The EMBO Journal最新文献_第7页

Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer. 靶向keap1失活肺癌中的泛素信号脆弱性

The EMBO Journal Pub Date : 2026-03-20 DOI: 10.1038/s44318-026-00737-9

Varun Jayeshkumar Shah,Oliver Hartmann,Martin Wegner,Cristian Prieto-Garcia,Rubina Kazi,Viktoria von Heyl Zu Herrnsheim,Amin Wanli,Igor Mačinković,Bianka Bohnacker,Koraljka Husnjak,Dmitry Namgaladze,Mathias Rosenfeldt,Manuel Kaulich,Markus E Diefenbacher,Ivan Dikic

{"title":"Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.","authors":"Varun Jayeshkumar Shah,Oliver Hartmann,Martin Wegner,Cristian Prieto-Garcia,Rubina Kazi,Viktoria von Heyl Zu Herrnsheim,Amin Wanli,Igor Mačinković,Bianka Bohnacker,Koraljka Husnjak,Dmitry Namgaladze,Mathias Rosenfeldt,Manuel Kaulich,Markus E Diefenbacher,Ivan Dikic","doi":"10.1038/s44318-026-00737-9","DOIUrl":"https://doi.org/10.1038/s44318-026-00737-9","url":null,"abstract":"Lung cancer cells rely on protein homeostasis regulators, particularly the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. To investigate how these genetic alterations drive tumor formation, we conducted CRISPR screens on metabolically stressed murine lung cancer models and identified specific cancer dependencies, including ubiquitin ligase subunit KEAP1. Although KEAP1 is frequently mutated in aggressive non-small cell lung cancers (NSCLC, ~15%), our findings reveal an unexpected proto-oncogenic role for KEAP1 in a genetically defined subset of NSCLC. Mechanistically, Keap1 deletion activated Nrf2 and upregulated Aldh3a1. This led to elevated reductive stress and suppressed tumor growth. Given the poor prognosis of KEAP1-mutated patients, combinatorial CRISPR dropout screens revealed druggable E3s and DUBs as Keap1-dependent co-vulnerabilities. Notably, depleting these co-dependencies, such as the E3 ligases Herc2, Ubr4 and Huwe1 ablated the in vivo development of Keap1-inactivated tumors. We demonstrate that targeting the UPS represents an underexplored, promising therapeutic approach for patients with KEAP1-inactivated tumors, especially under metabolic stress.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490085","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}

引用次数: 0

Functional rescue of a disease-linked ERAD pathway mutation via alternative splicing. 通过选择性剪接对疾病相关ERAD通路突变的功能修复。

The EMBO Journal Pub Date : 2026-03-20 DOI: 10.1038/s44318-026-00757-5

Huilun Helen Wang,Zhihong Wang,Liangguang Leo Lin,Sunil K Verma,Weronika Gniadzik,Hui Wang,Zexin Jason Li,Emily Whitestone,Lulu Jiang,Muge N Kuyumcu-Martinez,Shengyi Sun,Ling Qi

{"title":"Functional rescue of a disease-linked ERAD pathway mutation via alternative splicing.","authors":"Huilun Helen Wang,Zhihong Wang,Liangguang Leo Lin,Sunil K Verma,Weronika Gniadzik,Hui Wang,Zexin Jason Li,Emily Whitestone,Lulu Jiang,Muge N Kuyumcu-Martinez,Shengyi Sun,Ling Qi","doi":"10.1038/s44318-026-00757-5","DOIUrl":"https://doi.org/10.1038/s44318-026-00757-5","url":null,"abstract":"ER-associated degradation (ERAD) targets misfolded proteins in the endoplasmic reticulum (ER) for proteasomal degradation. Mutations in its most conserved branch involving the SEL1L-HRD1 complex cause ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI), characterized by developmental delay, microcephaly, and locomotor dysfunction. Its most severe form, ENDI with agammaglobulinemia (ENDI-A), results from a bi-allelic SEL1L-Cys141Tyr (C141Y) mutation within its fibronectin II (FNII) domain and currently lacks effective treatment. Here, we find that knock-in mouse models carrying the C141Y mutation are unexpectedly rescued via increased use of an alternative splice donor within exon 4 leading to bypass of the mutant FNII-encoding region. The resulting SEL1L variant restores ERAD activity, and rescues perinatal lethality, B cell deficiency, and neurodevelopmental defects. Leveraging this mechanism, we demonstrate that antisense oligonucleotide-mediated exon skipping in patient-derived fibroblasts generates a truncated yet functional SEL1L protein that fully restores ERAD function and ER proteostasis. These results establish RNA splicing-modulation as a viable therapeutic strategy for ERAD deficiency and broaden the clinical potential of exon-skipping therapy to diseases of protein misfolding.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490084","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}

