EMBO Journal最新文献_第6页

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

The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome. 人类疾病相关基因 ZNFX1 通过抑制 NLRP3 炎性体控制炎症。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-27 DOI: 10.1038/s44318-024-00236-9

Jing Huang, Yao Wang, Xin Jia, Changfeng Zhao, Meiqi Zhang, Mi Bao, Pan Fu, Cuiqin Cheng, Ruona Shi, Xiaofei Zhang, Jun Cui, Gang Wan, Anlong Xu

{"title":"The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome.","authors":"Jing Huang, Yao Wang, Xin Jia, Changfeng Zhao, Meiqi Zhang, Mi Bao, Pan Fu, Cuiqin Cheng, Ruona Shi, Xiaofei Zhang, Jun Cui, Gang Wan, Anlong Xu","doi":"10.1038/s44318-024-00236-9","DOIUrl":"10.1038/s44318-024-00236-9","url":null,"abstract":"Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5469-5493"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331677","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

Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates. 自噬适配体通过形成片状液体凝聚体来介导依赖于Parkin的有丝分裂。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-10-17 DOI: 10.1038/s44318-024-00272-5

Zi Yang, Saori R Yoshii, Yuji Sakai, Jing Zhang, Haruka Chino, Roland L Knorr, Noboru Mizushima

{"title":"Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.","authors":"Zi Yang, Saori R Yoshii, Yuji Sakai, Jing Zhang, Haruka Chino, Roland L Knorr, Noboru Mizushima","doi":"10.1038/s44318-024-00272-5","DOIUrl":"10.1038/s44318-024-00272-5","url":null,"abstract":"During PINK1- and Parkin-mediated mitophagy, autophagy adaptors are recruited to damaged mitochondria to promote their selective degradation. Autophagy adaptors such as optineurin (OPTN) and NDP52 facilitate mitophagy by recruiting the autophagy-initiation machinery, and assisting engulfment of damaged mitochondria through binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like nature of OPTN condensates is important for mitophagy activity, because reducing the fluidity of OPTN-ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like, rather than a stoichiometric, model of autophagy adaptors to explain the interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid-liquid phase separation in facilitating membrane-membrane contacts, likely through the generation of capillary forces.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5613-5634"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479757","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

PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis. PCPE-1是一种源自棕色脂肪组织的细胞因子，可促进肥胖引起的肝纤维化。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-08-19 DOI: 10.1038/s44318-024-00196-0

Yung Ting Hsiao, Yohko Yoshida, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Hironori Nakagami, Ryuichi Morishita, Kenya Kamimura, Shuji Terai, Tin May Aung, Ji Li, Takaaki Furihata, Jing Yuan Tang, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu

{"title":"PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis.","authors":"Yung Ting Hsiao, Yohko Yoshida, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Hironori Nakagami, Ryuichi Morishita, Kenya Kamimura, Shuji Terai, Tin May Aung, Ji Li, Takaaki Furihata, Jing Yuan Tang, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu","doi":"10.1038/s44318-024-00196-0","DOIUrl":"10.1038/s44318-024-00196-0","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4846-4869"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005777","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

Publisher Correction: miRNA-mediated gene silencing in Drosophila larval development involves GW182-dependent and independent mechanisms. 出版商更正：果蝇幼虫发育过程中 miRNA 介导的基因沉默涉及 GW182 依赖性和独立机制。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-10-31 DOI: 10.1038/s44318-024-00287-y

Eriko Matsuura-Suzuki, Kaori Kiyokawa, Shintaro Iwasaki, Yukihide Tomari

引用次数: 0

Single-nucleus RNA-seq dissection of choroid plexus tumor cell heterogeneity. 脉络丛肿瘤细胞异质性的单核 RNA-Seq 分析。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-10-31 DOI: 10.1038/s44318-024-00283-2

Anthony D Hill, Konstantin Okonechnikov, Marla K Herr, Christian Thomas, Supat Thongjuea, Martin Hasselblatt, Annarita Patrizi

引用次数: 0

Brain mitophagy in space and time. 大脑有丝分裂的空间和时间

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-10-30 DOI: 10.1038/s44318-024-00275-2

Vassiliki Nikoletopoulou

引用次数: 0

Developmental cues are encoded by the combinatorial phosphorylation of Arabidopsis RETINOBLASTOMA-RELATED protein RBR1. 拟南芥 RETINOBLASTOMA-RELATED 蛋白 RBR1 的组合磷酸化编码了发育线索。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-10-28 DOI: 10.1038/s44318-024-00282-3

