EMBO Reports最新文献

DYRK4 upregulates antiviral innate immunity by promoting IRF3 activation.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-19 DOI: 10.1038/s44319-024-00352-x

Xianhuang Zeng, Jiaqi Xu, Jiaqi Liu, Yang Liu, Siqi Yang, Junsong Huang, Chengpeng Fan, Mingxiong Guo, Guihong Sun

引用次数: 0

Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-18 DOI: 10.1038/s44319-024-00328-x

Desh Raj, Abhilash Vijay Nair, Anmol Singh, Swarnali Basu, Kabita Sarkar, Jyotsna Sharma, Shiva Sharma, Sanmi Sharma, Manisha Rathore, Shriya Singh, Shakti Prakash, Simran, Shikha Sahu, Aman Chandra Kaushik, Mohammad Imran Siddiqi, Uday C Ghoshal, Tulika Chandra, Vivek Bhosale, Arunava Dasgupta, Shashi Kumar Gupta, Sonia Verma, Rajdeep Guha, Dipshikha Chakravortty, Veena Ammanathan, Amit Lahiri

{"title":"Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol.","authors":"Desh Raj, Abhilash Vijay Nair, Anmol Singh, Swarnali Basu, Kabita Sarkar, Jyotsna Sharma, Shiva Sharma, Sanmi Sharma, Manisha Rathore, Shriya Singh, Shakti Prakash, Simran, Shikha Sahu, Aman Chandra Kaushik, Mohammad Imran Siddiqi, Uday C Ghoshal, Tulika Chandra, Vivek Bhosale, Arunava Dasgupta, Shashi Kumar Gupta, Sonia Verma, Rajdeep Guha, Dipshikha Chakravortty, Veena Ammanathan, Amit Lahiri","doi":"10.1038/s44319-024-00328-x","DOIUrl":"https://doi.org/10.1038/s44319-024-00328-x","url":null,"abstract":"Salmonella enterica serotype Typhimurium (Salmonella) resides and multiplies intracellularly in cholesterol-rich compartments called Salmonella-containing vacuoles (SCVs) with actin-rich tubular extensions known as Salmonella-induced filaments (SIFs). SCV maturation depends on host-derived cholesterol, but the transport mechanism of low-density lipoprotein (LDL)-derived cholesterol to SCVs remains unclear. Here we find that peroxisomes are recruited to SCVs and function as pro-bacterial organelle. The Salmonella effector protein SseI is required for the interaction between peroxisomes and the SCV. SseI contains a variant of the PTS1 peroxisome-targeting sequence, GKM, localizes to the peroxisomes and activates the host Ras GTPase, ADP-ribosylation factor-1 (ARF-1). Activation of ARF-1 leads to the recruitment of phosphatidylinsolitol-5-phosphate-4 kinase and the generation of phosphatidylinsolitol-4-5-bisphosphate on peroxisomes. This enhances the interaction of peroxisomes with lysosomes and allows for the transfer of lysosomal cholesterol to SCVs using peroxisomes as a bridge. Salmonella infection of peroxisome-depleted cells leads to the depletion of cholesterol on the SCVs, resulting in reduced SIF formation and bacterial proliferation. Taken together, our work identified peroxisomes as a target of Salmonella secretory effectors, and as conveyance of host cholesterol to enhance SCV stability, SIF integrity, and intracellular bacterial growth.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853401","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 trap of a closed fist : Is democracy capable of preventing a global ecological catastrophe?

