EMBO Journal最新文献_第10页

A human progeria-associated BAF-1 mutation modulates gene expression and accelerates aging in C. elegans. 人类早衰症相关的 BAF-1 基因突变会调节基因表达并加速优雅小鼠的衰老。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-10-04 DOI: 10.1038/s44318-024-00261-8

Raquel Romero-Bueno, Adrián Fragoso-Luna, Cristina Ayuso, Nina Mellmann, Alan Kavsek, Christian G Riedel, Jordan D Ward, Peter Askjaer

{"title":"A human progeria-associated BAF-1 mutation modulates gene expression and accelerates aging in C. elegans.","authors":"Raquel Romero-Bueno, Adrián Fragoso-Luna, Cristina Ayuso, Nina Mellmann, Alan Kavsek, Christian G Riedel, Jordan D Ward, Peter Askjaer","doi":"10.1038/s44318-024-00261-8","DOIUrl":"10.1038/s44318-024-00261-8","url":null,"abstract":"Alterations in the nuclear envelope are linked to a variety of rare diseases termed laminopathies. A single amino acid substitution at position 12 (A12T) of the human nuclear envelope protein BAF (Barrier to Autointegration Factor) causes Néstor-Guillermo Progeria Syndrome (NGPS). This premature ageing condition leads to growth retardation and severe skeletal defects, but the underlying mechanisms are unknown. Here, we have generated a novel in vivo model for NGPS by modifying the baf-1 locus in C. elegans to mimic the human NGPS mutation. These baf-1(G12T) mutant worms displayed multiple phenotypes related to fertility, lifespan, and stress resistance. Importantly, nuclear morphology deteriorated faster during aging in baf-1(G12T) compared to wild-type animals, recapitulating an important hallmark of cells from progeria patients. Although localization of BAF-1(G12T) was similar to wild-type BAF-1, lamin accumulation at the nuclear envelope was reduced in mutant worms. Tissue-specific chromatin binding and transcriptome analyses showed reduced BAF-1 association in most genes deregulated by the baf-1(G12T) mutation, suggesting that altered BAF chromatin association induces NGPS phenotypes via altered gene expression.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5718-5746"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat. IF1 是 ATP 合成酶水解活性的冷调节开关，支持棕色脂肪的热生成。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI: 10.1038/s44318-024-00215-0

Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt

{"title":"IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.","authors":"Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt","doi":"10.1038/s44318-024-00215-0","DOIUrl":"10.1038/s44318-024-00215-0","url":null,"abstract":"While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called \"reverse mode\" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4870-4891"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Carboxy-terminal polyglutamylation regulates signaling and phase separation of the Dishevelled protein. 羧基末端多谷氨酰化调节 Dishevelled 蛋白的信号传递和相分离。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1038/s44318-024-00254-7

Marek Kravec, Ondrej Šedo, Jana Nedvědová, Miroslav Micka, Marie Šulcová, Nikodém Zezula, Kristína Gömöryová, David Potěšil, Ranjani Sri Ganji, Sara Bologna, Igor Červenka, Zbyněk Zdráhal, Jakub Harnoš, Konstantinos Tripsianes, Carsten Janke, Cyril Bařinka, Vítězslav Bryja

