{"title":"Overcoming NK-mediated rejection by anti-3<sup>rd</sup>-party central memory veto CD8 T cells through downregulation of DNAM-1 on alloreactive NK cells.","authors":"Wei-Hsin Liu, Aloukick Kumar Singh, Christa Blagdon, Sandeep Kumar Yadav, Einav Shoshan, Esther Bachar-Lustig, Yair Reisner","doi":"10.1016/j.celrep.2025.115674","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115674","url":null,"abstract":"<p><p>Anti-3<sup>rd</sup>-party central memory veto CD8 T (veto Tcm) cells can overcome T cell-mediated graft rejection under mild conditioning without causing significant graft versus host disease (GVHD). We previously demonstrated that these veto Tcm cells can effectively delete anti-donor T cell clones through a Fas-FasL mechanism, whereas their ability to neutralize alloreactive natural killer (NK) cells and the mechanism of such potential activity remained unknown. Using \"nude\" mice as recipients of allogeneic T cell-depleted hematopoietic stem cell transplantation (HSCT), we demonstrate effective inhibition of NK-mediated rejection by Tcm cells. Ex vivo studies revealed that Tcm cells express high levels of CD155, the ligand of the activating receptor DNAX accessory molecule-1 (DNAM-1). Conjugate formation between alloreactive NK cells and the veto cells induces NK anergy through a unique mechanism mediated by DNAM-1 internalization and degradation. These insights on veto Tcm cells and their impact on alloreactive NK cells offer potential translational approaches for haploidentical bone marrow transplantation and off-the-shelf chimeric antigen receptor (CAR) cell therapies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115674"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967634","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}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115682
Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu
{"title":"Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.","authors":"Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu","doi":"10.1016/j.celrep.2025.115682","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115682","url":null,"abstract":"<p><p>The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115682"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954899","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}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115687
Elizabeth Abraham, Aleksandra Kostina, Brett Volmert, Thomas Roule, Ling Huang, Jingting Yu, April E Williams, Emily Megill, Aidan Douglas, Olivia M Pericak, Alex Morris, Eleonora Stronati, Arantza Larrinaga-Zamanillo, Raquel Fueyo, Mikel Zubillaga, Mark D Andrake, Naiara Akizu, Aitor Aguirre, Conchi Estaras
{"title":"A retinoic acid:YAP1 signaling axis controls atrial lineage commitment.","authors":"Elizabeth Abraham, Aleksandra Kostina, Brett Volmert, Thomas Roule, Ling Huang, Jingting Yu, April E Williams, Emily Megill, Aidan Douglas, Olivia M Pericak, Alex Morris, Eleonora Stronati, Arantza Larrinaga-Zamanillo, Raquel Fueyo, Mikel Zubillaga, Mark D Andrake, Naiara Akizu, Aitor Aguirre, Conchi Estaras","doi":"10.1016/j.celrep.2025.115687","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115687","url":null,"abstract":"<p><p>In cardiac progenitor cells (CPCs), retinoic acid (RA) signaling induces atrial lineage gene expression and acquisition of an atrial cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (i.e., scRNA-seq and snATAC-seq) to untreated and RA-treated human embryonic stem cell (hESC)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP1 and TEAD4 are integrated with the atrial transcription factor enhancer network and that YAP1 activates RA enhancers in CPCs. Furthermore, Yap1 deletion in mouse embryos compromises the expression of RA-induced genes, such as Nr2f2, in the CPCs of the second heart field. Accordingly, in hESC-derived patterned heart organoids, YAP1 regulates the formation of an atrial chamber but is dispensable for the formation of a ventricle. Overall, our findings revealed that YAP1 cooperates with RA signaling to induce atrial lineages during cardiogenesis.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115687"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987049","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}
{"title":"The m<sup><sup>5</sup></sup>C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.","authors":"Songyu Li, Ya Liu, Xiang Wu, Minjia Pan, Hongxia Zhao, Yunguang Hong, Qinghua Zhang, Shushu Hu, Aorong Ouyang, Guangru Li, Minhui Wu, Shanshan Fan, Zhirong Jia, Shanchao Zhao, Guocai Wu, Xiangwei Gao, Zhigang Yang, Zhanghui Chen","doi":"10.1016/j.celrep.2025.115661","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115661","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is one of the most prevalent heterogeneous hematologic malignancies with a complicated etiology. RNA post-transcriptional modifications have been linked to the incidence and progression of AML, while the detailed mechanism remains to be elucidated. In this study, we find that NOP2/Sun domain family member 2 (NSUN2), a