Journal of Clinical Investigation最新文献

{"title":"Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistant Staphylococcus aureus.","authors":"Robert J Ulrich, Magdalena Podkowik, Rebecca Tierce, Irnov Irnov, Gregory Putzel, Nora M Samhadaneh, Keenan A Lacey, Daiane Boff, Sabrina M Morales, Sohei Makita, Theodora K Karagounis, Erin E Zwack, Chunyi Zhou, Randie H Kim, Karl Drlica, Alejandro Pironti, Harm van Bakel, Victor J Torres, Bo Shopsin","doi":"10.1172/JCI177872","DOIUrl":"10.1172/JCI177872","url":null,"abstract":"<p><p>We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present study shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA's role in biofilm formation. Collectively, these data reveal a critical mechanism - epigenetic regulation of staphylococcal gene expression - by which phage can regulate virulence to drive adaptive leaps by S. aureus.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698691","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":"CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models.","authors":"Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K Gurkan, Stephanie J Miner, Dan R Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M Chinnaiyan","doi":"10.1172/JCI193745","DOIUrl":"10.1172/JCI193745","url":null,"abstract":"<p><p>Inactivation of cyclin-dependent kinase 12 (CDK12) defines an immunogenic molecular subtype of prostate cancer characterized by genomic instability and increased intratumoral T cell infiltration. This study revealed that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis showed that reduced CDK12/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12/13 depletion or targeted degradation induced cytosolic nucleic acid release, triggering STING pathway activation. CDK12/13 degradation delayed tumor growth and synergized with anti-PD-1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8+ T cell infiltration and activation within tumors. Notably, the antitumor effects of this combination required STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12-mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate antitumor immunity and potentiate responses to immunotherapies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 18","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069560","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":"Aggressive B cell lymphomas retain ATR-dependent determinants of T cell exclusion from the germinal center dark zone.","authors":"Valeria Cancila, Giorgio Bertolazzi, Allison Sy Chan, Giovanni Medico, Giulia Bastianello, Gaia Morello, Daniel Paysan, Clemence Lai, Liang Hong, Girija Shenoy, Patrick W Jaynes, Giovanna Schiavoni, Fabrizio Mattei, Silvia Piconese, Maria V Revuelta, Francesco Noto, Luca Businaro, Adele De Ninno, Ilenia Cammarata, Fabio Pagni, Saradha Venkatachalapathy, Sabina Sangaletti, Arianna Di Napoli, Giada Cicio, Davide Vacca, Silvia Lonardi, Luisa Lorenzi, Andrés Jm Ferreri, Beatrice Belmonte, Min Liu, Manikandan Lakshmanan, Michelle Sn Ong, Biyan Zhang, Tingyi See, Kong-Peng Lam, Gabriele Varano, Mario P Colombo, Silvio Bicciato, Giorgio Inghirami, Leandro Cerchietti, Maurilio Ponzoni, Roberta Zappasodi, Evelyn Metzger, Joseph Beechem, Fabio Facchetti, Marco Foiani, Stefano Casola, Anand D Jeyasekharan, Claudio Tripodo","doi":"10.1172/JCI187371","DOIUrl":"10.1172/JCI187371","url":null,"abstract":"<p><p>The germinal center (GC) dark zone (DZ) and light zone represent distinct anatomical regions in lymphoid tissue where B cell proliferation, immunoglobulin diversification, and selection are coordinated. Diffuse large B cell lymphomas (DLBCLs) with DZ-like gene expression profiles exhibit poor outcomes, though the reasons are unclear and are not directly related to proliferation. Physiological DZs exhibit an exclusion of T cells, prompting exploration of whether T cell paucity contributes to DZ-like DLBCL. We used spatial transcriptomic approaches to achieve higher resolution of T cell spatial heterogeneity in the GC and to derive potential pathways that underlie T cell exclusion. We showed that T cell exclusion from the DZ was linked to DNA damage response (DDR) and chromatin compaction molecular features characterizing the spatial DZ signature, and that these programs were independent of activation-induced cytidine deaminase (AID) activity. As ATR is a key regulator of DDR, we tested its role in the T cell inhibitory DZ transcriptional imprint. ATR inhibition reversed not only the DZ transcriptional signature, but also DZ T cell exclusion in DZ-like DLBCL in vitro microfluidic models and in in vivo samples of murine lymphoid tissue. These findings highlight that ATR activity underpins a physiological scenario of immune silencing. ATR inhibition may reverse the immune-silent state and enhance T cell-based immunotherapy in aggressive lymphomas with GC DZ-like characteristics.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659361","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":"Are you listening?","authors":"Amanda N Pinski","doi":"10.1172/JCI196864","DOIUrl":"10.1172/JCI196864","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 14","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637097","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":"Corrigendum to STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice.","authors":"Zan Huang, Terri D Richmond, Andrew G Muntean, Dwayne L Barber, Mitchell J Weiss, John D Crispino","doi":"10.1172/JCI195974","DOIUrl":"10.1172/JCI195974","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 14","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637099","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":"Sending science down yonder.","authors":"Anna Bright","doi":"10.1172/JCI196866","DOIUrl":"10.1172/JCI196866","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 