IF 6.5 1区生物学

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

Vladimir Leksa

引用次数: 0

Transposable element activity captures human pluripotent cell states.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-12 DOI: 10.1038/s44319-024-00343-y

Florencia Levin-Ferreyra, Srikanth Kodali, Yingzhi Cui, Alison R S Pashos, Patrizia Pessina, Justin Brumbaugh, Bruno Di Stefano

{"title":"Transposable element activity captures human pluripotent cell states.","authors":"Florencia Levin-Ferreyra, Srikanth Kodali, Yingzhi Cui, Alison R S Pashos, Patrizia Pessina, Justin Brumbaugh, Bruno Di Stefano","doi":"10.1038/s44319-024-00343-y","DOIUrl":"https://doi.org/10.1038/s44319-024-00343-y","url":null,"abstract":"Human pluripotent stem cells (hPSCs) exist in multiple, transcriptionally distinct states and serve as powerful models for studying human development. Despite their significance, the molecular determinants and pathways governing these pluripotent states remain incompletely understood. Here, we demonstrate that transposable elements act as sensitive indicators of distinct pluripotent cell states. We engineered hPSCs with fluorescent reporters to capture the temporal expression dynamics of two state-specific transposable elements, LTR5_Hs, and MER51B. This dual reporter system enables real-time monitoring and isolation of stem cells transitioning from naïve to primed pluripotency and further towards differentiation, serving as a more accurate readout of pluripotency states compared to conventional systems. Unexpectedly, we identified a rare, metastable cell population within primed hPSCs, marked by transcripts related to preimplantation embryo development and which is associated with a DNA damage response. Moreover, our system establishes the chromatin factor NSD1 and the RNA-binding protein FUS as potent molecular safeguards of primed pluripotency. Our study introduces a novel system for investigating cellular potency and provides key insights into the regulation of embryonic development.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817455","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

Cholesterol restriction primes antiviral innate immunity via SREBP1-driven noncanonical type I IFNs.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-12 DOI: 10.1038/s44319-024-00346-9

Tasuku Nishimura, Takahisa Kouwaki, Ken Takashima, Akie Ochi, Yohana S Mtali, Hiroyuki Oshiumi

{"title":"Cholesterol restriction primes antiviral innate immunity via SREBP1-driven noncanonical type I IFNs.","authors":"Tasuku Nishimura, Takahisa Kouwaki, Ken Takashima, Akie Ochi, Yohana S Mtali, Hiroyuki Oshiumi","doi":"10.1038/s44319-024-00346-9","DOIUrl":"https://doi.org/10.1038/s44319-024-00346-9","url":null,"abstract":"Cholesterol metabolism is associated with innate immune responses; however, the underlying mechanism remains unclear. Here, we perform chemical screening to isolate small molecules influencing RIG-I activity, a cytoplasmic viral RNA sensor. We find that statins, which inhibit cholesterol synthesis, dramatically enhance RIG-I-dependent antiviral responses in specific cell types. Since statins exhibit pleiotropic effects on type I interferon (IFN) responses, we further focus on their effects on RIG-I signaling. The restriction of cholesterol synthesis induces expression of noncanonical type I IFNs, such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This pathway subsequently enhances RIG-I-mediated signaling following viral infection. Administration of statins augments RIG-I-dependent cytokine expression in the lungs of mice. Conversely, a mouse obesity model shows a diminished RIG-I response. Single-cell transcriptome analyses reveal a subset of alveolar macrophages that increase RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study reveals SREBP1-mediated noncanonical type I IFN expression, linking cholesterol metabolism and RIG-I signaling.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817451","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

Acquired resistance to PD-L1 inhibition enhances a type I IFN-regulated secretory program in tumors.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-11 DOI: 10.1038/s44319-024-00333-0

Yuhao Shi, Amber McKenery, Melissa Dolan, Michalis Mastri, James W Hill, Adam Dommer, Sebastien Benzekry, Mark Long, Scott I Abrams, Igor Puzanov, John M L Ebos