methyltransferase of 5-methylcytosine (m<sup><sup>5</sup></sup>C) RNA methylation, is upregulated in AML and predicts a poor prognosis for patients with AML. Knockdown of NSUN2 in AML cells inhibits proliferation and colony formation and promotes apoptosis. Depletion of NSUN2 in AML mice reduces the tumor burden and prolongs survival. Mechanistically, NSUN2 promotes the expression of phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase 2 (SHMT2), two key enzymes in the serine/glycine biosynthesis pathway, by stabilizing the corresponding mRNAs through regulation of m<sup>5</sup>C modifications. Overall, our findings demonstrate a critical role of NSUN2 in AML development and highlight the therapeutic potential of targeting the NSUN2/m<sup><sup>5</sup></sup>C axis for the treatment of this cancer.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115661"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968447","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}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115671
Ludovic Zimmerlin, Ariana Angarita, Tea Soon Park, Rebecca Evans-Moses, Justin Thomas, Sirui Yan, Isabel Uribe, Isabella Vegas, Clara Kochendoerfer, Willem Buys, Anthony K L Leung, Elias T Zambidis
{"title":"Proteogenomic reprogramming to a functional human blastomere-like stem cell state via a PARP-DUX4 regulatory axis.","authors":"Ludovic Zimmerlin, Ariana Angarita, Tea Soon Park, Rebecca Evans-Moses, Justin Thomas, Sirui Yan, Isabel Uribe, Isabella Vegas, Clara Kochendoerfer, Willem Buys, Anthony K L Leung, Elias T Zambidis","doi":"10.1016/j.celrep.2025.115671","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115671","url":null,"abstract":"<p><p>Here, we show that conventional human pluripotent stem cells cultured with non-specific tankyrase-PARP1-inhibited conditions underwent proteogenomic reprogramming to functional blastomere-like tankyrase/PARP inhibitor-regulated naive stem cells (TIRN-SC). TIRN-SCs concurrently expressed hundreds of pioneer factors in hybrid 2C-8C-morula-ICM programs that were augmented by induced expression of DUX4. Injection of TIRN-SCs into 8C-staged murine embryos equipotently differentiated human cells to the extra-embryonic and embryonic compartments of chimeric blastocysts and fetuses. Ectopic expression of murine-E-Cadherin in TIRN-SCs further enhanced interspecific chimeric tissue targeting. TIRN-SC-derived trophoblast stem cells efficiently generated placental chimeras. Proteome-ubiquitinome analyses revealed increased TNKS and reduced PARP1 levels and an ADP-ribosylation-deficient, hyper-ubiquitinated proteome that impacted expression of both tankyrase and PARP1 substrates. ChIP-seq of NANOG-SOX2-OCT4 and PARP1 (NSOP) revealed genome-wide NSOP co-binding at DUX4-accessible enhancers of embryonic lineage factors; suggesting a DUX4-NSOP axis regulated TIRN-SC lineage plasticity. TIRN-SCs may serve as valuable models for studying the proteogenomic regulation of pre-lineage human embryogenesis. VIDEO ABSTRACT.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115671"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986114","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}
Cell reportsPub Date : 2025-05-06DOI: 10.1016/j.celrep.2025.115676
Alan M Elder, Heather R Fairchild, Kelsey T Kines, Lauren M Cozzens, Alexandria R Becks, Jill E Slansky, Steven M Anderson, Traci R Lyons
{"title":"Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer.","authors":"Alan M Elder, Heather R Fairchild, Kelsey T Kines, Lauren M Cozzens, Alexandria R Becks, Jill E Slansky, Steven M Anderson, Traci R Lyons","doi":"10.1016/j.celrep.2025.115676","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115676","url":null,"abstract":"<p><p>Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of cell death and inflammation. Here, we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to αPD-1/αPD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody reduces tumor growth and/or promotes complete regression of mouse mammary tumors, reduces some immunosuppressive phenotypes in the tumor microenvironment, and restores cytotoxic T cells, suggesting that SEMA7A may be a candidate for immune-based therapy for breast cancer patients.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115676"},"PeriodicalIF":7.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965891","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}