14","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637100","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":"Corrigendum to Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma.","authors":"Ravi K Amaravadi, Duonan Yu, Julian J Lum, Thi Bui, Maria A Christophorou, Gerard I Evan, Andrei Thomas-Tikhonenko, Craig B Thompson","doi":"10.1172/JCI195984","DOIUrl":"10.1172/JCI195984","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 14","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637098","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":"Cyclin D1 overexpression induces replication stress and microhomology-mediated end-joining dependence in mantle cell lymphoma.","authors":"Jithma P Abeykoon, Shuhei Asada, Guangli Zhu, Yuna Hirohashi, Lisa Moreau, Divya Iyer, Sirisha Mukkavalli, Kalindi Parmar, Gabriella Zambrano, Lige Jiang, Dongni Yi, Michelle Manske, Kimberly Gwin, Rebecca L King, James R Cerhan, Xiaosheng Wu, Zhenkun Lou, Geoffrey I Shapiro, Thomas Witzig, Alan D'Andrea","doi":"10.1172/JCI193006","DOIUrl":"10.1172/JCI193006","url":null,"abstract":"<p><p>Oncogene expression can cause replication stress (RS), leading to DNA double-strand breaks (DSBs) that require repair through pathways such as homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining (MMEJ). Cyclin D1 (encoded by CCND1) is a well-known oncoprotein overexpressed in cancer; however, its role in RS is unknown. Using mantle cell lymphoma (MCL) as a naturally occurring model of cyclin D1 overexpression, we examined the impact of cyclin D1 on RS and DSB repair mechanisms. Cyclin D1 overexpression elevated RS, increased DNA damage, especially during mitosis, and caused specific upregulation of MMEJ. Furthermore, cyclin D1 activated polymerase theta (POLQ) transcription by binding its promoter loci, driving POLΘ-mediated MMEJ that is essential to withstand cyclin D1-induced RS. Moreover, concurrent ATM deficiency further intensified RS, enhanced POLQ expression, and heightened reliance on MMEJ-mediated DNA damage repair. Consequently, inhibition of POLΘ in cyclin D1-overexpressed settings further exacerbated RS, causing single-strand DNA gap accumulations and chromosomal instability, ultimately leading to apoptosis, an effect amplified in ATM-deficient cells. Targeting MMEJ via POLΘ inhibition is therefore an effective strategy in the context of cyclin D1 overexpression and ATM deficiency and may provide a unique therapeutic approach for treating MCL and other malignancies characterized by similar alterations.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560206","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":"Tumoral RCOR2 promotes tumor development through dual epigenetic regulation of tumor plasticity and immunogenicity.","authors":"Lei Bao, Ming Zhu, Maowu Luo, Ashwani Kumar, Yan Peng, Chao Xing, Yingfei Wang, Weibo Luo","doi":"10.1172/JCI188801","DOIUrl":"10.1172/JCI188801","url":null,"abstract":"<p><p>Gain of plasticity and loss of MHC-II enable tumor cells to evade immune surveillance, contributing to tumor development. Here, we showed that the transcriptional corepressor RCOR2 is a key factor that integrates two epigenetic programs surveilling tumor plasticity and immunogenicity. RCOR2 was upregulated predominantly in tumor cells and promoted tumor development in mice through reducing tumor cell death by CD4+CD8+ T cells and inducing cancer stemness. Mechanistically, RCOR2 repressed RNF43 expression through LSD1-mediated demethylation of histone H3 at lysine 4 to induce activation of Wnt/β-catenin and tumor stemness. Simultaneously, RCOR2 inhibited CIITA expression through HDAC1/2-mediated deacetylation of histone H4 at lysine 16, leading to MHC-II silencing in tumor cells and subsequent impairment of CD4+CD8+ T cell immunosurveillance, thereby promoting immune evasion. RCOR2 loss potentiated anti-PD-1 therapy in mouse models of cancer and correlated with better response to anti-PD-1 therapy in human patients. Collectively, these findings uncover a \"two birds with one stone\" effect for RCOR2, highlighting its potential as a valuable target for improved cancer therapy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560261","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":"SPNS1 variants cause multiorgan disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis.","authors":"Menglan He, Mei Ding, Michaela Chocholouskova, Cheen Fei Chin, Martin Engvall, Helena Malmgren, Matias Wagner, Marlen C Lauffer, Jacob Heisinger, May Christine V Malicdan, Valerie Allamand, Madeleine Durbeej, Angelica Delgado Vega, Thomas Sejersen, Ann Nordgren, Federico Torta, David L Silver","doi":"10.1172/JCI193099","DOIUrl":"10.1172/JCI193099","url":null,"abstract":"<p><p>SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids, the degradative products of lysosomal phospholipid catabolism. However, an understanding of the role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking. Here, we identified members of 2 families with biallelic SPNS1 loss-of-function variants, who presented primarily with progressive liver and striated muscle injury. Patients' fibroblasts accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens. Notably, SPNS1 deficiency resulted in reduced biogenesis of cytosolic lipid droplets containing triglycerides and cholesteryl esters. Mechanistically, we found that lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis, whereas lysosomal buildup of lyso-ether-phospholipid inhibited lysosomal cholesterol egress, effects that were enhanced with inhibition of mTOR. These findings support a gene-disease association and reveal connectivity between lysosomal transport of lysophospholipids and storage of reserve cellular energy as triglycerides and the regulation of cholesterol homeostasis, processes that become important under nutrient limitation.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560260","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}