{"title":"Acquired resistance to PD-L1 inhibition enhances a type I IFN-regulated secretory program in tumors.","authors":"Yuhao Shi, Amber McKenery, Melissa Dolan, Michalis Mastri, James W Hill, Adam Dommer, Sebastien Benzekry, Mark Long, Scott I Abrams, Igor Puzanov, John M L Ebos","doi":"10.1038/s44319-024-00333-0","DOIUrl":"https://doi.org/10.1038/s44319-024-00333-0","url":null,"abstract":"Therapeutic inhibition of programmed cell death ligand (PD-L1) is linked to alterations in interferon (IFN) signaling. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined IFN-related secretory changes in tumor cells following resistance to PD-L1 inhibition. Here we report an anti-PD-L1 treatment-induced secretome (PTIS) in tumor models of acquired resistance that is regulated by type I IFNs. These secretory changes can suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing that tumor-intrinsic treatment adaptations can exert broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth can slow or stop when PTIS components are disrupted individually, or when type I IFN signaling machinery is blocked. Interestingly, genetic and therapeutic disruption of PD-L1 in vitro can only partially recapitulate the PTIS phenotype highlighting the importance of developing in vivo-based resistance models to more faithfully mimic clinically-relevant treatment failure. Together, this study shows acquired resistance to immune-checkpoint inhibitors 'rewires' tumor secretory programs controlled by type I IFNs that, in turn, can protect from immune cell attack.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812339","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

RudLOV is an optically synchronized cargo transport method revealing unexpected effects of dynasore.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-10 DOI: 10.1038/s44319-024-00342-z

Tatsuya Tago, Takumi Ogawa, Yumi Goto, Kiminori Toyooka, Takuro Tojima, Akihiko Nakano, Takunori Satoh, Akiko K Satoh

{"title":"RudLOV is an optically synchronized cargo transport method revealing unexpected effects of dynasore.","authors":"Tatsuya Tago, Takumi Ogawa, Yumi Goto, Kiminori Toyooka, Takuro Tojima, Akihiko Nakano, Takunori Satoh, Akiko K Satoh","doi":"10.1038/s44319-024-00342-z","DOIUrl":"https://doi.org/10.1038/s44319-024-00342-z","url":null,"abstract":"Live imaging of secretory cargoes is a powerful method for understanding the mechanisms of membrane trafficking. Inducing the synchronous release of cargoes from an organelle is key for enhancing microscopic observation. We developed an optical cargo-releasing method, 'retention using dark state of LOV2' (RudLOV), which enables precise spatial, temporal, and quantity control during cargo release. A limited amount of cargo-release using RudLOV is able to visualize cargo cisternal-movement and cargo-specific exit sites on the Golgi/trans-Golgi network. Moreover, by controlling the timing of cargo-release using RudLOV, we reveal the canonical and non-canonical effects of the well-known dynamin inhibitor dynasore, which inhibits early- but not late-Golgi transport and exits from the trans-Golgi network where dynamin-2 is active. Accumulation of COPI vesicles at the cis-side of the Golgi stacks in dynasore-treated cells suggests that dynasore targets COPI-uncoating/tethering/fusion machinery in the early-Golgi cisternae or endoplasmic reticulum but not in the late-Golgi cisternae. These results provide insight into the cisternal maturation of Golgi stacks.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806374","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

Selective cargo and membrane recognition by SNX17 regulates its interaction with Retriever.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-09 DOI: 10.1038/s44319-024-00340-1

Aurora Martín-González, Iván Méndez-Guzmán, Maialen Zabala-Zearreta, Andrea Quintanilla, Arturo García-López, Eva Martínez-Lombardía, David Albesa-Jové, Juan Carlos Acosta, María Lucas

