Juan Mo, Corina Anastasaki, Zhiguo Chen, Tracey Shipman, Jason Papke, Kevin Yin, David H Gutmann, Lu Q Le
{"title":"Corrigendum for Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins.","authors":"Juan Mo, Corina Anastasaki, Zhiguo Chen, Tracey Shipman, Jason Papke, Kevin Yin, David H Gutmann, Lu Q Le","doi":"10.1172/JCI199700","DOIUrl":"10.1172/JCI199700","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 20","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12520665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292369","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}
George R Heaton, Xingjian Li, Xianting Li, Xiaoting Zhou, Yuanxi Zhang, Duc Tung Vu, Marc Oeller, Ozge Karayel, Quyen Q Hoang, Meltem Ece Kars, Nitika Kamath, Minghui Wang, Leonid Tarassishin, Matthias Mann, Inga Peter, Zhenyu Yue
{"title":"Targeting specific kinase substrates rescues increased colitis severity induced by the Crohn's disease-linked LRRK2-N2081D variant.","authors":"George R Heaton, Xingjian Li, Xianting Li, Xiaoting Zhou, Yuanxi Zhang, Duc Tung Vu, Marc Oeller, Ozge Karayel, Quyen Q Hoang, Meltem Ece Kars, Nitika Kamath, Minghui Wang, Leonid Tarassishin, Matthias Mann, Inga Peter, Zhenyu Yue","doi":"10.1172/JCI190017","DOIUrl":"10.1172/JCI190017","url":null,"abstract":"<p><p>LRRK2 contains a kinase domain where the N2081D Crohn's disease (CD) risk and the G2019S Parkinson's disease (PD) pathogenic variants are located. It is not clear how the N2081D variant increases CD risk or how these adjacent mutations give rise to distinct disorders. To investigate the pathophysiology of the CD-linked LRRK2 N2081D variant, we generated a knock-in (KI) mouse model and compared its effects with those of the LRRK2-G2019S mutation. Lrrk2N2081D KI mice demonstrated heightened sensitivity to induced colitis, resulting in more severe intestinal damage than in Lrrk2G2019S KI and WT mice. Analysis of colon tissue revealed distinct mutation-dependent LRRK2 RAB substrate phosphorylation, with significantly elevated phosphorylated RAB10 levels in Lrrk2N2081D mice. In cells, we demonstrated that the N2081D mutation activates LRRK2 through a mechanism distinct from that of LRRK2-G2019S. We also found that proinflammatory stimulation enhances LRRK2 kinase activity, leading to mutation-dependent differences in RAB phosphorylation and inflammatory responses in dendritic cells (DCs). Finally, we show that knockout of Rab12, but not pharmacological LRRK2 kinase inhibition, significantly reduced colitis severity in Lrrk2N2081D mice. Our study characterizes the pathogenic mechanisms of LRRK2-linked CD, highlights structural and functional differences between disease-associated LRRK2 variants, and suggests RAB proteins as promising therapeutic targets for modulating LRRK2 activity in CD treatment.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 19","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199624","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}
Bowen Yan, Qingchen Yuan, Marco M Buttigieg, Prabhjot Kaur, Annalisse R McKee, Daniil E Shabashvili, Caitlyn Vlasschaert, Alexander G Bick, Michael J Rauh, Olga A Guryanova
{"title":"Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development in mice.","authors":"Bowen Yan, Qingchen Yuan, Marco M Buttigieg, Prabhjot Kaur, Annalisse R McKee, Daniil E Shabashvili, Caitlyn Vlasschaert, Alexander G Bick, Michael J Rauh, Olga A Guryanova","doi":"10.1172/JCI197100","DOIUrl":"10.1172/JCI197100","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Uju J Okaa, Cleison Ledesma Taira, Lucas Dos Santos Dias, Hannah Dobson, Gregory C Kujoth, Althea Campuzano, E Jane Homan, George R Thompson, Chiung-Yu Hung, George S Deepe, Marcel Wüthrich, Bruce S Klein
