Gnana P Krishnamoorthy, Anthony R Glover, Brian R Untch, Nickole Sigcha-Coello, Bin Xu, Dina Vukel, Yi Liu, Vera Tiedje, Jose Mario Bello Pineda, Katherine Berman, Prasanna P Tamarapu, Adrian Acuña-Ruiz, Mahesh Saqcena, Elisa de Stanchina, Laura Boucai, Ronald A Ghossein, Jeffrey A Knauf, Omar Abdel-Wahab, Robert K Bradley, James A Fagin
{"title":"RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs.","authors":"Gnana P Krishnamoorthy, Anthony R Glover, Brian R Untch, Nickole Sigcha-Coello, Bin Xu, Dina Vukel, Yi Liu, Vera Tiedje, Jose Mario Bello Pineda, Katherine Berman, Prasanna P Tamarapu, Adrian Acuña-Ruiz, Mahesh Saqcena, Elisa de Stanchina, Laura Boucai, Ronald A Ghossein, Jeffrey A Knauf, Omar Abdel-Wahab, Robert K Bradley, James A Fagin","doi":"10.1084/jem.20241029","DOIUrl":"10.1084/jem.20241029","url":null,"abstract":"<p><p>RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse HrasG12V/Rbm1OKO thyrocytes develop metastases that are reversed by RBM10 expression or by combined knockdown of VCL, CD44, and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusion in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFκB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction: Lymphatic transport in anti-tumor immunity and metastasis.","authors":"Mengzhu Sun, Julien Angelillo, Stéphanie Hugues","doi":"10.1084/jem.2023195403262025c","DOIUrl":"10.1084/jem.2023195403262025c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elizabeth G Schmitz, Malachi Griffith, Obi L Griffith, Megan A Cooper
{"title":"Identifying genetic errors of immunity due to mosaicism.","authors":"Elizabeth G Schmitz, Malachi Griffith, Obi L Griffith, Megan A Cooper","doi":"10.1084/jem.20241045","DOIUrl":"https://doi.org/10.1084/jem.20241045","url":null,"abstract":"<p><p>Inborn errors of immunity are monogenic disorders of the immune system that lead to immune deficiency and/or dysregulation in patients. Identification of precise genetic causes of disease aids diagnosis and advances our understanding of the human immune system; however, a significant portion of patients lack a molecular diagnosis. Somatic mosaicism, genetic changes in a subset of cells, is emerging as an important mechanism of immune disease in both young and older patients. Here, we review the current landscape of somatic genetic errors of immunity and methods for the detection and validation of somatic variants.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11998702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion.","authors":"Wenxing Qin, Yuran Duan, Zhiqiang Hu, Yueru Hou, Ting Wen, Yuan Ouyang, Zheng Wang, Xue Sun, Xiaohan Chen, Katherine L Wang, Shudi Luo, Guimei Ji, Yuli Shen, Bofei Dong, Yanni Lin, Qi Tian, Zhanpeng Guo, Shiqi Wu, Ling Xiao, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Wuchang Zhang, Shengzhong Duan, Xueli Bai, Tong Liu, Jie He, Zhimin Lu, Daqian Xu","doi":"10.1084/jem.20240902","DOIUrl":"10.1084/jem.20240902","url":null,"abstract":"<p><p>Hypoxia induces immunosuppressive phenotypes in tumor cells even in the presence of cytosolic DNA accumulation. The mechanisms by which tumor cells suppress hypoxia-induced cGAS-STING activation for immune evasion remain largely unclear. Here, we demonstrate that hypoxic stimulation induces JNK1/2-mediated S151 phosphorylation of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis. This phosphorylation triggers the interaction between PCK1 and cGAS. The PCK1 associated with cGAS competitively consumes GTP, a substrate shared by both PCK1 and cGAS. Consequently, PCK1 inhibits GTP-dependent cGAS activation and subsequent STING-promoted immune cell infiltration and activation in the tumor microenvironment, leading to promoted tumor growth in mice. The blockade of PCK1 function, in combination with anti-PD-1 antibody treatment, exhibits an additive therapeutic effect on tumor growth. Additionally, PCK1 S151 phosphorylation is inversely correlated with cGAS-STING activation in human breast cancer specimens and patient survival. These findings reveal a novel regulation of cGAS-STING pathway and uncover the metabolic control of immune response in tumor cells.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An in-depth look at lung lymphatics.","authors":"David G Jackson","doi":"10.1084/jem.20250119","DOIUrl":"10.1084/jem.20250119","url":null,"abstract":"<p><p>In this issue of JEM, Cleary et al. (https://doi.org/10.1084/jem.20241359) present a new intravital imaging technique using a 3D-printed window device that enables lung lymphatics and their participation in immune cell trafficking events to be visualized in action for the first time in mechanically ventilated mice.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Evi Duthoo, Elien Beyls, Lynn Backers, Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere, Sebastian Riemann, Bram Parton, Likun Du, Veronique Debacker, Marieke De Bruyne, Levi Hoste, Ans Baeyens, Anne Vral, Eva Van Braeckel, Jens Staal, Geert Mortier, Tessa Kerre, Qiang Pan-Hammarström, Claus S Sørensen, Filomeen Haerynck, Kathleen B M Claes, Simon J Tavernier
