Horizontal gene transfer (HGT) is an important source of gene innovation in prokaryotic and eukaryotic organisms. Several genes acquired by hosts of parasitoid wasps via HGT have been reported to protect hosts from parasitoid wasps. In contrast, little is known about whether HGT-acquired genes in parasitoid wasps are involved in attacking their hosts. Here, we report a prokaryote-type CDP-diacylglycerol synthase (PTCDS) gene that was horizontally transferred into the last common ancestor of two parasitoid wasps, Leptopilina heterotoma and L. syphax, from the bacterial family Rickettsiaceae. We experimentally demonstrated that PTCDS is linked to ensure the appropriate storage amount of venom in the venom reservoir of parasitoid wasps. PTCDS knockdown downregulated the expression of certain vesicle-mediated transport genes, thereby reducing the secretion of venom into venom reservoir without altering its composition. This resulted in a significant increase in the proportion of encapsulated wasp eggs in parasitized hosts, ultimately leading to host immune-mediated killing. We conclude that parasitoid wasps use the foreign gene PTCDS to influence venom amounts against host defence, providing new insight into the arms race between parasitoid wasps and hosts.
{"title":"A bacterial gene acquired by parasitoid wasps contributes to venom secretion against host defence.","authors":"Zhiguo Liu,Mei Tao,Zixuan Xu,Junwei Zhang,Yang Li,Zhi Dong,Qichao Zhang,Lan Pang,Yifeng Sheng,Yueqi Lu,Ting Feng,Wenqi Shi,Longtao Yu,Antonis Rokas,Jiani Chen,Xing-Xing Shen,Jianhua Huang","doi":"10.1038/s44318-026-00702-6","DOIUrl":"https://doi.org/10.1038/s44318-026-00702-6","url":null,"abstract":"Horizontal gene transfer (HGT) is an important source of gene innovation in prokaryotic and eukaryotic organisms. Several genes acquired by hosts of parasitoid wasps via HGT have been reported to protect hosts from parasitoid wasps. In contrast, little is known about whether HGT-acquired genes in parasitoid wasps are involved in attacking their hosts. Here, we report a prokaryote-type CDP-diacylglycerol synthase (PTCDS) gene that was horizontally transferred into the last common ancestor of two parasitoid wasps, Leptopilina heterotoma and L. syphax, from the bacterial family Rickettsiaceae. We experimentally demonstrated that PTCDS is linked to ensure the appropriate storage amount of venom in the venom reservoir of parasitoid wasps. PTCDS knockdown downregulated the expression of certain vesicle-mediated transport genes, thereby reducing the secretion of venom into venom reservoir without altering its composition. This resulted in a significant increase in the proportion of encapsulated wasp eggs in parasitized hosts, ultimately leading to host immune-mediated killing. We conclude that parasitoid wasps use the foreign gene PTCDS to influence venom amounts against host defence, providing new insight into the arms race between parasitoid wasps and hosts.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070019","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 : 2026-01-28DOI: 10.1038/s44318-025-00680-1
Monica Gobran,Peter Lenart
{"title":"Mitotic entry: Bora takes Polo to Aurora, and gives them a hug.","authors":"Monica Gobran,Peter Lenart","doi":"10.1038/s44318-025-00680-1","DOIUrl":"https://doi.org/10.1038/s44318-025-00680-1","url":null,"abstract":"","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"296 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070020","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 : 2026-01-28DOI: 10.1038/s44318-025-00679-8
Anaïs Pillan,Philippine Ormancey,Celia Ben Choug,Stephen Orlicky,Nicolas Tavernier,Lucie Van Hove,Batool Ossareh-Nazari,Nicolas Joly,Frank Sicheri,Thierry Lorca,Lionel Pintard
The evolutionarily conserved, intrinsically disordered protein Bora is critical for initiating the activation of mitotic kinases. Once phosphorylated at Ser112 by Cyclin A-Cdk1 kinase, phospho-Bora activates unphosphorylated Aurora A kinase (AURKA), directing it towards Polo-like kinase 1 (Plk1), thus promoting Cyclin B-Cdk1 activation and mitotic entry. Here, by combining structural modeling and in vitro assays, we provide evidence that Bora wraps around the N-terminal lobe of AURKA to position its phospho-Ser112 near AURKA's T-loop, mimicking T-loop phosphorylation. Additionally, Bora transiently interacts with the αC helix of the Plk1 kinase domain through a conserved motif, guiding AURKA activity towards the Plk1 T-loop, which is otherwise impervious to phosphorylation by AURKA. We highlight the importance of this motif for Bora function in vitro and during mitotic entry in Xenopus laevis egg extracts. Our results reveal critical molecular details of mitotic kinase activation, which could lead to the development of pathway-specific inhibitors.
