The Journal of Clinical Investigation最新文献

{"title":"EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis","authors":"Haizhong Feng, Giselle Y. Lopez, Chung Kwon Kim, Angel Alvarez, Christopher G. Duncan, Ryo Nishikawa, Motoo Nagane, An-Jey A. Su, Philip E. Auron, Matthew L. Hedberg, Lin Wang, Jeffery J. Raizer, John A. Kessler, Andrew T. Parsa, Wei-Qiang Gao, Sung-Hak Kim, Mutsuko Minata, Ichiro Nakano, Jennifer R. Grandis, Roger E. McLendon, Darell D. Bigner, Hui-Kuan Lin, Frank B. Furnari, Webster K. Cavenee, Bo Hu, Hai Yan, Shi-Yuan Cheng","doi":"10.1172/jci194718","DOIUrl":"https://doi.org/10.1172/jci194718","url":null,"abstract":"<h5 style=\"display: inline-block;\">EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis</h5>\u0000Haizhong Feng, … , Hai Yan, Shi-Yuan Cheng\u0000Haizhong Feng, … , Hai Yan, Shi-Yuan Cheng <span>\u0000Research Article\u0000</span><span>\u0000Oncology\u0000</span><span data-badge-popover=\"bottom\" data-badge-type=\"2\" data-doi=\"10.1172/JCI73093\" data-hide-no-mentions=\"true\"></span>","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinoma","authors":"Weiyun Li, Jun Xiao, Xin Zhou, Ming Xu, Chaobo Hu, Xiaoyan Xu, Yao Lu, Chang Liu, Shengjie Xue, Lei Nie, Haibin Zhang, Zhiqi Li, Yanbo Zhang, Fu Ji, Lijian Hui, Wufan Tao, Bin Wei, Hongyan Wang","doi":"10.1172/jci193453","DOIUrl":"https://doi.org/10.1172/jci193453","url":null,"abstract":"<h5 style=\"display: inline-block;\">STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinoma</h5>\u0000Weiyun Li, … , Bin Wei, Hongyan Wang\u0000Weiyun Li, … , Bin Wei, Hongyan Wang <span>\u0000Research Article\u0000</span><span>\u0000Oncology\u0000</span><span data-badge-popover=\"bottom\" data-badge-type=\"2\" data-doi=\"10.1172/JCI81203\" data-hide-no-mentions=\"true\"></span>","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy","authors":"Rocio Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, Sara K. Pittman, Jil A.W. Daw, Jason E. Gestwicki, Heather L. True, Conrad C. Weihl","doi":"10.1172/jci194757","DOIUrl":"https://doi.org/10.1172/jci194757","url":null,"abstract":"<h5 style=\"display: inline-block;\">Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy</h5>\u0000Rocio Bengoechea, … , Heather L. True, Conrad C. Weihl\u0000Rocio Bengoechea, … , Heather L. True, Conrad C. Weihl <span>\u0000Research Article\u0000</span><span>\u0000Cell biology\u0000</span><span>\u0000Muscle biology\u0000</span><span data-badge-popover=\"bottom\" data-badge-type=\"2\" data-doi=\"10.1172/JCI136167\" data-hide-no-mentions=\"true\"></span>","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"152 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders","authors":"Xiuying Bai, Dengshun Miao, Sophia Xiao, Dinghong Qiu, René St-Arnaud, Martin Petkovich, Ajay Gupta, David Goltzman, Andrew C. Karaplis","doi":"10.1172/jci193400","DOIUrl":"https://doi.org/10.1172/jci193400","url":null,"abstract":"<h5 style=\"display: inline-block;\">CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders</h5>\u0000Xiuying Bai, … , David Goltzman, Andrew C. Karaplis\u0000Xiuying Bai, … , David Goltzman, Andrew C. Karaplis <span>\u0000Research Article\u0000</span><span>\u0000Endocrinology\u0000</span><span data-badge-popover=\"bottom\" data-badge-type=\"2\" data-doi=\"10.1172/JCI81928\" data-hide-no-mentions=\"true\"></span>","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virus-associated inflammation imprints an inflammatory profile on monocyte-derived macrophages in the human liver","authors":"Juan Diego Sanchez Vasquez, Shirin Nkongolo, Daniel Traum, Valentin Sotov, Samuel C. Kim, Deeqa Mahamed, Aman Mehrotra, Anjali Patel, Diana Y. Chen, Scott Fung, Anuj Gaggar, Jordan J. Feld, Kyong-Mi Chang, Jeffrey J. Wallin, Ben X. Wang, Harry L.A. Janssen, Adam J. Gehring","doi":"10.1172/jci175241","DOIUrl":"https://doi.org/10.1172/jci175241","url":null,"abstract":"Chronic liver injury triggers the activation and recruitment of immune cells, causing antigen-independent tissue damage and liver disease progression. Tissue inflammation can reshape macrophage composition through monocyte replacement. Replacement of tissue macrophages with monocytes differentiating in an inflammatory environment can potentially imprint a phenotype that switches the liver from an immune-tolerant organ to one predisposed to tissue damage. We longitudinally