{"title":"Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients.","authors":"Evi Duthoo, Elien Beyls, Lynn Backers, Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere, Sebastian Riemann, Bram Parton, Likun Du, Veronique Debacker, Marieke De Bruyne, Levi Hoste, Ans Baeyens, Anne Vral, Eva Van Braeckel, Jens Staal, Geert Mortier, Tessa Kerre, Qiang Pan-Hammarström, Claus S Sørensen, Filomeen Haerynck, Kathleen B M Claes, Simon J Tavernier","doi":"10.1084/jem.20241432","DOIUrl":"10.1084/jem.20241432","url":null,"abstract":"<p><p>Ataxia telangiectasia and Rad3-related (ATR) kinase and its interacting protein ATRIP orchestrate the replication stress response. Homozygous splice variants in the ATRIP gene, resulting in ATRIP deficiency, were identified in two patients of independent ancestry with microcephaly, primordial dwarfism, and recurrent infections. The c.829+5G>T patient exhibited lymphopenia, poor vaccine responses, autoimmune features with hemolytic anemia, and neutropenia. Immunophenotyping revealed reduced CD16+/CD56dim NK cells and absent naïve T cells, MAIT cells, and iNKT cells. Lymphocytic defects were characterized by TCR oligoclonality, abnormal class switch recombination, and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation under genotoxic stress. ATRIP-deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-SelectTIME confirmed reduced cell fitness for both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP's critical role in protecting immune cells from replication stress, and offers new insights into its canonical functions.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin J Broomfield, Chin Wee Tan, Raymond Z Qin, Hanna Abberger, Brigette C Duckworth, Carolina Alvarado, Lennard Dalit, Chee Leng Lee, Rekha Shandre Mugan, Zihnil A I Mazrad, Hiromi Muramatsu, Liana Mackiewicz, Bailey E Williams, Jinjin Chen, Asuka Takanashi, Stewart Fabb, Marc Pellegrini, Kelly L Rogers, Woohyun J Moon, Colin W Pouton, Melissa J Davis, Stephen L Nutt, Norbert Pardi, Verena C Wimmer, Joanna R Groom
{"title":"Transient inhibition of type I interferon enhances CD8+ T cell stemness and vaccine protection.","authors":"Benjamin J Broomfield, Chin Wee Tan, Raymond Z Qin, Hanna Abberger, Brigette C Duckworth, Carolina Alvarado, Lennard Dalit, Chee Leng Lee, Rekha Shandre Mugan, Zihnil A I Mazrad, Hiromi Muramatsu, Liana Mackiewicz, Bailey E Williams, Jinjin Chen, Asuka Takanashi, Stewart Fabb, Marc Pellegrini, Kelly L Rogers, Woohyun J Moon, Colin W Pouton, Melissa J Davis, Stephen L Nutt, Norbert Pardi, Verena C Wimmer, Joanna R Groom","doi":"10.1084/jem.20241148","DOIUrl":"10.1084/jem.20241148","url":null,"abstract":"<p><p>Developing vaccines that promote CD8+ T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1+ stem cell-like memory CD8+ T (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCM cell formation are unclear. Here, we identify the temporal window for type I interferon receptor (IFNAR) blockade to drive TSCM cell generation following viral infection and mRNA-lipid nanoparticle vaccination. We reveal a reversible developmental trajectory where transcriptionally distinct TSCM cells emerged from a transitional precursor of exhausted T cellular state concomitant with viral clearance. TSCM cell differentiation correlated with T cell retention within the lymph node paracortex due to disrupted CXCR3 chemokine gradient formation. These effects were linked to increased antigen load and a counterintuitive increase in IFNγ, which controlled cell location. Vaccination with the IFNAR blockade promoted TSCM cell differentiation and enhanced protection against chronic infection. These findings propose an approach to vaccine design whereby modulation of inflammation promotes memory formation and function.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A \"second hit\" impacts disease severity in a dominantly inherited genetic skin disorder.","authors":"Pierre A Coulombe","doi":"10.1084/jem.20242377","DOIUrl":"10.1084/jem.20242377","url":null,"abstract":"<p><p>In this issue of JEM, Bergson et al. (https://doi.org/10.1084/jem.20240827) identified variants in HMCN1 that co-segregate with and account for variations in disease severity in individuals with a diagnosis of epidermolysis bullosa simplex (EBS) resulting from pathogenic variants in KRT14. The authors show that hemicentin-1 binds keratin 14 at the protein level and that silencing HMCN1 expression disrupts the organization of K14-containing filaments in epidermal keratinocytes and their attachment to the extracellular matrix. These findings address the clinical heterogeneity observed in EBS, a rare genetic skin disorder, with general implications for all genodermatoses.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KLF2 expression in IgG plasma cells at their induction site regulates the migration program.","authors":"Wataru Ise, Takuya Koike, Nozomi Shimada, Hiromi Yamamoto, Yuki Tai, Taiichiro Shirai, Ryoji Kawakami, Mana Kuwabara, Chie Kawai, Kyoko Shida, Takeshi Inoue, Nozomi Hojo, Kenji Ichiyama, Shimon Sakaguchi, Katsuyuki Shiroguchi, Kazuhiro Suzuki, Tomohiro Kurosaki","doi":"10.1084/jem.20241019","DOIUrl":"10.1084/jem.20241019","url":null,"abstract":"<p><p>Newly generated plasma cells in secondary lymphoid organs migrate to niches in the bone marrow, wherein they survive as long-lived plasma cells (LLPCs). Although LLPCs have been extensively characterized, it is still unclear what the key determinant(s) are for plasma cell longevity. One model postulates that plasma cell heterogeneity is established at the induction site, thereby instructing their longevity. Here, we found that, among newly generated IgG plasma cells, integrin β7hi marks plasma cells predisposed to home to the bone marrow, whereas integrin β7lo cells remain in secondary lymphoid organs. Mechanistically, this egress-prone fraction had a higher expression of the KLF2 transcription factor, the loss of which resulted in defective egress by downregulating S1PR1 and CD11b. Disruption of plasma cell egress results in defective antibody durability, thereby making mice more susceptible to influenza reinfection. Thus, the migration program of plasma cells established at the induction site plays a critical role in determining antibody durability.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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