{"title":"Molecular basis for the activation of Aurora A and Plk1 kinases during mitotic entry.","authors":"Anaïs Pillan,Philippine Ormancey,Celia Ben Choug,Stephen Orlicky,Nicolas Tavernier,Lucie Van Hove,Batool Ossareh-Nazari,Nicolas Joly,Frank Sicheri,Thierry Lorca,Lionel Pintard","doi":"10.1038/s44318-025-00679-8","DOIUrl":"https://doi.org/10.1038/s44318-025-00679-8","url":null,"abstract":"The evolutionarily conserved, intrinsically disordered protein Bora is critical for initiating the activation of mitotic kinases. Once phosphorylated at Ser112 by Cyclin A-Cdk1 kinase, phospho-Bora activates unphosphorylated Aurora A kinase (AURKA), directing it towards Polo-like kinase 1 (Plk1), thus promoting Cyclin B-Cdk1 activation and mitotic entry. Here, by combining structural modeling and in vitro assays, we provide evidence that Bora wraps around the N-terminal lobe of AURKA to position its phospho-Ser112 near AURKA's T-loop, mimicking T-loop phosphorylation. Additionally, Bora transiently interacts with the αC helix of the Plk1 kinase domain through a conserved motif, guiding AURKA activity towards the Plk1 T-loop, which is otherwise impervious to phosphorylation by AURKA. We highlight the importance of this motif for Bora function in vitro and during mitotic entry in Xenopus laevis egg extracts. Our results reveal critical molecular details of mitotic kinase activation, which could lead to the development of pathway-specific inhibitors.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070021","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 : 2026-01-28DOI: 10.1038/s44318-025-00681-0
Arianna Esposito-Verza,Duccio Conti,Paulo D Rodrigues Pedroso,Lina Oberste-Lehn,Carolin Koerner,Sabine Wohlgemuth,Artem Mansurkhodzhaev,Ingrid R Vetter,Marion E Pesenti,Andrea Musacchio
Activation of PLK1, a master mitotic kinase, requires phosphorylation of its activation segment on Thr210, within a basic consensus sequence for Aurora kinases. Aurora B-dependent phosphorylation of Thr210 has been reported, but other evidence identified a strict requirement for the Aurora A partner Bora for Thr210 phosphorylation. Here, we investigate the elusive mechanistic basis for this requirement. We show that Aurora A:Bora phosphorylates Thr210 of PLK1 in vitro. On the contrary, T210 was not phosphorylated by isolated Aurora A, additional Aurora A:activator complexes, or Aurora B:INCENP, even when used at high kinase/substrate ratios. A transient interaction of Bora and PLK1, identified by structural modeling and probed mutationally, is uniquely required for Thr210 phosphorylation. Dependency on Bora for Thr210 phosphorylation is eliminated after mutating Lys208, in the Aurora consensus, into arginine. This conservative mutation turns PLK1 into a substrate of nearly all tested active Aurora kinases, including Aurora B. Collectively, these results shine a new light on the specificity of the PLK1 activation mechanism.
