EMBO Reports最新文献_第3页

TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver. TRIM32通过控制肝脏中胰岛素受体的降解来调节胰岛素敏感性。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-02 DOI: 10.1038/s44319-024-00348-7

Shilpa Thakur, Priya Rawat, Budheswar Dehury, Prosenjit Mondal

{"title":"TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver.","authors":"Shilpa Thakur, Priya Rawat, Budheswar Dehury, Prosenjit Mondal","doi":"10.1038/s44319-024-00348-7","DOIUrl":"https://doi.org/10.1038/s44319-024-00348-7","url":null,"abstract":"Impaired insulin receptor signaling is strongly linked to obesity-related metabolic conditions like non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes (T2DM). However, the exact mechanisms behind impaired insulin receptor (INSR) signaling in obesity induced by a high-fat diet remain elusive. In this study, we identify an E3 ubiquitin ligase, tripartite motif-containing protein 32 (TRIM32), as a key regulator of hepatic insulin signaling that targets the insulin receptor (INSR) for ubiquitination and proteasomal degradation in high-fat diet (HFD) mice. HFD induces the nuclear translocation of SREBP-1c (Sterol Regulatory Element-Binding Protein 1c), resulting in increased expression of TRIM32 in hepatocytes. TRIM32 ubiquitylates INSR and facilitates its proteasomal degradation, leading to severe insulin resistance and fat accumulation within the liver of high-fat diet induced obese (DIO) mice. Conversely, liver-specific knockdown of TRIM32 enhances INSR expression and hepatic insulin sensitivity. Reduced AMPK signaling and phosphorylation of SREBP-1c at S372 in high-fat DIO mice promotes the nuclear translocation of SREBP-1c, leading to increased TRIM32 expression. In conclusion, our results demonstrate that TRIM32 promotes diet-induced hepatic insulin resistance by targeting the INSR to degradation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921163","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

Nuclear PD-L1 triggers tumour-associated inflammation upon DNA damage. 核PD-L1在DNA损伤时触发肿瘤相关炎症。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-02 DOI: 10.1038/s44319-024-00354-9

Naoe T Nihira, Wenwen Wu, Mitsue Hosoi, Yukiko Togashi, Shigeaki Sunada, Yasuo Miyoshi, Yoshio Miki, Tomohiko Ohta

{"title":"Nuclear PD-L1 triggers tumour-associated inflammation upon DNA damage.","authors":"Naoe T Nihira, Wenwen Wu, Mitsue Hosoi, Yukiko Togashi, Shigeaki Sunada, Yasuo Miyoshi, Yoshio Miki, Tomohiko Ohta","doi":"10.1038/s44319-024-00354-9","DOIUrl":"https://doi.org/10.1038/s44319-024-00354-9","url":null,"abstract":"Immune checkpoint inhibitors against PD-1/PD-L1 are highly effective in immunologically hot tumours such as triple-negative breast cancer, wherein constitutive DNA damage promotes inflammation, while inducing PD-L1 expression to avoid attack by cytotoxic T cells. However, whether and how PD-L1 regulates the DNA damage response and inflammation remains unclear. Here, we show that nuclear PD-L1 activates the ATR-Chk1 pathway and induces proinflammatory chemocytokines upon genotoxic stress. PD-L1 interacts with ATR and is essential for Chk1 activation and chromatin binding. cGAS-STING and NF-κB activation in the late phase of the DNA damage response is inhibited by PD-L1 deletion or by inhibitors of ATR and Chk1. Consequently, the induction of proinflammatory chemocytokines at this stage is inhibited by deletion of PD-L1, but restored by the ATR activator Garcinone C. Inhibition of nuclear localisation by PD-L1 mutations or the HDAC2 inhibitor Santacruzamate A inhibits chemocytokine induction. Conversely, the p300 inhibitor C646, which accelerates PD-L1 nuclear localisation, promotes chemocytokine induction. These findings suggest that nuclear PD-L1 strengthens the properties of hot tumours and contributes to shaping the tumour microenvironment.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921084","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

RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis. RAGE是胆汁淤积期间导管反应介导纤维化的关键调节因子。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-02 DOI: 10.1038/s44319-024-00356-7