引用次数: 0

TBP regulates transposable element expression in early mouse embryos. TBP调节小鼠早期胚胎转座因子的表达。

The EMBO Journal Pub Date : 2026-03-20 DOI: 10.1038/s44318-026-00736-w

Clara Hermant,Carlos Michel Mourra-Díaz,Marlies E Oomen,Natasha Jansz,Camille Noll,Antoine Canat,Mrinmoy Pal,Tsunetoshi Nakatani,Tamas Schauer,Maria-Elena Torres-Padilla

{"title":"TBP regulates transposable element expression in early mouse embryos.","authors":"Clara Hermant,Carlos Michel Mourra-Díaz,Marlies E Oomen,Natasha Jansz,Camille Noll,Antoine Canat,Mrinmoy Pal,Tsunetoshi Nakatani,Tamas Schauer,Maria-Elena Torres-Padilla","doi":"10.1038/s44318-026-00736-w","DOIUrl":"https://doi.org/10.1038/s44318-026-00736-w","url":null,"abstract":"The activation of the embryonic genome is a crucial step in development. In addition to thousands of genes, many transposable elements (TEs) are robustly transcribed during early mammalian development. However, their transcriptional regulators remain largely unexplored. Here, we set out to identify transcription factors regulating the expression of TEs from the LINE, SINE and ERVL families during mouse preimplantation development. In particular, the MaLR family are the most abundant ERVL in the mouse genome and are also the most abundant constituent of the transcriptome in early mouse embryos. We find that the general transcription factor TBP binds and activates MaLRs in mouse embryos. Loss-of-function of TBP leads to downregulation of MaLRs, specifically the ORR1A family, which is the youngest ORR subclass and contributes a significant portion of major zygotic genome activation transcripts. Our work identifies regulators of TE expression in vivo and highlights a previously unrecognised role for the general transcription factor TBP in regulating a highly specific TE transcriptional programme.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"268 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490083","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}

引用次数: 0

Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair. Ca 2 +泄漏是非规范ATG8/LC3脂化和膜修复的保守信号。

The EMBO Journal Pub Date : 2026-03-20 DOI: 10.1038/s44318-026-00741-z

Di Chen,Antony Fearns,Christopher J Peddie,Maximiliano G Gutierrez

{"title":"Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.","authors":"Di Chen,Antony Fearns,Christopher J Peddie,Maximiliano G Gutierrez","doi":"10.1038/s44318-026-00741-z","DOIUrl":"https://doi.org/10.1038/s44318-026-00741-z","url":null,"abstract":"Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490086","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}

引用次数: 0

The mechanism of ribosomal recruitment during translation initiation on the Type 2 encephalomyocarditis virus IRES. 2型脑心肌炎病毒IRES翻译起始时核糖体募集的机制。

The EMBO Journal Pub Date : 2026-03-18 DOI: 10.1038/s44318-026-00735-x

Sayan Bhattacharjee,Irina S Abaeva,Zuben P Brown,Yani Arhab,Hengameh Fallah,Christopher U T Hellen,Joachim Frank,Tatyana V Pestova