{"title":"Molecular requirements for PLK1 activation by T-loop phosphorylation.","authors":"Arianna Esposito-Verza,Duccio Conti,Paulo D Rodrigues Pedroso,Lina Oberste-Lehn,Carolin Koerner,Sabine Wohlgemuth,Artem Mansurkhodzhaev,Ingrid R Vetter,Marion E Pesenti,Andrea Musacchio","doi":"10.1038/s44318-025-00681-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00681-0","url":null,"abstract":"Activation of PLK1, a master mitotic kinase, requires phosphorylation of its activation segment on Thr210, within a basic consensus sequence for Aurora kinases. Aurora B-dependent phosphorylation of Thr210 has been reported, but other evidence identified a strict requirement for the Aurora A partner Bora for Thr210 phosphorylation. Here, we investigate the elusive mechanistic basis for this requirement. We show that Aurora A:Bora phosphorylates Thr210 of PLK1 in vitro. On the contrary, T210 was not phosphorylated by isolated Aurora A, additional Aurora A:activator complexes, or Aurora B:INCENP, even when used at high kinase/substrate ratios. A transient interaction of Bora and PLK1, identified by structural modeling and probed mutationally, is uniquely required for Thr210 phosphorylation. Dependency on Bora for Thr210 phosphorylation is eliminated after mutating Lys208, in the Aurora consensus, into arginine. This conservative mutation turns PLK1 into a substrate of nearly all tested active Aurora kinases, including Aurora B. Collectively, these results shine a new light on the specificity of the PLK1 activation mechanism.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"143 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070022","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}
Lysosomes are emerging as important signaling hubs for antiviral defense, yet how they enable type I interferon (IFN-β) production is unclear. Here, we identify an evolutionarily repurposed lysosomal pathway, centered on the LAMTOR-Rag GTPase complex, that governs IFN-β production through dual transcriptional and post-transcriptional regulation. Genetic ablation of LAMTOR or Rag GTPases in macrophages abolishes IFN-β responses despite intact pattern recognition receptor (PRR) signaling, uncovering a lysosome-specific checkpoint essential for antiviral immunity. Mechanistically, Rag GTPase activity controls IRF expression to prime IFN transcription, while upon PRR stimulation, the tumor suppressor FLCN recruits p38 MAPK to lysosomes, where Rag-dependent p38 phosphorylation stabilizes Ifnb1 mRNA. Nutrient availability dynamically modulates Rag nucleotide states and thereby its activation, linking IFN production to metabolic capacity. Notably, this checkpoint operates independently of mTORC1, illustrating how an ancient nutrient-sensing module has been co-opted for immune regulation. Disruption of the LAMTOR-Rag-FLCN-p38 axis impairs IFN induction in vitro and antiviral responses in vivo, underscoring its physiological significance. Our findings support the role of the lysosome as a central signaling hub integrating metabolic and immune cues, suggesting future directions for potential therapeutic strategies against viral infections.
{"title":"The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.","authors":"Zeming Feng,Lulu Wang,Shujun Chen,Sihan Cao,Miao Lei,Xiuzhen Yang,Kaixiong Ma,Shi Yu,Huina Hu,Kaixuan Zheng,Xin Xu,Qi Zheng,Shaobo Wang,Wenxiang Hu,Chun-Yan Lim","doi":"10.1038/s44318-026-00695-2","DOIUrl":"https://doi.org/10.1038/s44318-026-00695-2","url":null,"abstract":"Lysosomes are emerging as important signaling hubs for antiviral defense, yet how they enable type I interferon (IFN-β) production is unclear. Here, we identify an evolutionarily repurposed lysosomal pathway, centered on the LAMTOR-Rag GTPase complex, that governs IFN-β production through dual transcriptional and post-transcriptional regulation. Genetic ablation of LAMTOR or Rag GTPases in macrophages abolishes IFN-β responses despite intact pattern recognition receptor (PRR) signaling, uncovering a lysosome-specific checkpoint essential for antiviral immunity. Mechanistically, Rag GTPase activity controls IRF expression to prime IFN transcription, while upon PRR stimulation, the tumor suppressor FLCN recruits p38 MAPK to lysosomes, where Rag-dependent p38 phosphorylation stabilizes Ifnb1 mRNA. Nutrient availability dynamically modulates Rag nucleotide states and thereby its activation, linking IFN production to metabolic capacity. Notably, this checkpoint operates independently of mTORC1, illustrating how an ancient nutrient-sensing module has been co-opted for immune regulation. Disruption of the LAMTOR-Rag-FLCN-p38 axis impairs IFN induction in vitro and antiviral responses in vivo, underscoring its physiological significance. Our findings support the role of the lysosome as a central signaling hub integrating metabolic and immune cues, suggesting future directions for potential therapeutic strategies against viral infections.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021697","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 : 2026-01-20DOI: 10.1038/s44318-025-00687-8
Junchao Shi,Xudong Zhang,Chen Cai,Shichao Liu,Jiancheng Yu,Emma R James,Lihua Liu,Benjamin R Emery,Megan R McMurray Bires,Elizabeth Torres-Arce,Hukam C Rawal,Joemy Ramsay,Jason Kunisaki,Changcheng Zhou,David S Milstone,Mary Elizabeth Patti,Xiaoxu Yang,Tim G Jenkins,Aaron Quinlan,Bradley R Cairns,Paul Schimmel,James M Hotaling,Kenneth I Aston,Tong Zhou,Qi Chen
Sperm aging impacts male fertility and offspring health, highlighting the need for reliable aging biomarkers to guide reproductive decisions. However, the molecular determinants of sperm fitness during aging remain ill-defined. Here, we profiled sperm small non-coding RNAs (sncRNAs) using PANDORA-seq, which overcomes RNA modification-induced detection bias to capture previously undetectable sncRNA species associated with mouse and human spermatozoa throughout the lifespan. We identified an "aging cliff" in mouse sperm RNA profiles-a sharp age-specific transition marked by significant shifts in genomic and mitochondrial tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs). Notably, rsRNAs in mouse sperm heads exhibited a transformative length shift, with longer rsRNAs increasing and shorter ones decreasing with age, suggesting altered biogenesis or processing with age. Remarkably, this sperm head-specific shift in rsRNA length was consistently observed in two independent human aging cohorts. Moreover, transfecting a combination of tsRNAs and rsRNAs resembling the RNA species in aged sperm was able to induce transcriptomic changes in mouse embryonic stem cells, impacting metabolism and neurodegeneration pathways, mirroring the phenotypes observed in offspring fathered by aged sperm. These findings provide novel insights into longitudinal dynamics of sncRNAs during sperm aging, highlighting an rsRNA length shift conserved in mice and humans.