{"title":"Endoglucanase-2 (Eng2), a shared immunodominant antigen in dimorphic fungi that elicits immunity during infection.","authors":"Uju J Okaa, Cleison Ledesma Taira, Lucas Dos Santos Dias, Hannah Dobson, Gregory C Kujoth, Althea Campuzano, E Jane Homan, George R Thompson, Chiung-Yu Hung, George S Deepe, Marcel Wüthrich, Bruce S Klein","doi":"10.1172/JCI191103","DOIUrl":"10.1172/JCI191103","url":null,"abstract":"<p><p>Herein, we describe a shared surface and cell wall protein, Endoglucanase 2 (Eng2), expressed on the etiological agents that cause the endemic systemic mycoses of North America - Blastomyces, Coccidioides and Histoplasma. We demonstrate that despite sequence variation of the protein across these related fungi, exposure to Eng2 vaccinates and protects inbred and humanized HLA-DR4 strains of mice against lethal experimental infections with these fungi by eliciting adaptive immunity mediated by CD4 T cells. We also show that CD4 T cell precursors against Eng2 are detectable in naïve individuals and that patients who have recovered from these infections evince a memory and recall CD4 T cell response to Eng2 and its immunodominant epitopes that we have mapped. We create and catalogue new tools and information such as immunodominant peptide epitopes of Eng2 from each fungus recognized by inbred mice and human subjects and we engineer peptide-MHC II tetramers for tracking T cells in inbred and HLA-DR4 humanized mice that will be useful for those who study these infections in mice and humans. Lastly, because most patients demonstrate memory and recall responses against Eng2, our work offers new tools for diagnosis of this collection of infectious diseases across North America.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shenaz Khan, Robert J Gaivin, Zhiyu Liu, Vincent Li, Ivy Samuels, Jinsook Son, Patrick Osei-Owusu, Jeffrey L Garvin, Domenico Accili, Jeffrey R Schelling
{"title":"Fatty acid transport protein-2 inhibition enhances glucose tolerance through α-cell-mediated GLP-1 secretion.","authors":"Shenaz Khan, Robert J Gaivin, Zhiyu Liu, Vincent Li, Ivy Samuels, Jinsook Son, Patrick Osei-Owusu, Jeffrey L Garvin, Domenico Accili, Jeffrey R Schelling","doi":"10.1172/JCI192011","DOIUrl":"10.1172/JCI192011","url":null,"abstract":"<p><p>Type 2 diabetes affects more than 38 million people in the US, and a major complication is kidney disease. During the analysis of lipotoxicity in diabetic kidney disease, global fatty acid transport protein-2 (FATP2) gene deletion was noted to markedly reduce plasma glucose in db/db mice due to sustained insulin secretion. To identify the mechanism, we observed that islet FATP2 expression was restricted to α-cells, and α-cell FATP2 was functional. Basal glucagon and alanine-stimulated gluconeogenesis were reduced in FATP2KO db/db compared to db/db mice. Direct evidence of FATP2KO-induced α-cell-mediated glucagon-like peptide-1 (GLP-1) secretion included increased GLP-1-positive α-cell mass in FATP2KO db/db mice, small molecule FATP2 inhibitor enhancement of GLP-1 secretion in αTC1-6 cells and human islets, and exendin[9-39]-inhibitable insulin secretion in FATP2 inhibitor-treated human islets. FATP2-dependent enteroendocrine GLP-1 secretion was excluded by demonstration of similar glucose tolerance and plasma GLP-1 concentrations in db/db FATP2KO mice following oral versus intraperitoneal glucose loading, non-overlapping FATP2 and preproglucagon mRNA expression, and lack of FATP2/GLP-1 co-immunolocalization in intestine. We conclude that FATP2 deletion or inhibition exerts glucose-lowering effects through α-cell-mediated GLP-1 secretion and paracrine ß-cell insulin release.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Scholten, Lamiaa El-Shennawy, Yuzhi Jia, Youbin Zhang, Elizabeth Hyun, Carolina Reduzzi, Andrew D Hoffmann, Hannah F Almubarak, Fangjia Tong, Nurmaa K Dashzeveg, Yuanfei Sun, Joshua R Squires, Janice Lu, Leonidas C Platanias, Clive H Wasserfall, William J Gradishar, Massimo Cristofanilli, Deyu Fang, Huiping Liu