Jorge Zamora-Zaragoza, Katinka Klap, Jaheli Sánchez-Pérez, Jean-Philippe Vielle-Calzada, Viola Willemsen, Ben Scheres

{"title":"Developmental cues are encoded by the combinatorial phosphorylation of Arabidopsis RETINOBLASTOMA-RELATED protein RBR1.","authors":"Jorge Zamora-Zaragoza, Katinka Klap, Jaheli Sánchez-Pérez, Jean-Philippe Vielle-Calzada, Viola Willemsen, Ben Scheres","doi":"10.1038/s44318-024-00282-3","DOIUrl":"https://doi.org/10.1038/s44318-024-00282-3","url":null,"abstract":"RETINOBLASTOMA-RELATED (RBR) proteins orchestrate cell division, differentiation, and survival in response to environmental and developmental cues through protein-protein interactions that are governed by multisite phosphorylation. Here we explore, using a large collection of transgenic RBR phosphovariants to complement protein function in Arabidopsis thaliana, whether differences in the number and position of RBR phosphorylation events cause a diversification of the protein's function. While the number of point mutations influence phenotypic strength, phosphosites contribute differentially to distinct phenotypes. RBR pocket domain mutations associate primarily with cell proliferation, while mutations in the C-region are linked to stem cell maintenance. Both phospho-mimetic and a phospho-defective variants promote cell death, suggesting that distinct mechanisms can lead to similar cell fates. We observed combinatorial effects between phosphorylated T406 and phosphosites in different protein domains, suggesting that specific, additive, and combinatorial phosphorylation events fine-tune RBR function. Suppression of dominant phospho-defective RBR phenotypes with a mutation that inhibits RBR interacting with LXCXE motifs, and an exhaustive protein-protein interaction assay, not only revealed the importance of DREAM complex members in phosphorylation-regulated RBR function but also pointed to phosphorylation-independent RBR roles in environmental responses. Thus, combinatorial phosphorylation defined and separated developmental, but not environmental, functions of RBR.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters. 细菌 SLC17 有机阴离子转运体同源物 DgoT 的转运机制。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-10-25 DOI: 10.1038/s44318-024-00279-y

Natalia Dmitrieva, Samira Gholami, Claudia Alleva, Paolo Carloni, Mercedes Alfonso-Prieto, Christoph Fahlke

{"title":"Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters.","authors":"Natalia Dmitrieva, Samira Gholami, Claudia Alleva, Paolo Carloni, Mercedes Alfonso-Prieto, Christoph Fahlke","doi":"10.1038/s44318-024-00279-y","DOIUrl":"https://doi.org/10.1038/s44318-024-00279-y","url":null,"abstract":"The solute carrier 17 (SLC17) family contains anion transporters that accumulate neurotransmitters in secretory vesicles, remove carboxylated monosaccharides from lysosomes, or extrude organic anions from the kidneys and liver. We combined classical molecular dynamics simulations, Markov state modeling and hybrid first principles quantum mechanical/classical mechanical (QM/MM) simulations with experimental approaches to describe the transport mechanisms of a model bacterial protein, the D-galactonate transporter DgoT, at atomic resolution. We found that protonation of D46 and E133 precedes galactonate binding and that substrate binding induces closure of the extracellular gate, with the conserved R47 coupling substrate binding to transmembrane helix movement. After isomerization to an inward-facing conformation, deprotonation of E133 and subsequent proton transfer from D46 to E133 opens the intracellular gate and permits galactonate dissociation either in its unprotonated form or after proton transfer from E133. After release of the second proton, apo DgoT returns to the outward-facing conformation. Our results provide a framework to understand how various SLC17 transport functions with distinct transport stoichiometries can be attained through subtle variations in proton and substrate binding/unbinding.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells. BMP通过Bcl11b调控的NuRD复合物抑制Wnt信号传导，以维持肠道干细胞。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-10-21 DOI: 10.1038/s44318-024-00276-1

Yehua Li, Xiaodan Wang, Meimei Huang, Xu Wang, Chunlin Li, Siqi Li, Yuhui Tang, Shicheng Yu, Yalong Wang, Wanglu Song, Wei Wu, Yuan Liu, Ye-Guang Chen

{"title":"BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells.","authors":"Yehua Li, Xiaodan Wang, Meimei Huang, Xu Wang, Chunlin Li, Siqi Li, Yuhui Tang, Shicheng Yu, Yalong Wang, Wanglu Song, Wei Wu, Yuan Liu, Ye-Guang Chen","doi":"10.1038/s44318-024-00276-1","DOIUrl":"https://doi.org/10.1038/s44318-024-00276-1","url":null,"abstract":"Lgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0