{"title":"Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging.","authors":"Junchao Shi,Xudong Zhang,Chen Cai,Shichao Liu,Jiancheng Yu,Emma R James,Lihua Liu,Benjamin R Emery,Megan R McMurray Bires,Elizabeth Torres-Arce,Hukam C Rawal,Joemy Ramsay,Jason Kunisaki,Changcheng Zhou,David S Milstone,Mary Elizabeth Patti,Xiaoxu Yang,Tim G Jenkins,Aaron Quinlan,Bradley R Cairns,Paul Schimmel,James M Hotaling,Kenneth I Aston,Tong Zhou,Qi Chen","doi":"10.1038/s44318-025-00687-8","DOIUrl":"https://doi.org/10.1038/s44318-025-00687-8","url":null,"abstract":"Sperm aging impacts male fertility and offspring health, highlighting the need for reliable aging biomarkers to guide reproductive decisions. However, the molecular determinants of sperm fitness during aging remain ill-defined. Here, we profiled sperm small non-coding RNAs (sncRNAs) using PANDORA-seq, which overcomes RNA modification-induced detection bias to capture previously undetectable sncRNA species associated with mouse and human spermatozoa throughout the lifespan. We identified an \"aging cliff\" in mouse sperm RNA profiles-a sharp age-specific transition marked by significant shifts in genomic and mitochondrial tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs). Notably, rsRNAs in mouse sperm heads exhibited a transformative length shift, with longer rsRNAs increasing and shorter ones decreasing with age, suggesting altered biogenesis or processing with age. Remarkably, this sperm head-specific shift in rsRNA length was consistently observed in two independent human aging cohorts. Moreover, transfecting a combination of tsRNAs and rsRNAs resembling the RNA species in aged sperm was able to induce transcriptomic changes in mouse embryonic stem cells, impacting metabolism and neurodegeneration pathways, mirroring the phenotypes observed in offspring fathered by aged sperm. These findings provide novel insights into longitudinal dynamics of sncRNAs during sperm aging, highlighting an rsRNA length shift conserved in mice and humans.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"123 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005510","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 : 2026-01-20DOI: 10.1038/s44318-025-00690-z
Yonas M Tesfamariam,Maria H Christensen,Stefan Diehl,Tabea Klein,Julius M Lingnau,Sabine Normann,Elena Hagelauer,Miriam Herbert,Sophie Reimer,Richa P Joshi,Pujan Engels,Steffen Pritzl,Pietro Fontana,Thomas Zillinger,Gunther Hartmann,Anna Eis-Hübinger,Martin C Lam,Klaus J Walgenbach,Felix Meissner,Hao Wu,Florian I Schmidt
The innate immune system is known for its ability to recognize cytosolic DNA as evidence of infection, but detailed studies of this process have been mostly limited to mice and cell lines. To investigate inflammasome responses in human primary cells, we used engineered viruses encoding the inflammasome reporter caspase-1CARD-EGFP. We show that released genomes of vaccinia virus and monkeypox virus trigger robust inflammasome assembly in human primary cells. To determine the involved inflammasome sensors, we generated nanobodies against AIM2. Three of them inhibit AIM2 inflammasome assembly by blocking the polymerization of the AIM2 Pyrin domain, most potently as bivalent nanobodies. Utilizing an engineered vaccinia virus expressing bivalent AIM2 nanobodies, we demonstrate that inflammasomes in primary human macrophages and keratinocytes are nucleated by AIM2, while CD14+ monocytes assemble NLRP3 inflammasomes. This finding resolves the discrepancy between the previously reported activation of AIM2 inflammasomes in mice and NLRP3 inflammasomes in humans, and provides the first evidence for cell-type-specific regulation of DNA-triggered inflammasome activation. The newly developed AIM2-specific nanobodies offer a precise tool to dissect and potentially target AIM2 inflammasome assembly in other disease contexts.