{"title":"Double-positive T cells form heterotypic clusters with circulating tumor cells to foster cancer metastasis.","authors":"David Scholten, Lamiaa El-Shennawy, Yuzhi Jia, Youbin Zhang, Elizabeth Hyun, Carolina Reduzzi, Andrew D Hoffmann, Hannah F Almubarak, Fangjia Tong, Nurmaa K Dashzeveg, Yuanfei Sun, Joshua R Squires, Janice Lu, Leonidas C Platanias, Clive H Wasserfall, William J Gradishar, Massimo Cristofanilli, Deyu Fang, Huiping Liu","doi":"10.1172/JCI193521","DOIUrl":"10.1172/JCI193521","url":null,"abstract":"<p><p>The immune ecosystem is central to maintaining effective defensive responses. However, it remains largely understudied how immune cells in the peripheral blood interact with circulating tumor cells (CTCs) in metastasis. Here, blood analysis of patients with advanced breast cancer revealed that over 75% of CTC-positive blood specimens contained heterotypic CTC clusters with CD45+ white blood cells (WBCs), which correlates with breast cancer subtypes, racial groups, and decreased survival. CTC-WBC clusters included overrepresented T cells and underrepresented neutrophils. Specifically, a rare subset of CD4 and CD8 double-positive T (DPT) cells was 140-fold enriched in CTC clusters versus their frequency in WBCs. DPT cells shared properties with CD4+ and CD8+ T cells but exhibited unique features of T cell exhaustion and immune suppression. Mechanistically, the integrin heterodimer α4β1, also named very late antigen 4 (VLA-4), in DPT cells and its ligand, VCAM1, in tumor cells are essential mediators of DPT-CTC clusters. Neoadjuvant administration of anti-VLA-4 neutralizing antibodies markedly blocked CTC-DPT clusters, inhibited metastasis, and extended mouse survival. These findings highlight a pivotal role of rare DPT cells in fostering cancer dissemination through CTC clustering. It lays a foundation for developing innovative biomarker-guided therapeutic strategies to prevent and target cancer metastasis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 18","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069524","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}
Haifeng Zhang, Yun He, Shengchuan Dai, Zhe Xu, Yan Luo, Ting Wan, Dianhong Luo, Dennis Jones, Shibo Tang, Hong Chen, William C Sessa, Wang Min
{"title":"Expression of Concern for AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.","authors":"Haifeng Zhang, Yun He, Shengchuan Dai, Zhe Xu, Yan Luo, Ting Wan, Dianhong Luo, Dennis Jones, Shibo Tang, Hong Chen, William C Sessa, Wang Min","doi":"10.1172/JCI198646","DOIUrl":"10.1172/JCI198646","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 18","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069495","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}
Haizhong Feng, Bo Hu, Kun-Wei Liu, Yanxin Li, Xinghua Lu, Tao Cheng, Jia-Jean Yiin, Songjian Lu, Susan Keezer, Tim Fenton, Frank B Furnari, Ronald L Hamilton, Kristiina Vuori, Jann N Sarkaria, Motoo Nagane, Ryo Nishikawa, Webster K Cavenee, Shi-Yuan Cheng
{"title":"Retraction of Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans.","authors":"Haizhong Feng, Bo Hu, Kun-Wei Liu, Yanxin Li, Xinghua Lu, Tao Cheng, Jia-Jean Yiin, Songjian Lu, Susan Keezer, Tim Fenton, Frank B Furnari, Ronald L Hamilton, Kristiina Vuori, Jann N Sarkaria, Motoo Nagane, Ryo Nishikawa, Webster K Cavenee, Shi-Yuan Cheng","doi":"10.1172/JCI198611","DOIUrl":"10.1172/JCI198611","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 18","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069579","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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