sampled the liver of patients with chronic hepatitis B who had active liver inflammation and were starting antiviral therapy. Antiviral therapy suppressed viral replication and liver inflammation, which coincided with decreased myeloid activation markers. Single-cell RNA-Seq mapped peripheral inflammatory markers to a monocyte-derived macrophage population, distinct from Kupffer cells, with an inflammatory transcriptional profile. The inflammatory macrophages (iMacs) differentiated from blood monocytes and were unique from macrophage found in healthy or cirrhotic liver. iMacs retained their core transcriptional signature after inflammation resolved, indicating inflammation-mediated remodeling of the macrophage population in the human liver that may affect progressive liver disease and immunotherapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria","authors":"Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel","doi":"10.1172/jci182467","DOIUrl":"https://doi.org/10.1172/jci182467","url":null,"abstract":"Plasmacytoid dendritic cells (pDCs), professional type I IFN–producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated, and the operating molecular mechanisms are unknown. Certain signaling lymphocyte activation molecule family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here, human blood transcriptomic analyses reveal the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. They activate pDC maturation and cytokine production during infection with bacteria that induce acute (<i>Salmonella</i>) or chronic (<i>Brucella</i>) inflammation. SLAMF7 and SLAMF8 signal through NF-κB, IRF7, and STAT-1, and limit mitochondrial ROS accumulation upon <i>Salmonella</i> infection. Remarkably, this SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-κB activation. Overall, our results unravel essential shared multifaceted roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with potential for future diagnostic and therapeutic applications.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease","authors":"Jacob A. Torres, Mina Rezaei, Caroline Broderick, Louis Lin, Xiaofang Wang, Bernd Hoppe, Benjamin D. Cowley Jr., Vincenzo Savica, Vicente E. Torres, Saeed Khan, Ross P. Holmes, Michal Mrug, Thomas Weimbs","doi":"10.1172/jci193824","DOIUrl":"https://doi.org/10.1172/jci193824","url":null,"abstract":"<h5 style=\"display: inline-block;\">Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease</h5>\u0000Jacob A. Torres, … , Michal Mrug, Thomas Weimbs\u0000Jacob A. Torres, … , Michal Mrug, Thomas Weimbs <span>\u0000Research Article\u0000</span><span>\u0000Nephrology\u0000</span><span data-badge-popover=\"bottom\" data-badge-type=\"2\" data-doi=\"10.1172/JCI128503\" data-hide-no-mentions=\"true\"></span>","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis","authors":"Joanna Kocot, Peter Kosa, Shinji Ashida, Nicolette A. Pirjanian, Raphaela Goldbach-Mansky, Karin Peterson, Valentina Fossati, Steven M. Holland, Bibiana Bielekova","doi":"10.1172/jci183941","DOIUrl":"https://doi.org/10.1172/jci183941","url":null,"abstract":"Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial, <u>t</u>argeting <u>r</u>esidual <u>a</u>ctivity by <u>p</u>recision, biomarker-guided combination therapies of <u>m</u>ultiple <u>s</u>clerosis (TRAP-MS) (ClinicalTrials.gov NCT03109288), to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA). The clemastine arm was stopped per protocol-defined criteria when 3 of 9 patients triggered individual safety stopping criteria. Clemastine-treated patients had significantly higher treatment-induced disability progression slopes compared with the remaining TRAP-MS participants. Quantification of approximately 7,000 proteins in CSF samples collected before and after clemastine treatment showed significant increases in purinergic signaling and pyroptosis. Mechanistic studies showed that clemastine with sublytic doses of extracellular adenosine triphosphate (ATP) activates inflammasome and induces pyroptotic cell death in macrophages. Clemastine with ATP also caused pyroptosis of induced pluripotent stem cell–derived human oligodendrocytes. Antagonist of the purinergic channel P2RX7, which is strongly expressed in oligodendrocytes and myeloid cells, blocked these toxic effects of clemastine. Finally, reanalysis of published single-nucleus RNA-Seq (snRNA-Seq) studies