{"title":"Carboxy-terminal polyglutamylation regulates signaling and phase separation of the Dishevelled protein.","authors":"Marek Kravec, Ondrej Šedo, Jana Nedvědová, Miroslav Micka, Marie Šulcová, Nikodém Zezula, Kristína Gömöryová, David Potěšil, Ranjani Sri Ganji, Sara Bologna, Igor Červenka, Zbyněk Zdráhal, Jakub Harnoš, Konstantinos Tripsianes, Carsten Janke, Cyril Bařinka, Vítězslav Bryja","doi":"10.1038/s44318-024-00254-7","DOIUrl":"10.1038/s44318-024-00254-7","url":null,"abstract":"Polyglutamylation is a reversible posttranslational modification that is catalyzed by enzymes of the tubulin tyrosine ligase-like (TTLL) family. Here, we found that TTLL11 generates a previously unknown type of polyglutamylation that is initiated by the addition of a glutamate residue to the free C-terminal carboxyl group of a substrate protein. TTLL11 efficiently polyglutamylates the Wnt signaling protein Dishevelled 3 (DVL3), thereby changing the interactome of DVL3. Polyglutamylation increases the capacity of DVL3 to get phosphorylated, to undergo phase separation, and to act in the noncanonical Wnt pathway. Both carboxy-terminal polyglutamylation and the resulting reduction in phase separation capacity of DVL3 can be reverted by the deglutamylating enzyme CCP6, demonstrating a causal relationship between TTLL11-mediated polyglutamylation and phase separation. Thus, C-terminal polyglutamylation represents a new type of posttranslational modification, broadening the range of proteins that can be modified by polyglutamylation and providing the first evidence that polyglutamylation can modulate protein phase separation.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5635-5666"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

p21 regulates expression of ECM components and promotes pulmonary fibrosis via CDK4 and Rb. p21 可调节 ECM 成分的表达，并通过 CDK4 和 Rb 促进肺纤维化。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1038/s44318-024-00246-7

Nurit Papismadov, Naama Levi, Lior Roitman, Amit Agrawal, Yossi Ovadya, Ulysse Cherqui, Reut Yosef, Hagay Akiva, Hilah Gal, Valery Krizhanovsky

{"title":"p21 regulates expression of ECM components and promotes pulmonary fibrosis via CDK4 and Rb.","authors":"Nurit Papismadov, Naama Levi, Lior Roitman, Amit Agrawal, Yossi Ovadya, Ulysse Cherqui, Reut Yosef, Hagay Akiva, Hilah Gal, Valery Krizhanovsky","doi":"10.1038/s44318-024-00246-7","DOIUrl":"10.1038/s44318-024-00246-7","url":null,"abstract":"Fibrosis and accumulation of senescent cells are common tissue changes associated with aging. Here, we show that the CDK inhibitor p21 (CDKN1A), known to regulate the cell cycle and the viability of senescent cells, also controls the expression of extracellular matrix (ECM) components in senescent and proliferating cells of the fibrotic lung, in a manner dependent on CDK4 and Rb phosphorylation. p21 knockout protects mice from the induction of lung fibrosis. Moreover, inducible p21 silencing during fibrosis development alleviates disease pathology, decreasing the inflammatory response and ECM accumulation in the lung, and reducing the amount of senescent cells. Furthermore, p21 silencing limits fibrosis progression even when introduced during disease development. These findings show that one common mechanism regulates both cell cycle progression and expression of ECM components, and suggest that targeting p21 might be a new approach for treating age-related fibrotic pathologies.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5360-5380"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ezrin, radixin, and moesin are dispensable for macrophage migration and cellular cortex mechanics. Ezrin、radixin 和 moesin 对于巨噬细胞迁移和细胞皮层力学是不可或缺的。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-07-18 DOI: 10.1038/s44318-024-00173-7

Perrine Verdys, Javier Rey Barroso, Adeline Girel, Joseph Vermeil, Martin Bergert, Thibaut Sanchez, Arnaud Métais, Thomas Mangeat, Elisabeth Bellard, Claire Bigot, Catherine Astarie-Dequeker, Arnaud Labrousse, Jean-Philippe Girard, Isabelle Maridonneau-Parini, Christel Vérollet, Frédéric Lagarrigue, Alba Diz-Muñoz, Julien Heuvingh, Matthieu Piel, Olivia du Roure, Véronique Le Cabec, Sébastien Carréno, Renaud Poincloux

