{"title":"Male sex determination maintains proteostasis and extends lifespan of daf-18/PTEN deficient C. elegans.","authors":"Zhi Qu, Lu Zhang, Xue Yin, Fangzhou Dai, Wei Huang, Yutong Zhang, Dongyang Ran, Shanqing Zheng","doi":"10.1038/s44319-025-00368-x","DOIUrl":"10.1038/s44319-025-00368-x","url":null,"abstract":"<p><p>Although females typically have a survival advantage, those with PTEN functional abnormalities face a higher risk of developing tumors than males. However, the differences in how each sex responds to PTEN dysfunction have rarely been studied. We use Caenorhabditis elegans to investigate how male and hermaphrodite worms respond to dysfunction of the PTEN homolog daf-18. Our study reveals that male worms can counterbalance the negative effects of daf-18 deficiency, resulting in longer adult lifespan. The survival advantage depends on the loss of DAF-18 protein phosphatase activity, while its lipid phosphatase activity is dispensable. The deficiency in DAF-18 protein phosphatase activity leads to the failure of dephosphorylation of the endoplasmic reticulum membrane protein C18E9.2/SEC62, causing increased levels of unfolded and aggregated proteins in hermaphrodites. In contrast, males maintain proteostasis through a UNC-23/NEF-mediated protein ubiquitination and degradation process, providing them with a survival advantage. We find that sex determination is a key factor in regulating the differential expression of unc-23 between sexes in response to daf-18 loss. These findings highlight the unique role of the male sex determination pathway in regulating protein degradation.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1084-1113"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002268","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}
EMBO ReportsPub Date : 2025-02-01Epub Date: 2025-01-02DOI: 10.1038/s44319-024-00347-8
Rebecca Schunk, Marc Halder, Michael Schäfer, Elijah Johannes, Andreas Heim, Andreas Boland, Thomas U Mayer
{"title":"A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I.","authors":"Rebecca Schunk, Marc Halder, Michael Schäfer, Elijah Johannes, Andreas Heim, Andreas Boland, Thomas U Mayer","doi":"10.1038/s44319-024-00347-8","DOIUrl":"10.1038/s44319-024-00347-8","url":null,"abstract":"<p><p>To ensure the correct euploid state of embryos, it is essential that vertebrate oocytes await fertilization arrested at metaphase of meiosis II. This MII arrest is mediated by XErp1/Emi2, which inhibits the ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome). Cyclin B3 in complex with Cdk1 (cyclin-dependent kinase 1) is essential to prevent an untimely arrest of vertebrate oocytes in meiosis I by targeting XErp1/Emi2 for degradation. Yet, the molecular mechanism of XErp1/Emi2 degradation in MI is not well understood. Here, by combining TRIM-Away in oocytes with egg extract and in vitro studies, we demonstrate that a hitherto unknown phosphate-binding pocket in cyclin B3 is essential for efficient XErp1/Emi2 degradation in meiosis I. This pocket enables Cdk1/cyclin B3 to bind pre-phosphorylated XErp1/Emi2 facilitating further phosphorylation events, which ultimately target XErp1/Emi2 for degradation in a Plk1- (Polo-like kinase 1) dependent manner. Key elements of this degradative mechanism are conserved in frog and mouse. Our studies identify a novel, evolutionarily conserved determinant of Cdk/cyclin substrate specificity essential to prevent an untimely oocyte arrest at meiosis I with catastrophic consequences upon fertilization.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"768-790"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920942","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}
{"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":"10.1038/s44319-024-00348-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"791-809"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811033/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-02-01Epub Date: 2025-01-09DOI: 10.1038/s44319-024-00364-7
Yuxiao Wang, Ruei-Zeng Lin, Meghan Harris, Bianca Lavayen, Neha Diwanji, Bruce McCreedy, Robert Hofmeister, Daniel Getts