{"title":"Poxvirus dsDNA genomes differentially activate AIM2 or NLRP3 inflammasomes in human primary cells.","authors":"Yonas M Tesfamariam,Maria H Christensen,Stefan Diehl,Tabea Klein,Julius M Lingnau,Sabine Normann,Elena Hagelauer,Miriam Herbert,Sophie Reimer,Richa P Joshi,Pujan Engels,Steffen Pritzl,Pietro Fontana,Thomas Zillinger,Gunther Hartmann,Anna Eis-Hübinger,Martin C Lam,Klaus J Walgenbach,Felix Meissner,Hao Wu,Florian I Schmidt","doi":"10.1038/s44318-025-00690-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00690-z","url":null,"abstract":"The innate immune system is known for its ability to recognize cytosolic DNA as evidence of infection, but detailed studies of this process have been mostly limited to mice and cell lines. To investigate inflammasome responses in human primary cells, we used engineered viruses encoding the inflammasome reporter caspase-1CARD-EGFP. We show that released genomes of vaccinia virus and monkeypox virus trigger robust inflammasome assembly in human primary cells. To determine the involved inflammasome sensors, we generated nanobodies against AIM2. Three of them inhibit AIM2 inflammasome assembly by blocking the polymerization of the AIM2 Pyrin domain, most potently as bivalent nanobodies. Utilizing an engineered vaccinia virus expressing bivalent AIM2 nanobodies, we demonstrate that inflammasomes in primary human macrophages and keratinocytes are nucleated by AIM2, while CD14+ monocytes assemble NLRP3 inflammasomes. This finding resolves the discrepancy between the previously reported activation of AIM2 inflammasomes in mice and NLRP3 inflammasomes in humans, and provides the first evidence for cell-type-specific regulation of DNA-triggered inflammasome activation. The newly developed AIM2-specific nanobodies offer a precise tool to dissect and potentially target AIM2 inflammasome assembly in other disease contexts.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"93 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005509","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 : 2026-01-16DOI: 10.1038/s44318-025-00666-z
Carissa Emerson Hunter,Yi Xing
Alternative splicing (AS) is a key mechanism for generating regulatory and phenotypic diversity in multicellular eukaryotes. Large-scale comparative transcriptomic studies have revealed that AS leads to lineage-specific and tissue-specific transcriptomic and proteomic changes, underscoring its contribution to the evolution of gene products and functions. In this review, we highlight the patterns and mechanisms of AS evolution across species, exploring how technological advancements are transforming our understanding of splicing evolution. Furthermore, we discuss mechanistic and functional insights from recent studies, including groundbreaking discoveries on how AS has shaped phenotypic evolution in mammals.
{"title":"The splice of life: how alternative splicing shapes regulatory and phenotypic evolution.","authors":"Carissa Emerson Hunter,Yi Xing","doi":"10.1038/s44318-025-00666-z","DOIUrl":"https://doi.org/10.1038/s44318-025-00666-z","url":null,"abstract":"Alternative splicing (AS) is a key mechanism for generating regulatory and phenotypic diversity in multicellular eukaryotes. Large-scale comparative transcriptomic studies have revealed that AS leads to lineage-specific and tissue-specific transcriptomic and proteomic changes, underscoring its contribution to the evolution of gene products and functions. In this review, we highlight the patterns and mechanisms of AS evolution across species, exploring how technological advancements are transforming our understanding of splicing evolution. Furthermore, we discuss mechanistic and functional insights from recent studies, including groundbreaking discoveries on how AS has shaped phenotypic evolution in mammals.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986233","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 : 2026-01-15DOI: 10.1038/s44318-025-00686-9
Akshaya Nambiar,René Martin,Kamakshi Tomar,Hans-Joachim Knölker,Sandhya P Koushika,Subramaniam K,Ravi Manjithaya
Autophagy requires precise regulation of autophagosome-lysosome fusion, yet the molecular details of this process remain incompletely understood. Here, we identify the class V myosin MYO5A as a critical regulator of autophagic flux. The genetic or pharmacological inhibition of MYO5A in Saccharomyces cerevisiae, mammalian cells, or Caenorhabditis elegans blocked autophagic flux by preventing autophagosome-lysosome fusion. MYO5A facilitates the maturation of autophagosomes into fusion-competent intermediates as its loss altered the localization of fusion machinery on autophagosomes and reduced the pool of stationary autophagosomes, a step that proved critical for subsequent fusion with lysosomes. Domain mapping and targeted mutagenesis revealed that two LIR motifs (PAYRVL and QAYIGL) within the coiled-coil and globular tail domains of MYO5A mediate its direct interaction with LC3 on autophagosomes. Live imaging in mammalian cells and C. elegans added support for this role, revealing how MYO5A regulates autophagic flux to ensure fusion. Together, these findings establish MYO5A as a regulator of autophagy and highlight its potential as a target for fine-tuning autophagic flux.