{"title":"Ezrin, radixin, and moesin are dispensable for macrophage migration and cellular cortex mechanics.","authors":"Perrine Verdys, Javier Rey Barroso, Adeline Girel, Joseph Vermeil, Martin Bergert, Thibaut Sanchez, Arnaud Métais, Thomas Mangeat, Elisabeth Bellard, Claire Bigot, Catherine Astarie-Dequeker, Arnaud Labrousse, Jean-Philippe Girard, Isabelle Maridonneau-Parini, Christel Vérollet, Frédéric Lagarrigue, Alba Diz-Muñoz, Julien Heuvingh, Matthieu Piel, Olivia du Roure, Véronique Le Cabec, Sébastien Carréno, Renaud Poincloux","doi":"10.1038/s44318-024-00173-7","DOIUrl":"10.1038/s44318-024-00173-7","url":null,"abstract":"The cellular cortex provides crucial mechanical support and plays critical roles during cell division and migration. The proteins of the ERM family, comprised of ezrin, radixin, and moesin, are central to these processes by linking the plasma membrane to the actin cytoskeleton. To investigate the contributions of the ERM proteins to leukocyte migration, we generated single and triple ERM knockout macrophages. Surprisingly, we found that even in the absence of ERM proteins, macrophages still form the different actin structures promoting cell migration, such as filopodia, lamellipodia, podosomes, and ruffles. Furthermore, we discovered that, unlike every other cell type previously investigated, the single or triple knockout of ERM proteins does not affect macrophage migration in diverse contexts. Finally, we demonstrated that the loss of ERMs in macrophages does not affect the mechanical properties of their cortex. These findings challenge the notion that ERMs are universally essential for cortex mechanics and cell migration and support the notion that the macrophage cortex may have diverged from that of other cells to allow for their uniquely adaptive cortical plasticity.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4822-4845"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis. 合成肽可诱导一种由辅助因子诱导的抑制型转录因子凝聚，从而抑制肿瘤发生。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-10-02 DOI: 10.1038/s44318-024-00257-4

Yang Tang, Fan Chen, Gemin Fang, Hui Zhang, Yanni Zhang, Hanying Zhu, Xinru Zhang, Yi Han, Zhifa Cao, Fenghua Guo, Wenjia Wang, Dan Ye, Junyi Ju, Lijie Tan, Chuanchuan Li, Yun Zhao, Zhaocai Zhou, Liwei An, Shi Jiao

{"title":"A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis.","authors":"Yang Tang, Fan Chen, Gemin Fang, Hui Zhang, Yanni Zhang, Hanying Zhu, Xinru Zhang, Yi Han, Zhifa Cao, Fenghua Guo, Wenjia Wang, Dan Ye, Junyi Ju, Lijie Tan, Chuanchuan Li, Yun Zhao, Zhaocai Zhou, Liwei An, Shi Jiao","doi":"10.1038/s44318-024-00257-4","DOIUrl":"10.1038/s44318-024-00257-4","url":null,"abstract":"Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This \"glue\" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5586-5612"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transplacental SARS-CoV-2 protein ORF8 binds to complement C1q to trigger fetal inflammation. 经胎盘感染的 SARS-CoV-2 蛋白 ORF8 与补体 C1q 结合，引发胎儿炎症。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-10-10 DOI: 10.1038/s44318-024-00260-9

Tamiris Azamor, Débora Familiar-Macedo, Gielenny M Salem, Chineme Onwubueke, Ivonne Melano, Lu Bian, Zilton Vasconcelos, Karin Nielsen-Saines, Xianfang Wu, Jae U Jung, Feng Lin, Oluwatosin Goje, Edward Chien, Steve Gordon, Charles B Foster, Hany Aly, Ruth M Farrell, Weiqiang Chen, Suan-Sin Foo