{"title":"OTUD4 inhibits ferroptosis by stabilizing GPX4 and suppressing autophagic degradation to promote tumor progression.","authors":"Jinglian Chen, Chengqing Huang, Jiale Mei, Qiuhua Lin, Wenbo Chen, Jiali Tang, Xinjie Wei, Caixia Mo, Yueyan Zhang, Qi Zeng, Xianwei Mo, Weizhong Tang, Tao Luo","doi":"10.1016/j.celrep.2025.115681","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115681","url":null,"abstract":"<p><p>Ferroptosis, a regulated cell demise predicated on iron metabolism and lipid peroxidation, has increasingly become a focal point in oncological therapies. Nonetheless, its governance, particularly the role of deubiquitination, is not fully delineated. This investigation concentrates on the deubiquitinase OTUD4, scrutinizing its functional and molecular implications in ferroptosis within tumor cells. By engineering OTUD4 knockout cell lines via CRISPR-Cas9, we observed that these cells exhibit heightened sensitivity to ferroptosis inducers, augmenting ferroptotic cell death and robustly diminishing tumor growth both in vitro and in vivo. Mechanistically, OTUD4 not only sustains protein stability by directly deubiquitinating GPX4 but also impedes its degradation via RHEB-mediated autophagy, collectively stalling the ferroptosis pathway. In vivo assays substantiate that OTUD4 deletion, when combined with regorafenib, drastically reduces tumor proliferation, showcasing potent synergistic antitumor activity. This study pioneers the revelation of OTUD4's bifunctional role in modulating ferroptosis through deubiquitination and autophagy, underscoring its potential as a therapeutic target in oncology.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115681"},"PeriodicalIF":7.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984668","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}
Cell reportsPub Date : 2025-05-06DOI: 10.1016/j.celrep.2025.115656
Hyeji Jung, Byeongchan Kim, Gyubin Jang, Hyeonho Kim, Ae-Ree Lee, Sung-Hyun Yoon, Kyung-Seo Lee, Gaeun Hyun, Younghye Kim, Jaewon Ko, Je-Wook Yu, Ji Won Um
{"title":"The NLRP3 inflammasome in microglia regulates repetitive behavior by modulating NMDA glutamate receptor functions.","authors":"Hyeji Jung, Byeongchan Kim, Gyubin Jang, Hyeonho Kim, Ae-Ree Lee, Sung-Hyun Yoon, Kyung-Seo Lee, Gaeun Hyun, Younghye Kim, Jaewon Ko, Je-Wook Yu, Ji Won Um","doi":"10.1016/j.celrep.2025.115656","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115656","url":null,"abstract":"<p><p>Neuroinflammation is a well-established risk factor for various neurological disorders and cognitive decline. However, the precise molecular mechanisms linking inflammation with neuropsychiatric symptoms remain unclear. Here, using NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) conditional knockin (cKI) mice harboring a D301N point mutation originating in patients with autoinflammatory diseases, we found that activation of the NLRP3 inflammasome by administration of lipopolysaccharide induced anxiety-like and repetitive behaviors frequently found in patients with neuropsychiatric disorders, as well as increasing NMDAR (N-methyl-D-aspartate receptor)-mediated excitatory synaptic functions in the medial prefrontal cortex of mice. In addition, interleukin 1β (IL-1β), a downstream cytokine of the NLRP3 inflammasome, enhanced NMDAR activation and increased surface levels of the selective NMDAR subunit GluN2A in cultured cortical neurons. Strikingly, treatment with an NMDAR antagonist or IL-1 receptor antagonist completely normalized the specific behavioral deficits in Nlrp3<sup>D301N</sup>-cKI mice. Collectively, our results demonstrate that NLRP3-mediated neuroinflammation elicits repetitive behavior through impaired NMDAR functions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115656"},"PeriodicalIF":7.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976255","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}
Cell reportsPub Date : 2025-05-06DOI: 10.1016/j.celrep.2025.115670
Sanziana Rotariu, Gisela Zalcman, Nagham Badreddine, Florence Appaix, Stefania Sarno, Ingrid Bureau, Elodie Fino
{"title":"Somatostatin interneurons select dorsomedial striatal representations of the initial motor learning phase.","authors":"Sanziana Rotariu, Gisela Zalcman, Nagham Badreddine, Florence Appaix, Stefania Sarno, Ingrid Bureau, Elodie Fino","doi":"10.1016/j.celrep.2025.115670","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115670","url":null,"abstract":"<p><p>The dorsomedial striatum (DMS) is an associative node involved in the initial formation of motor sequences and the adaptation of ongoing actions. During early associative or motor learning tasks, DMS shows a global reduction of activity, eventually refining a subset of active neurons whose number correlates with animal performance. Understanding how this representation emerges is crucial to deciphering the plasticity mechanisms underlying early phases of learning. Here, we propose that local inhibitory interneurons shape early DMS representation and influence task performance. We report that the selective manipulation of somatostatin (SOM)-positive interneurons disrupts DMS activity reorganization and modulates early-learning performance. This effect is cell specific, as manipulation of parvalbumin-positive interneurons has no effect. We also identify the high plasticity of SOM-mediated feedforward inhibition as a critical modulator of striatal projection neuron firing activity. Hence, SOM interneurons are key DMS circuit organizers and set the pace of early learning.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115670"},"PeriodicalIF":7.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981220","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}
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