{"title":"MYO5A-mediated stabilization promotes the acquisition of fusion competence in sealed autophagosomes.","authors":"Akshaya Nambiar,René Martin,Kamakshi Tomar,Hans-Joachim Knölker,Sandhya P Koushika,Subramaniam K,Ravi Manjithaya","doi":"10.1038/s44318-025-00686-9","DOIUrl":"https://doi.org/10.1038/s44318-025-00686-9","url":null,"abstract":"Autophagy requires precise regulation of autophagosome-lysosome fusion, yet the molecular details of this process remain incompletely understood. Here, we identify the class V myosin MYO5A as a critical regulator of autophagic flux. The genetic or pharmacological inhibition of MYO5A in Saccharomyces cerevisiae, mammalian cells, or Caenorhabditis elegans blocked autophagic flux by preventing autophagosome-lysosome fusion. MYO5A facilitates the maturation of autophagosomes into fusion-competent intermediates as its loss altered the localization of fusion machinery on autophagosomes and reduced the pool of stationary autophagosomes, a step that proved critical for subsequent fusion with lysosomes. Domain mapping and targeted mutagenesis revealed that two LIR motifs (PAYRVL and QAYIGL) within the coiled-coil and globular tail domains of MYO5A mediate its direct interaction with LC3 on autophagosomes. Live imaging in mammalian cells and C. elegans added support for this role, revealing how MYO5A regulates autophagic flux to ensure fusion. Together, these findings establish MYO5A as a regulator of autophagy and highlight its potential as a target for fine-tuning autophagic flux.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971932","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 : 2026-01-14DOI: 10.1038/s44318-026-00692-5
Iñaki Ruiz-Trillo,Elena Casacuberta,Nicholas H Brown,Ricard Solé
How animals evolved from their unicellular ancestor is a fundamental biological question. The fact that all animals are monophyletic-sharing a single common ancestor-implies their origin from unicellular eukaryotes was likely driven by rare and highly advantageous innovations. While the fossil record and initial genomic comparisons suggested animals originated by the rapid acquisition of many novel genes, new research on animal's closest unicellular relatives reveals most of those genes originated before animals evolved. Here we present a new model for animal origins, which shares similarities with the origin of one of the greatest technological innovations of our time: the smartphone. We show that the origin of both animals and smartphones was due to the integration and repurposing of pre-existing components driven by a novel "operating system", rather than the sudden emergence of many new parts. This model offers testable predictions and a new theoretical framework for understanding complex biological innovation.
{"title":"A smartphone analogy to explore the origin of animals.","authors":"Iñaki Ruiz-Trillo,Elena Casacuberta,Nicholas H Brown,Ricard Solé","doi":"10.1038/s44318-026-00692-5","DOIUrl":"https://doi.org/10.1038/s44318-026-00692-5","url":null,"abstract":"How animals evolved from their unicellular ancestor is a fundamental biological question. The fact that all animals are monophyletic-sharing a single common ancestor-implies their origin from unicellular eukaryotes was likely driven by rare and highly advantageous innovations. While the fossil record and initial genomic comparisons suggested animals originated by the rapid acquisition of many novel genes, new research on animal's closest unicellular relatives reveals most of those genes originated before animals evolved. Here we present a new model for animal origins, which shares similarities with the origin of one of the greatest technological innovations of our time: the smartphone. We show that the origin of both animals and smartphones was due to the integration and repurposing of pre-existing components driven by a novel \"operating system\", rather than the sudden emergence of many new parts. This model offers testable predictions and a new theoretical framework for understanding complex biological innovation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"101 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968608","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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