neurons, IP, and IPP cells in a stochastic manner, followed by relatively stable transition patterns between direct and indirect neurogenesis across successive generations. These findings provide a comprehensive and novel understanding of the dynamics of cell division during cortical neurogenesis.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s44318-025-00630-x
Moritz Peiseler
{"title":"From microscopes to maps: enabling a new era of open and reproducible data sharing in intravital imaging.","authors":"Moritz Peiseler","doi":"10.1038/s44318-025-00630-x","DOIUrl":"https://doi.org/10.1038/s44318-025-00630-x","url":null,"abstract":"","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"190 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sororin is essential for establishing sister chromatid cohesion concurrently with DNA replication in metazoans. Although acetylation of the cohesin subunit SMC3 by ESCO1/2 is necessary for Sororin recruitment, it is by itself not sufficient. Here, we demonstrate that DNA replication-coupled Poly(ADP-Ribose) Polymerase (PARP) activity is an additional prerequisite in human cells. During normal S-phase, PARP1 PARylates a microprotein encoded by the alternative ORF C11ORF98, which we designate RSMC (28S rRNA/ribosome and Sororin micro-cofactor). This PARylation strengthens the interaction of RSMC with Sororin, enhancing both chromatin recruitment and anti-Wapl activity of Sororin in concert with SMC3 acetylation. Notably, overexpression of RSMC is able to rescue cohesion defects induced by the PARP inhibitor olaparib. These findings highlight understudied microproteins as critical regulators of fundamental cellular processes, such as sister chromatid cohesion.
{"title":"S-phase PARylation of microprotein RSMC enhances the function of Sororin in sister chromatid cohesion.","authors":"Meiqian Jiang,Jiaxin Zhang,Jiankun He,Yu Miao,Linhui Wang,Haitao Zhong,Yingying Gong,Zhen Li,Li-Lin Du,Xingzhi Xu,Chunlai Chen,Alibek Ydyrys,Yisui Xia,Qinhong Cao,Huiqiang Lou,Wenya Hou","doi":"10.1038/s44318-025-00641-8","DOIUrl":"https://doi.org/10.1038/s44318-025-00641-8","url":null,"abstract":"Sororin is essential for establishing sister chromatid cohesion concurrently with DNA replication in metazoans. Although acetylation of the cohesin subunit SMC3 by ESCO1/2 is necessary for Sororin recruitment, it is by itself not sufficient. Here, we demonstrate that DNA replication-coupled Poly(ADP-Ribose) Polymerase (PARP) activity is an additional prerequisite in human cells. During normal S-phase, PARP1 PARylates a microprotein encoded by the alternative ORF C11ORF98, which we designate RSMC (28S rRNA/ribosome and Sororin micro-cofactor). This PARylation strengthens the interaction of RSMC with Sororin, enhancing both chromatin recruitment and anti-Wapl activity of Sororin in concert with SMC3 acetylation. Notably, overexpression of RSMC is able to rescue cohesion defects induced by the PARP inhibitor olaparib. These findings highlight understudied microproteins as critical regulators of fundamental cellular processes, such as sister chromatid cohesion.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"160 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-03DOI: 10.1038/s44318-025-00603-0
Anna Schönbichler,Anna Orlova,Carmen Kreindl,Lukas Endler,Richard Wilson,Lindsay Kosack,Anna Hofmann,Csilla Viczenczova,Jocelyn Darby,Fettah Erdogan,Amanda L Patchett,Anna Koren,Stefan Kubicek,Mathias Müller,Andrew S Flies,Andreas Bergthaler,Richard Moriggl
Two transmissible cancers, Devil Facial Tumour 1 (DFT1) and Devil Facial Tumour 2 (DFT2), have caused a significant decline in the Tasmanian devil population. DFT1 is driven by ERBB, while DFT2 is driven by PDGFRA. We show that DFT cancer cells exhibit distinct kinase phosphorylation profiles that dictate their responses to tyrosine kinase inhibitors. Upon long-term treatment, both DFT cell lines develop resistance, with DFT1 cells rapidly evading ERBB inhibition without major copy number alterations or significant changes in phosphorylation, suggesting signalling plasticity and engagement of alternative oncogenic drivers. In contrast, DFT2 cells exhibit a slowed development of resistance to imatinib, a selective kinase inhibitor with known activity against PDGFRs. Moreover, DFT2 cell resistance is accompanied by copy number alterations and an activation of ERBB and JAK/STAT signalling with MHCI downregulation, resembling DFT1 signalling. Dual targeting of ERBB and PDGFR shows synergistic effects in DFT1 and may prevent resistance emergence. These findings provide critical insight into the adaptive capacity of transmissible cancers and inform conservation strategies. Moreover, they highlight broader principles of kinase-driven resistance relevant to human cancers with high pathway plasticity.