{"title":"Selective cargo and membrane recognition by SNX17 regulates its interaction with Retriever.","authors":"Aurora Martín-González, Iván Méndez-Guzmán, Maialen Zabala-Zearreta, Andrea Quintanilla, Arturo García-López, Eva Martínez-Lombardía, David Albesa-Jové, Juan Carlos Acosta, María Lucas","doi":"10.1038/s44319-024-00340-1","DOIUrl":"https://doi.org/10.1038/s44319-024-00340-1","url":null,"abstract":"The Retriever complex recycles a wide range of transmembrane proteins from endosomes to the plasma membrane. The cargo adapter protein SNX17 has been implicated in recruiting the Retriever complex to endosomal membranes, yet the details of this interaction have remained elusive. Through biophysical and structural model-guided mutagenesis studies with recombinant proteins and liposomes, we have gained a deeper understanding of this process. Here, we demonstrate a direct interaction between SNX17 and Retriever, specifically between the C-terminal region of SNX17 and the interface of the Retriever subunits VPS35L and VPS26C. This interaction is enhanced upon the binding of SNX17 to its cargo in solution, due to the disruption of an intramolecular autoinhibitory interaction between the C-terminal region of SNX17 and the cargo binding pocket. In addition, SNX17 binding to membranes containing phosphatidylinositol-3-phosphate also promotes Retriever recruitment in a cargo-independent manner. Therefore, this work provides evidence of the dual activation mechanisms by which SNX17 modulates Retriever recruitment to the proximity of cargo and membranes, offering significant insights into the regulatory mechanisms of protein recycling at endosomes.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799804","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 role of ER exit sites in maintaining P-body organization and integrity during Drosophila melanogaster oogenesis.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-09 DOI: 10.1038/s44319-024-00344-x

Samantha N Milano, Livia V Bayer, Julie J Ko, Caroline E Casella, Diana P Bratu

{"title":"The role of ER exit sites in maintaining P-body organization and integrity during Drosophila melanogaster oogenesis.","authors":"Samantha N Milano, Livia V Bayer, Julie J Ko, Caroline E Casella, Diana P Bratu","doi":"10.1038/s44319-024-00344-x","DOIUrl":"10.1038/s44319-024-00344-x","url":null,"abstract":"Processing bodies (P-bodies) are cytoplasmic membrane-less organelles which host multiple mRNA processing events. While the fundamental principles of P-body organization are beginning to be elucidated in vitro, a nuanced understanding of how their assembly is regulated in vivo remains elusive. Here, we investigate the potential link between ER exit sites and P-bodies in Drosophila melanogaster egg chambers. Employing a combination of live and super-resolution imaging, we find that P-bodies associated with ER exit sites are larger and less mobile than cytoplasmic P-bodies, indicating that they constitute a distinct class of P-bodies. Moreover, we demonstrate that altering the composition of ER exit sites has differential effects on core P-body proteins (Me31B, Cup, and Trailer Hitch), suggesting a potential role for ER exit sites in P-body organization. Furthermore, we show that in the absence of ER exit sites, P-body integrity is compromised and the stability and translational repression efficiency of the maternal mRNA, oskar, are reduced. Together, our data highlights the crucial role of ER exit sites in governing P-body organization.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799805","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

Rarγ-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-12-04 DOI: 10.1038/s44319-024-00335-y

Dario De Felice, Alessandro Alaimo, Davide Bressan, Sacha Genovesi, Elisa Marmocchi, Nicole Annesi, Giulia Beccaceci, Davide Dalfovo, Federico Cutrupi, Stefano Medaglia, Veronica Foletto, Marco Lorenzoni, Francesco Gandolfi, Srinivasaraghavan Kannan, Chandra S Verma, Alessandro Vasciaveo, Michael M Shen, Alessandro Romanel, Fulvio Chiacchiera, Francesco Cambuli, Andrea Lunardi

{"title":"Rarγ-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer.","authors":"Dario De Felice, Alessandro Alaimo, Davide Bressan, Sacha Genovesi, Elisa Marmocchi, Nicole Annesi, Giulia Beccaceci, Davide Dalfovo, Federico Cutrupi, Stefano Medaglia, Veronica Foletto, Marco Lorenzoni, Francesco Gandolfi, Srinivasaraghavan Kannan, Chandra S Verma, Alessandro Vasciaveo, Michael M Shen, Alessandro Romanel, Fulvio Chiacchiera, Francesco Cambuli, Andrea Lunardi","doi":"10.1038/s44319-024-00335-y","DOIUrl":"10.1038/s44319-024-00335-y","url":null,"abstract":"Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RARγ activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1F254E255 is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779577","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