{"title":"The mechanism of ribosomal recruitment during translation initiation on the Type 2 encephalomyocarditis virus IRES.","authors":"Sayan Bhattacharjee,Irina S Abaeva,Zuben P Brown,Yani Arhab,Hengameh Fallah,Christopher U T Hellen,Joachim Frank,Tatyana V Pestova","doi":"10.1038/s44318-026-00735-x","DOIUrl":"https://doi.org/10.1038/s44318-026-00735-x","url":null,"abstract":"The encephalomyocarditis virus (EMCV) internal ribosomal entry side (IRES) and other Type 2 IRESs favor translation of the viral genome during infection. The domains H-L of these IRESs specifically interact with the cellular translation initiation factors eIF4G/eIF4A through their essential JK domain. However, the JK domain is not sufficient for IRES activity, which also strictly requires the preceding domain I of unknown function. To identify interactions that drive ribosomal attachment to eIF4G/eIF4A-bound Type 2 IRESs, we determined the cryo-EM structure of 48S initiation complexes formed on the EMCV IRES. The apical cloverleaf of domain I contacts ribosomal proteins uS13 and uS19 via its subdomain Id, whereas the essential GNRA tetraloop in subdomain Ic interacts with the TψC domain of initiator tRNA. The IRES-tRNA interaction also provides a mechanism for release of the IRES after eIF2 is replaced by eIF5B during subunit joining to allow attachment of 60S subunits. Functional assays supported the exceptional role of these interactions for initiation on this IRES. The strong conservation of the apex of domain I amongst Type 2 IRESs suggests that the reported interactions provide a common general mechanism of ribosomal attachment on them all.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"189 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478985","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}

引用次数: 0

Mechanistic insights into coordinated var transcriptional switching in malaria parasites. 疟疾寄生虫协调变异转录转换的机制见解。

The EMBO Journal Pub Date : 2026-03-18 DOI: 10.1038/s44318-026-00751-x

Joseph E Visone,Francesca Florini,Evi Hadjimichael,Valay Patel,Kirk W Deitsch

{"title":"Mechanistic insights into coordinated var transcriptional switching in malaria parasites.","authors":"Joseph E Visone,Francesca Florini,Evi Hadjimichael,Valay Patel,Kirk W Deitsch","doi":"10.1038/s44318-026-00751-x","DOIUrl":"https://doi.org/10.1038/s44318-026-00751-x","url":null,"abstract":"The exceptional virulence of the human malaria parasite, Plasmodium falciparum, is attributed to the adhesive properties of infected red blood cells and the parasite's ability to avoid antibody recognition through antigenic variation. Both properties are derived from the hypervariable surface protein PfEMP1, which is encoded by members of the multi-copy var gene family. Waves of parasitemia during an infection are thought to correspond to var transcriptional switching, enabling parasites to avoid elimination by antibodies targeting previously expressed forms of PfEMP1. The mechanisms underlying and regulating var transcriptional switching remain incompletely understood. Here, we show how transient activation of the var2csa locus mediates var switching, while the expression of non-coding RNAs from this locus contributes to repression of var2csa transcription and affects var switching frequencies. Furthermore, we find that an upstream open reading frame in the 5'-untranslated region of the var2csa transcript destabilizes the var2csa mRNA through the induction of the nonsense-mediated RNA decay pathway. This process promotes transcriptional activation of an alternative var gene. Our findings provide molecular insights into the coordinated transcriptional switching of the var gene family, which contributes to chronic infection.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"121 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478912","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}

引用次数: 0

Simultaneous inhibition of bacterial virulence and anti-phage defense systems by synergistic bacteriophage counter-defense proteins. 协同噬菌体反防御蛋白同时抑制细菌毒力和抗噬菌体防御系统。

The EMBO Journal Pub Date : 2026-03-18 DOI: 10.1038/s44318-026-00740-0

Jingru Zhao,Yuhao Zhu,Chenchen Wang,Fan Tian,Jun Deng,Jianglin Liao,Zhuojun Zhong,Jiazhen Liu,Nannan Guo,Shuai Le,Haihua Liang