{"title":"Transplacental SARS-CoV-2 protein ORF8 binds to complement C1q to trigger fetal inflammation.","authors":"Tamiris Azamor, Débora Familiar-Macedo, Gielenny M Salem, Chineme Onwubueke, Ivonne Melano, Lu Bian, Zilton Vasconcelos, Karin Nielsen-Saines, Xianfang Wu, Jae U Jung, Feng Lin, Oluwatosin Goje, Edward Chien, Steve Gordon, Charles B Foster, Hany Aly, Ruth M Farrell, Weiqiang Chen, Suan-Sin Foo","doi":"10.1038/s44318-024-00260-9","DOIUrl":"10.1038/s44318-024-00260-9","url":null,"abstract":"Prenatal SARS-CoV-2 infection is associated with higher rates of pregnancy and birth complications, despite that vertical transmission rates are thought to be low. Here, multi-omics analyses of human placental tissues, cord tissues/plasma, and amniotic fluid from 23 COVID-19 mother-infant pairs revealed robust inflammatory responses in both maternal and fetal compartments. Pronounced expression of complement proteins (C1q, C3, C3b, C4, C5) and inflammatory cytokines (TNF, IL-1α, and IL-17A/E) was detected in the fetal compartment of COVID-19-affected pregnancies. While ~26% of fetal tissues were positive for SARS-CoV-2 RNA, more than 60% of fetal tissues contained SARS-CoV-2 ORF8 proteins, suggesting transplacental transfer of this viral accessory protein. ORF8-positive fetal compartments exhibited increased inflammation and complement activation compared to ORF8-negative COVID-19 pregnancies. In human placental trophoblasts in vitro, exogenous ORF8 exposure resulted in complement activation and inflammatory responses. Co-immunoprecipitation analysis demonstrated that ORF8 binds to C1q specifically by interacting with a 15-peptide region on ORF8 (C37-A51) and the globular domain of C1q subunit A. In conclusion, an ORF8-C1q-dependent complement activation pathway was identified in COVID-19-affected pregnancies, likely contributing to fetal inflammation independently of fetal virus exposure.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5494-5529"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cellular senescence, p21, and the path to fibrosis. 细胞衰老、p21 和纤维化之路。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1038/s44318-024-00245-8

Paolo S Turano, Utz Herbig

引用次数: 0

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy. DELE1 可维持肌肉蛋白稳态，促进线粒体肌病患者的生长和存活。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-10-08 DOI: 10.1038/s44318-024-00242-x

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra

{"title":"DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.","authors":"Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra","doi":"10.1038/s44318-024-00242-x","DOIUrl":"10.1038/s44318-024-00242-x","url":null,"abstract":"Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5548-5585"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Requirement of Nek2a and cyclin A2 for Wapl-dependent removal of cohesin from prophase chromatin. Wapl依赖性地从原期染色质中移除粘合素需要Nek2a和细胞周期蛋白A2。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-13 DOI: 10.1038/s44318-024-00228-9

Susanne Hellmuth, Olaf Stemmann

{"title":"Requirement of Nek2a and cyclin A2 for Wapl-dependent removal of cohesin from prophase chromatin.","authors":"Susanne Hellmuth, Olaf Stemmann","doi":"10.1038/s44318-024-00228-9","DOIUrl":"10.1038/s44318-024-00228-9","url":null,"abstract":"Sister chromatid cohesion is mediated by the cohesin complex. In mitotic prophase cohesin is removed from chromosome arms in a Wapl- and phosphorylation-dependent manner. Sgo1-PP2A protects pericentromeric cohesion by dephosphorylation of cohesin and its associated Wapl antagonist sororin. However, Sgo1-PP2A relocates to inner kinetochores well before sister chromatids are separated by separase, leaving pericentromeric regions unprotected. Why deprotected cohesin is not removed by Wapl remains enigmatic. By reconstituting Wapl-dependent cohesin removal from chromatin in vitro, we discovered a requirement for Nek2a and Cdk1/2-cyclin A2. These kinases phosphorylate cohesin-bound Pds5b, thereby converting it from a sororin- to a Wapl-interactor. Replacement of endogenous Pds5b by a phosphorylation mimetic variant causes premature sister chromatid separation (PCS). Conversely, phosphorylation-resistant Pds5b impairs chromosome arm separation in prometaphase-arrested cells and suppresses PCS in the absence of Sgo1. Early mitotic degradation of Nek2a and cyclin A2 may therefore explain why only separase, but not Wapl, can trigger anaphase.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5237-5259"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0