{"title":"CRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery.","authors":"Yuxiao Wang, Ruei-Zeng Lin, Meghan Harris, Bianca Lavayen, Neha Diwanji, Bruce McCreedy, Robert Hofmeister, Daniel Getts","doi":"10.1038/s44319-024-00364-7","DOIUrl":"10.1038/s44319-024-00364-7","url":null,"abstract":"<p><p>To address a wide range of genetic diseases, genome editing tools that can achieve targeted delivery of large genes without causing double-strand breaks (DSBs) or requiring DNA templates are necessary. Here, we introduce CRISPR-Enabled Autonomous Transposable Element (CREATE), a genome editing system that combines the programmability and precision of CRISPR/Cas9 with the RNA-mediated gene insertion capabilities of the human LINE-1 (L1) element. CREATE employs a modified L1 mRNA to carry a payload gene, and a Cas9 nickase to facilitate targeted editing by L1-mediated reverse transcription and integration without relying on DSBs or DNA templates. Using this system, we demonstrate programmable insertion of a 1.1 kb gene expression cassette into specific genomic loci of human cell lines and primary T cells. Mechanistic studies reveal that CREATE editing is highly specific with no observed off-target events. Together, these findings establish CREATE as a programmable, RNA-based gene delivery technology with broad therapeutic potential.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1062-1083"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946542","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}
EMBO ReportsPub Date : 2025-02-01Epub Date: 2025-01-31DOI: 10.1038/s44319-025-00382-z
David R Smith
{"title":"The ingredients of a great scientific lecture.","authors":"David R Smith","doi":"10.1038/s44319-025-00382-z","DOIUrl":"10.1038/s44319-025-00382-z","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"909-910"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074237","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}
EMBO ReportsPub Date : 2025-02-01DOI: 10.1038/s44319-024-00338-9
Shinichiro Nakada, Ginny I Chen, Anne-Claude Gingras, Daniel Durocher
{"title":"Author Correction: PP4 is a γH2AX phosphatase required for recovery from the DNA damage checkpoint.","authors":"Shinichiro Nakada, Ginny I Chen, Anne-Claude Gingras, Daniel Durocher","doi":"10.1038/s44319-024-00338-9","DOIUrl":"10.1038/s44319-024-00338-9","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1184-1185"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983065","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}
EMBO ReportsPub Date : 2025-02-01Epub Date: 2025-01-03DOI: 10.1038/s44319-024-00339-8
Lisa Leib, Jana Juli, Liane Jurida, Christin Mayr-Buro, Jasmin Priester, Hendrik Weiser, Stefanie Wirth, Simon Hanel, Daniel Heylmann, Axel Weber, M Lienhard Schmitz, Argyris Papantonis, Marek Bartkuhn, Jochen Wilhelm, Uwe Linne, Johanna Meier-Soelch, Michael Kracht
{"title":"The proximity-based protein interactome and regulatory logics of the transcription factor p65 NF-κB/RELA.","authors":"Lisa Leib, Jana Juli, Liane Jurida, Christin Mayr-Buro, Jasmin Priester, Hendrik Weiser, Stefanie Wirth, Simon Hanel, Daniel Heylmann, Axel Weber, M Lienhard Schmitz, Argyris Papantonis, Marek Bartkuhn, Jochen Wilhelm, Uwe Linne, Johanna Meier-Soelch, Michael Kracht","doi":"10.1038/s44319-024-00339-8","DOIUrl":"10.1038/s44319-024-00339-8","url":null,"abstract":"<p><p>The protein interactome of p65/RELA, the most active subunit of the transcription factor (TF) NF-κB, has not been previously determined in living cells. Using p65-miniTurbo fusion proteins and biotin tagging, we identify >350 RELA interactors from untreated and IL-1α-stimulated cells, including many TFs (47% of all interactors) and >50 epigenetic regulators belonging to different classes of chromatin remodeling complexes. A comparison with the interactomes of two point mutants of p65 reveals that the interactions primarily require intact dimerization rather than DNA-binding properties. A targeted RNAi screen for 38 interactors and subsequent functional transcriptome and bioinformatics studies identify gene regulatory (sub)networks, each controlled by RELA in combination with one of the TFs ZBTB5, GLIS2, TFE3/TFEB, or S100A8/A9. The large, dynamic and versatile high-resolution interactome of RELA and its gene regulatory logics provides a rich resource and a new framework for explaining how RELA cooperativity determines gene expression patterns.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1144-1183"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926559","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}