Wai-Ling Macrina Lam, Gisela Gabernet, Tanja Poth, Melanie Sator-Schmitt, Morgana Barroso Oquendo, Bettina Kast, Sabrina Lohr, Aurora de Ponti, Lena Weiß, Martin Schneider, Dominic Helm, Karin Müller-Decker, Peter Schirmacher, Mathias Heikenwälder, Ursula Klingmüller, Doris Schneller, Fabian Geisler, Sven Nahnsen, Peter Angel

{"title":"RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis.","authors":"Wai-Ling Macrina Lam, Gisela Gabernet, Tanja Poth, Melanie Sator-Schmitt, Morgana Barroso Oquendo, Bettina Kast, Sabrina Lohr, Aurora de Ponti, Lena Weiß, Martin Schneider, Dominic Helm, Karin Müller-Decker, Peter Schirmacher, Mathias Heikenwälder, Ursula Klingmüller, Doris Schneller, Fabian Geisler, Sven Nahnsen, Peter Angel","doi":"10.1038/s44319-024-00356-7","DOIUrl":"10.1038/s44319-024-00356-7","url":null,"abstract":"Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921113","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

miRNA-target complementarity in cnidarians resembles its counterpart in plants. 刺胞动物中的mirna靶点互补与植物中的mirna靶点互补相似。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-02 DOI: 10.1038/s44319-024-00350-z

Yael Admoni, Arie Fridrich, Paris K Weavers, Reuven Aharoni, Talya Razin, Miguel Salinas-Saavedra, Michal Rabani, Uri Frank, Yehu Moran

{"title":"miRNA-target complementarity in cnidarians resembles its counterpart in plants.","authors":"Yael Admoni, Arie Fridrich, Paris K Weavers, Reuven Aharoni, Talya Razin, Miguel Salinas-Saavedra, Michal Rabani, Uri Frank, Yehu Moran","doi":"10.1038/s44319-024-00350-z","DOIUrl":"https://doi.org/10.1038/s44319-024-00350-z","url":null,"abstract":"microRNAs (miRNAs) are important post-transcriptional regulators that activate silencing mechanisms by annealing to mRNA transcripts. While plant miRNAs match their targets with nearly-full complementarity leading to mRNA cleavage, miRNAs in most animals require only a short sequence called 'seed' to inhibit target translation. Recent findings showed that miRNAs in cnidarians, early-branching metazoans, act similarly to plant miRNAs, by exhibiting full complementarity and target cleavage; however, it remained unknown if seed-based regulation was possible in cnidarians. Here, we investigate the miRNA-target complementarity requirements for miRNA activity in the cnidarian Nematostella vectensis. We show that bilaterian-like complementarity of seed-only or seed and supplementary 3' matches are insufficient for miRNA-mediated knockdown. Furthermore, miRNA-target mismatches in the cleavage site decrease knockdown efficiency. Finally, miRNA silencing of a target with three seed binding sites in the 3' untranslated region that mimics typical miRNA targeting was repressed in zebrafish but not in Nematostella and another cnidarian, Hydractinia symbiolongicarpus. Altogether, these results unravel striking similarities between plant and cnidarian miRNAs supporting a possible common evolutionary origin of miRNAs in plants and animals.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921065","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

The dynamics of loss of heterozygosity events in genomes. 基因组中杂合性事件丢失的动力学。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-02 DOI: 10.1038/s44319-024-00353-w

Abhishek Dutta, Joseph Schacherer

引用次数: 0

Soul Men and Women-what must science do to regain public trust? 灵魂男女--科学必须做些什么才能重新赢得公众的信任？

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1038/s44319-024-00325-0

Arthur Caplan

引用次数: 0

Local translatome sustains synaptic function in impaired Wallerian degeneration. 在沃勒里变性受损的情况下，局部转译体能维持突触功能。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-01 Epub Date: 2024-10-31 DOI: 10.1038/s44319-024-00301-8

Maria Paglione, Leonardo Restivo, Sarah Zakhia, Arnau Llobet Rosell, Marco Terenzio, Lukas J Neukomm

{"title":"Local translatome sustains synaptic function in impaired Wallerian degeneration.","authors":"Maria Paglione, Leonardo Restivo, Sarah Zakhia, Arnau Llobet Rosell, Marco Terenzio, Lukas J Neukomm","doi":"10.1038/s44319-024-00301-8","DOIUrl":"10.1038/s44319-024-00301-8","url":null,"abstract":"After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat overexpression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections 1 week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of the mTORC1 pathway, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca2+ homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"61-83"},"PeriodicalIF":6.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557441","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