revealed increased P2RX7 expression and pyroptosis transcriptional signature in microglia and oligodendrocytes in the MS brain, especially in chronic active lesions. The CSF proteomic pyroptosis score was increased in untreated MS patients, was higher in patients with progressive than relapsing-remitting disease, and correlated significantly with the rates of MS progression. Collectively, this identifies pyroptosis as a likely mechanism of CNS injury underlying PIRA even outside of clemastine toxicity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples.","authors":"Daniel Saarela,Pawel Lis,Sara Gomes,Raja S Nirujogi,Wentao Dong,Eshaan S Rawat,Sophie Glendinning,Karolina Zeneviciute,Enrico Bagnoli,Rotimi Fasimoye,Cindy Lin,Kwamina Nyame,Fanni A Boros,Friederike Zunke,Frederic Lamoliatte,Sadik Elshani,Matthew Jaconelli,Judith Jm Jans,Margriet A Huisman,Christian Posern,Lena M Westermann,Angela Schulz,Peter M van Hasselt,Dario R Alessi,Monther Abu-Remaileh,Esther M Sammler","doi":"10.1172/jci183592","DOIUrl":"https://doi.org/10.1172/jci183592","url":null,"abstract":"Lysosomes are implicated in a wide spectrum of human diseases including monogenic lysosomal storage disorders (LSDs), age-associated neurodegeneration and cancer. Profiling lysosomal content using tag-based lysosomal immunoprecipitation (LysoTagIP) in cell and animal models has substantially moved the field forward, but studying lysosomal dysfunction in human patients remains challenging. Here, we report the development of the 'tagless LysoIP' method, designed to enable the rapid enrichment of lysosomes, via immunoprecipitation, using the endogenous integral lysosomal membrane protein TMEM192, directly from clinical samples and human cell lines (e.g., induced pluripotent stem cell derived neurons). Isolated lysosomes were intact and suitable for subsequent multimodal omics analyses. To validate our approach, we applied the tagless LysoIP to enrich lysosomes from peripheral blood mononuclear cells derived from fresh blood of healthy donors and patients with CLN3 disease, an autosomal recessive neurodegenerative LSD. Metabolic profiling of isolated lysosomes revealed massive accumulation of glycerophosphodiesters (GPDs) in patients' lysosomes. Interestingly, a patient with a milder phenotype and genotype displayed lower accumulation of lysosomal GPDs, consistent with their potential role as disease biomarkers. Altogether, the tagless LysoIP provides a framework to study native lysosomes from patient samples, identify disease biomarkers, and discover human-relevant disease mechanisms.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-classical action of Ku70 promotes Treg suppressive function through a FOXP3-dependent mechanism in lung adenocarcinoma.","authors":"Qianru Huang,Na Tian,Jianfeng Zhang,Shiyang Song,Hao Cheng,Xinnan Liu,Wenle Zhang,Youqiong Ye,Yanhua Du,Xueyu Dai,Rui Liang,Dan Li,Sheng-Ming Dai,Chuan Wang,Zhi Chen,Qianjun Zhou,Bin Li","doi":"10.1172/jci178079","DOIUrl":"https://doi.org/10.1172/jci178079","url":null,"abstract":"Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted non-classical functions of Ku70 in cellular processes. However, its function in immune homeostasis and anti-tumor immunity remains unknown. Here, we discovered a marked association between elevated Ku70 expression and unfavorable prognosis in lung adenocarcinoma, focusing specifically on increased Ku70 levels in tumor-infiltrated Treg cells. Using a lung-colonizing tumor model of in mice with Treg-specific Ku70 deficiency, we demonstrated that deletion of Ku70 in Treg cells led to a stronger anti-tumor response and slower tumor growth due to impaired immune-suppressive capacity of Treg cells. Furthermore, we confirmed that Ku70 played a critical role in sustaining the suppressive function of human Treg cells. We found that Ku70 bound to FOXP3 and occupied FOXP3-bound genomic sites to support its transcriptional activities. These findings not only unveil a non-homologous end joining (NHEJ)-independent role of Ku70 crucial for Treg suppressive function, but also underscore the potential of targeting Ku70 as an effective strategy in cancer therapy, aiming to both restrain cancer cells and enhance pulmonary anti-tumor immunity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"168 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}