{"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":"10.1038/s44319-024-00354-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"635-655"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811057/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-02-01Epub Date: 2025-01-09DOI: 10.1038/s44319-024-00365-6
Adrian W Hodel, Jesse A Rudd-Schmidt, Tahereh Noori, Christopher J Lupton, Veronica C T Cheuk, Joseph A Trapani, Bart W Hoogenboom, Ilia Voskoboinik
{"title":"Acidic pH can attenuate immune killing through inactivation of perforin.","authors":"Adrian W Hodel, Jesse A Rudd-Schmidt, Tahereh Noori, Christopher J Lupton, Veronica C T Cheuk, Joseph A Trapani, Bart W Hoogenboom, Ilia Voskoboinik","doi":"10.1038/s44319-024-00365-6","DOIUrl":"10.1038/s44319-024-00365-6","url":null,"abstract":"<p><p>Cytotoxic lymphocytes are crucial to our immune system, primarily eliminating virus-infected or cancerous cells via perforin/granzyme killing. Perforin forms transmembrane pores in the plasma membrane, allowing granzymes to enter the target cell cytosol and trigger apoptosis. The prowess of cytotoxic lymphocytes to efficiently eradicate target cells has been widely harnessed in immunotherapies against haematological cancers. Despite efforts to achieve a similar outcome against solid tumours, the immunosuppressive and acidic tumour microenvironment poses a persistent obstacle. Using different types of effector cells, including therapeutically relevant anti-CD19 CAR T cells, we demonstrate that the acidic pH typically found in solid tumours hinders the efficacy of immune therapies by impeding perforin pore formation within the immunological synapse. A nanometre-scale study of purified recombinant perforin undergoing oligomerization reveals that pore formation is inhibited specifically by preventing the formation of a transmembrane β-barrel. The absence of perforin pore formation directly prevents target cell death. This finding uncovers a novel layer of immune effector inhibition that must be considered in the development of effective immunotherapies for solid tumours.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"929-947"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946446","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}
EMBO ReportsPub Date : 2025-02-01Epub Date: 2025-01-09DOI: 10.1038/s44319-024-00361-w
Valeria E Marotta, Dorota Sabat-Pośpiech, Andrew B Fielding, Amy H Ponsford, Amanda Thomaz, Francesca Querques, Mark R Morgan, Ian A Prior, Judy M Coulson
{"title":"OTUD6B regulates KIFC1-dependent centrosome clustering and breast cancer cell survival.","authors":"Valeria E Marotta, Dorota Sabat-Pośpiech, Andrew B Fielding, Amy H Ponsford, Amanda Thomaz, Francesca Querques, Mark R Morgan, Ian A Prior, Judy M Coulson","doi":"10.1038/s44319-024-00361-w","DOIUrl":"10.1038/s44319-024-00361-w","url":null,"abstract":"<p><p>Cancer cells often display centrosome amplification, requiring the kinesin KIFC1/HSET for centrosome clustering to prevent multipolar spindles and cell death. In parallel siRNA screens of deubiquitinase enzymes, we identify OTUD6B as a positive regulator of KIFC1 expression that is required for centrosome clustering in triple-negative breast cancer (TNBC) cells. OTUD6B can localise to centrosomes and the mitotic spindle and interacts with KIFC1. In OTUD6B-deficient cells, we see increased KIFC1 polyubiquitination and premature KIFC1 degradation during mitosis. Depletion of OTUD6B increases multipolar spindles without inducing centrosome amplification. Phenotypic rescue is dependent on OTUD6B catalytic activity and evident upon KIFC1 overexpression. OTUD6B is commonly overexpressed in breast cancer, correlating with KIFC1 protein expression and worse patient survival. TNBC cells with centrosome amplification, but not normal breast epithelial cells, depend on OTUD6B to proliferate. Indeed CRISPR-Cas9 editing results in only OTUD6B<sup>-/+</sup> TNBC cells which fail to divide and die. As a deubiquitinase that supports KIFC1 expression, allowing pseudo-bipolar cell division and survival of cancer cells with centrosome amplification, OTUD6B has potential as a novel target for cancer-specific therapies.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1003-1035"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946543","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}