BBSome-deficient cells activate intraciliary CDC42 to trigger actin-dependent ciliary ectocytosis. BBSome 缺陷细胞激活睫状体内 CDC42，触发肌动蛋白依赖性睫状体外吞。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-01 Epub Date: 2024-11-25 DOI: 10.1038/s44319-024-00326-z

Avishek Prasai, Olha Ivashchenko, Kristyna Maskova, Sofiia Bykova, Marketa Schmidt Cernohorska, Ondrej Stepanek, Martina Huranova

{"title":"BBSome-deficient cells activate intraciliary CDC42 to trigger actin-dependent ciliary ectocytosis.","authors":"Avishek Prasai, Olha Ivashchenko, Kristyna Maskova, Sofiia Bykova, Marketa Schmidt Cernohorska, Ondrej Stepanek, Martina Huranova","doi":"10.1038/s44319-024-00326-z","DOIUrl":"10.1038/s44319-024-00326-z","url":null,"abstract":"Bardet-Biedl syndrome (BBS) is a pleiotropic ciliopathy caused by dysfunction of the BBSome, a cargo adaptor essential for export of transmembrane receptors from cilia. Although actin-dependent ectocytosis has been proposed to compensate defective cargo retrieval, its molecular basis remains unclear, especially in relation to BBS pathology. In this study, we investigated how actin polymerization and ectocytosis are regulated within the cilium. Our findings reveal that ciliary CDC42, a RHO-family GTPase triggers in situ actin polymerization, ciliary ectocytosis, and cilia shortening in BBSome-deficient cells. Activation of the Sonic Hedgehog pathway further enhances CDC42 activity specifically in BBSome-deficient cilia. Inhibition of CDC42 in BBSome-deficient cells decreases the frequency and duration of ciliary actin polymerization events, causing buildup of G protein coupled receptor 161 (GPR161) in bulges along the axoneme during Sonic Hedgehog signaling. Overall, our study identifies CDC42 as a key trigger of ciliary ectocytosis. Hyperactive ciliary CDC42 and ectocytosis and the resulting loss of ciliary material might contribute to BBS disease severity.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"36-60"},"PeriodicalIF":6.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715673","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 trap of a closed fist : Is democracy capable of preventing a global ecological catastrophe? 握紧拳头的陷阱：民主能够防止全球生态灾难吗？

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-01 Epub Date: 2024-12-12 DOI: 10.1038/s44319-024-00341-0

Vladimir Leksa

引用次数: 0

Experience-driven development of decision-related representations in the auditory cortex. 听觉皮层中决策相关表征的经验驱动发展。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-01 Epub Date: 2024-11-11 DOI: 10.1038/s44319-024-00309-0

Itay Kazanovich, Shir Itzhak, Jennifer Resnik

{"title":"Experience-driven development of decision-related representations in the auditory cortex.","authors":"Itay Kazanovich, Shir Itzhak, Jennifer Resnik","doi":"10.1038/s44319-024-00309-0","DOIUrl":"10.1038/s44319-024-00309-0","url":null,"abstract":"Associating sensory stimuli with behavioral significance induces substantial changes in stimulus representations. Recent studies suggest that primary sensory cortices not only adjust representations of task-relevant stimuli, but actively participate in encoding features of the decision-making process. We sought to determine whether this trait is innate in sensory cortices or if choice representation develops with time and experience. To trace choice representation development, we perform chronic two-photon calcium imaging in the primary auditory cortex of head-fixed mice while they gain experience in a tone detection task with a delayed decision window. Our results reveal a progressive increase in choice-dependent activity within a specific subpopulation of neurons, aligning with growing task familiarity and adapting to changing task rules. Furthermore, task experience correlates with heightened synchronized activity in these populations and the ability to differentiate between different types of behavioral decisions. Notably, the activity of this subpopulation accurately decodes the same action at different task phases. Our findings establish a dynamic restructuring of population activity in the auditory cortex to encode features of the decision-making process that develop over time and refines with experience.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"84-100"},"PeriodicalIF":6.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617010","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