{"title":"Simultaneous inhibition of bacterial virulence and anti-phage defense systems by synergistic bacteriophage counter-defense proteins.","authors":"Jingru Zhao,Yuhao Zhu,Chenchen Wang,Fan Tian,Jun Deng,Jianglin Liao,Zhuojun Zhong,Jiazhen Liu,Nannan Guo,Shuai Le,Haihua Liang","doi":"10.1038/s44318-026-00740-0","DOIUrl":"https://doi.org/10.1038/s44318-026-00740-0","url":null,"abstract":"Bacteriophages have evolved diverse inhibitors targeting key bacterial processes, including virulence and anti-phage defense systems, which could inspire novel antimicrobial strategies and enhance phage therapy approaches. In this study, we characterize Dap2, a protein encoded by a Pseudomonas aeruginosa phage PaoP5, which disrupts host virulence by sequestering the type III secretion system (T3SS) transcriptional activator ExsA, thus suppressing bacterial pathogenicity. Furthermore, Dap2 also directly binds the host Lon protease to prevent degradation of the phage-encoded HNH endonuclease. Deletion of dap2 in PaoP5 strongly impairs phage genome packaging due to insufficient levels of HNH. Finally, Dap2 synergizes with its genomically adjacent partner Dap1, a previously identified HNH-binding protein providing partial Lon resistance, to completely protect HNH against degradation. Together, these findings reveal a dual-function phage protein that simultaneously modulates bacterial virulence and anti-phage immunity, and showcase a synergistic mechanism for complete neutralization of bacterial defense system against which individual components provide only partial protection.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478911","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}

引用次数: 0

The WNK-OXSR1 osmosensing pathway mediates intestinal regeneration via Hippo-YAP signaling. WNK-OXSR1渗透传感通路通过Hippo-YAP信号介导肠道再生。

The EMBO Journal Pub Date : 2026-03-18 DOI: 10.1038/s44318-026-00738-8

Heming Cao,Xiawei Huang,Xiaobing Jiang,Jingrong Deng,Jiahui Wang,Chengfang Wu,Minhuang Hu,Bei Zeng,Zhihao Hu,Huimin Pan,Yuxia Yang,Kewei Zheng,Rui Shen,Mingqing Zhang,Bo Liu

{"title":"The WNK-OXSR1 osmosensing pathway mediates intestinal regeneration via Hippo-YAP signaling.","authors":"Heming Cao,Xiawei Huang,Xiaobing Jiang,Jingrong Deng,Jiahui Wang,Chengfang Wu,Minhuang Hu,Bei Zeng,Zhihao Hu,Huimin Pan,Yuxia Yang,Kewei Zheng,Rui Shen,Mingqing Zhang,Bo Liu","doi":"10.1038/s44318-026-00738-8","DOIUrl":"https://doi.org/10.1038/s44318-026-00738-8","url":null,"abstract":"Animals activate regenerative processes to repair injuries and restore homeostasis following tissue damage. A central question in regeneration is how damage signals are sensed and translated into regenerative growth. Tissue injuries lead to the release of intracellular contents and bodily fluids and disturb the osmotic balance. However, the role of osmolarity in regeneration remains largely unexplored. Using Drosophila and mouse intestine, as well as samples from inflammatory bowel disease (IBD) patients, we identify a key role for the osmolarity-sensing WNK-OXSR1 kinase cascade in intestinal regeneration. Mechanistically, OXSR1 phosphorylates the RhoB GTPase at threonine 37 upon intestinal injury, thereby disrupting its interaction with ARHGAP17 and increasing the levels of GTP-bound RhoB. RhoB activation in turn leads to enhanced F-actin polymerization and YAP activation, thus promoting tissue regeneration. We further show that pharmacological inhibition of WNK or OXSR1 reduces the oncogenic potential of intestinal regeneration. These findings reveal osmolarity as a critical damage signal in regeneration and position WNK-OXSR1 as a potential therapeutic target for stimulating intestinal repair.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"89 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478910","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}