{"title":"Tyrosine kinase targeting uncovers oncogenic pathway plasticity in Tasmanian devil transmissible cancers.","authors":"Anna Schönbichler,Anna Orlova,Carmen Kreindl,Lukas Endler,Richard Wilson,Lindsay Kosack,Anna Hofmann,Csilla Viczenczova,Jocelyn Darby,Fettah Erdogan,Amanda L Patchett,Anna Koren,Stefan Kubicek,Mathias Müller,Andrew S Flies,Andreas Bergthaler,Richard Moriggl","doi":"10.1038/s44318-025-00603-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00603-0","url":null,"abstract":"Two transmissible cancers, Devil Facial Tumour 1 (DFT1) and Devil Facial Tumour 2 (DFT2), have caused a significant decline in the Tasmanian devil population. DFT1 is driven by ERBB, while DFT2 is driven by PDGFRA. We show that DFT cancer cells exhibit distinct kinase phosphorylation profiles that dictate their responses to tyrosine kinase inhibitors. Upon long-term treatment, both DFT cell lines develop resistance, with DFT1 cells rapidly evading ERBB inhibition without major copy number alterations or significant changes in phosphorylation, suggesting signalling plasticity and engagement of alternative oncogenic drivers. In contrast, DFT2 cells exhibit a slowed development of resistance to imatinib, a selective kinase inhibitor with known activity against PDGFRs. Moreover, DFT2 cell resistance is accompanied by copy number alterations and an activation of ERBB and JAK/STAT signalling with MHCI downregulation, resembling DFT1 signalling. Dual targeting of ERBB and PDGFR shows synergistic effects in DFT1 and may prevent resistance emergence. These findings provide critical insight into the adaptive capacity of transmissible cancers and inform conservation strategies. Moreover, they highlight broader principles of kinase-driven resistance relevant to human cancers with high pathway plasticity.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Directed axonal trafficking of mRNA via ribonucleoprotein (RNP) complexes is essential for neuronal function and survival. However, mechanisms governing retrograde RNP transport remain poorly understood. Here, we reveal that Annexin A7 (ANXA7) promotes the recruitment of aggregation-prone T-cell intracellular antigen 1 (TIA1)-containing RNPs to cytoplasmic dynein, enabling their retrograde trafficking to the soma for degradation. Both persistent and transient Ca²⁺ elevation disrupted this function of ANXA7, leading to the detachment of TIA1 granules from dynein, impairing their transport, and subsequently triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, preventing their transport and inducing pathological aggregation of TIA1, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression reinforces trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. We describe here a Ca2+ -regulated mechanism which modulates retrograde axonal trafficking of RNPs and prevents the formation of pathological aggregates in axons.
{"title":"Annexin A7 enhances TIA1 axonal trafficking to counteract pathological aggregation in neurons.","authors":"Yu Feng,Tongshu Luan,Zhenda Zhang,Wei Wang,Yuanyuan Chu,Sijia Wan,Xiaorong Pan,Jie Li,Yifan Liu,Yaqian Xu,Kun Dou,Tong Wang","doi":"10.1038/s44318-025-00609-8","DOIUrl":"https://doi.org/10.1038/s44318-025-00609-8","url":null,"abstract":"Directed axonal trafficking of mRNA via ribonucleoprotein (RNP) complexes is essential for neuronal function and survival. However, mechanisms governing retrograde RNP transport remain poorly understood. Here, we reveal that Annexin A7 (ANXA7) promotes the recruitment of aggregation-prone T-cell intracellular antigen 1 (TIA1)-containing RNPs to cytoplasmic dynein, enabling their retrograde trafficking to the soma for degradation. Both persistent and transient Ca²⁺ elevation disrupted this function of ANXA7, leading to the detachment of TIA1 granules from dynein, impairing their transport, and subsequently triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, preventing their transport and inducing pathological aggregation of TIA1, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression reinforces trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. We describe here a Ca2+ -regulated mechanism which modulates retrograde axonal trafficking of RNPs and prevents the formation of pathological aggregates in axons.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145440777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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