引用次数: 0

Structural basis for EtfD-mediated coupling of β-oxidation and the respiratory chain in mycobacteria. etfd介导的分枝杆菌β-氧化与呼吸链耦合的结构基础。

The EMBO Journal Pub Date : 2026-03-17 DOI: 10.1038/s44318-026-00726-y

Gautier M Courbon,Vadim Makarov,Stewart T Cole,Dirk Schnapinger,Sabine Ehrt,John L Rubinstein

{"title":"Structural basis for EtfD-mediated coupling of β-oxidation and the respiratory chain in mycobacteria.","authors":"Gautier M Courbon,Vadim Makarov,Stewart T Cole,Dirk Schnapinger,Sabine Ehrt,John L Rubinstein","doi":"10.1038/s44318-026-00726-y","DOIUrl":"https://doi.org/10.1038/s44318-026-00726-y","url":null,"abstract":"Targeting β-oxidation has been proposed as a strategy for shortening tuberculosis (TB) treatment by killing non-replicating Mycobacterium tuberculosis within granulomas where the pathogen relies on host-derived lipids. The protein EtfD is thought to couple β-oxidation of fatty acids with the respiratory chain in mycobacteria. However, the structure of EtfD is not known and, as the presumed link between two complex processes, its activity has been difficult to measure, impeding its exploitation as a drug target. Here we show that Mycobacterium smegmatis, a fast growing and nonpathogenic model for M. tuberculosis, relies on EtfD for extracting energy from β-oxidation. The electron cryomicroscopy structure of M. smegmatis EtfD reveals an unusual linear [3Fe-4S] cluster that has not been seen in other protein structures, and suggests how EtfD transfers electrons from β-oxidation to the respiratory chain. We devised an assay that couples EtfD activity to a fluorescent readout of proton pumping by the respiratory chain, which can be used to identify compounds that block mycobacteria from using β-oxidation to power oxidative phosphorylation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471644","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}

引用次数: 0

Asymmetric sheath coordination controls flagellar architecture and function in Leptospira spirochete. 不对称鞘位控制钩端螺旋体鞭毛结构和功能。

The EMBO Journal Pub Date : 2026-03-17 DOI: 10.1038/s44318-026-00731-1

Akihiro Kawamoto,Toshiki Kuribayashi,Masatomo Morita,Shuichi Nakamura,Nobuo Koizumi

{"title":"Asymmetric sheath coordination controls flagellar architecture and function in Leptospira spirochete.","authors":"Akihiro Kawamoto,Toshiki Kuribayashi,Masatomo Morita,Shuichi Nakamura,Nobuo Koizumi","doi":"10.1038/s44318-026-00731-1","DOIUrl":"https://doi.org/10.1038/s44318-026-00731-1","url":null,"abstract":"Bacterial flagella are essential for motility, but their structure and how they generate movement vary greatly. Most motile bacteria use external helical flagella, whereas spirochetes have periplasmic flagella (PFs) that distort the cell body to drive forward movement. Here, we generated sheath protein knockout mutants and used high-resolution cryo-electron microscopy to elucidate the mechanisms underlying PF assembly, curvature, and rigidity in Leptospira biflexa. The PF consists of a FlaB1-based core filament surrounded asymmetrically by sheath proteins. Weak but essential binding of FlaA2 to the core enables asymmetric localization of the coiling protein FcpA. FcpA alone can induce curvature, whereas FcpB acts as a structural wedge that reinforces PF rigidity and enables efficient swimming in liquid. Specific glycosylation of FlaB1 mediates sheath-core interactions and may guide the assembly of sheath components. We propose that sheath proteins interact transiently with the core and may be anchored to the outer membrane, allowing core rotation beneath a static sheath. These findings reveal how cooperative interactions among sheath components confer structural and mechanical specialization to spirochete flagella.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471645","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}

引用次数: 0