The Journal of Clinical Investigation最新文献

{"title":"Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants.","authors":"Saiti S Halder,Michael J Rynkiewicz,Lynne Kim,Meaghan Barry,Ahmed Ga Zied,Lorenzo R Sewanan,Jonathan A Kirk,Jeffrey R Moore,William Lehman,Stuart G Campbell","doi":"10.1172/jci179135","DOIUrl":"https://doi.org/10.1172/jci179135","url":null,"abstract":"Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the 'closed' regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"234 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488300","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":"Combined HDAC8 and checkpoint kinase inhibition induces tumor-selective synthetic lethality in preclinical models.","authors":"Ting-Yu Chang,Yan Yan,Zih-Yao Yu,Moeez Rathore,Nian-Zhe Lee,Hui-Ju Tseng,Li-Hsin Cheng,Wei-Jan Huang,Wei Zhang,Ernest R Chan,Yulan Qing,Ming-Lun Kang,Rui Wang,Kelvin K Tsai,John J Pink,William E Harte,Stanton L Gerson,Sung-Bau Lee","doi":"10.1172/jci165448","DOIUrl":"https://doi.org/10.1172/jci165448","url":null,"abstract":"The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488297","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":"Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits.","authors":"Antwi-Boasiako Oteng,Liu Liu,Yinghong Cui,Oksana Gavrilova,Huiyan Lu,Min Chen,Lee S Weinstein,Jonathan E Campbell,Jo E Lewis,Fiona M Gribble,Frank Reimann,Jürgen Wess","doi":"10.1172/jci182325","DOIUrl":"https://doi.org/10.1172/jci182325","url":null,"abstract":"Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K-cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of Gs, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488303","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":"Timing of antiretroviral therapy initiation affects intact HIV reservoirs following analytical treatment interruption.","authors":"Maegan R Manning,Jana Blazkova,Jesse S Justement,Victoria Shi,Brooke D Kennedy,M Ali Rai,Catherine A Seamon,Kathleen Gittens,Michael C Sneller,Susan Moir,Tae-Wook Chun","doi":"10.1172/jci181632","DOIUrl":"https://doi.org/10.1172/jci181632","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"124 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439283","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":"TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis.","authors":"Siqi Ming,Xingyu Li,Qiang Xiao,Siying Qu,Qiaohua Wang,Qiongyan Fang,Pingping Liang,Yating Xu,Jingwen Yang,Yongqiang Yang,Xi Huang,Yongjian Wu","doi":"10.1172/jci159400","DOIUrl":"https://doi.org/10.1172/jci159400","url":null,"abstract":"Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly up-regulated in sepsis patients and correlated with the severity of sepsis. Knock out of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2 knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit Bruton tyrosine kinas (BTK)-mediated FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO, which may provide a promising target for the clinical treatment of sepsis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443758","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":"EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease.","authors":"Xiaofang Tang,Wei Wei,Yuqing Sun,Timothy E Weaver,Ernesto S Nakayasu,Geremy Clair,John M Snowball,Cheng-Lun Na,Karen S Apsley,Emily P Martin,Darrell N Kotton,Konstantinos-Dionysios Alysandratos,Jiuzhou Huo,Jeffery D Molkentin,William A Gower,Xinhua Lin,Jeffrey A Whitsett","doi":"10.1172/jci173861","DOIUrl":"https://doi.org/10.1172/jci173861","url":null,"abstract":"The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443762","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":"Calcineurin inhibitor blocks tolerance by suppressing donor T cell terminal exhaustion after allogeneic hematopoietic cell transplantation.","authors":"Hajime Senjo,Daigo Hashimoto,Takanori Teshima","doi":"10.1172/jci184332","DOIUrl":"https://doi.org/10.1172/jci184332","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"56 77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439497","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":"Distinguishing between help and harm: Helper T cell subsets and immune-related adverse events.","authors":"Alexandra M Haugh,Adil I Daud","doi":"10.1172/jci184310","DOIUrl":"https://doi.org/10.1172/jci184310","url":null,"abstract":"The precise conditions by which cytokines drive cancer is relevant to improving immune checkpoint inhibition (ICI) responses while decreasing toxicity. In this issue of the JCI, Kao et al. investigated T helper cell pathways in patients with solid tumors receiving ICI. The authors evaluated T cell populations, cytokine signatures, immune related adverse events (irAEs), and survival outcomes. Patients with a history of autoimmune disorders were more likely to develop irAEs. Notably, blood samples from patients on treatment showed that elevations in IL-5, IL-6, IL-17f, and TNF-α were associated with an increased risk for grade 2 or higher irAEs. Moreover, IL-6 was associated with decreased objective response rate and worse cancer-specific and all-cause mortality. These findings may help guide decisions for optimizing ICI efficacy while minimizing toxicity and suggest that IL-6 blockade may improve response and decrease toxicity in solid tumors.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439366","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":"Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.","authors":"Jonathan Bohlen,Ivan Bagarić,Taja Vatovec,Masato Ogishi,Syed F Ahmed,Axel Cederholm,Lori Buetow,Steicy Sobrino,Corentin Le Floc'h,Carlos A Arango-Franco,Luis Seabra,Marine Michelet,Federica Barzaghi,Davide Leardini,Francesco Saettini,Francesca Vendemini,Francesco Baccelli,Albert Catala,Eleonora Gambineri,Marinella Veltroni,Yurena Aguilar de la Red,Gillian I Rice,Filippo Consonni,Laureline Berteloot,Laetitia Largeaud,Francesca Conti,Cécile Roullion,Cécile Masson,Boris Bessot,Yoann Seeleuthner,Tom Le Voyer,Darawan Rinchai,Jérémie Rosain,Anna-Lena Neehus,Lucia Erazo-Borrás,Hailun Li,Zarah Janda,En-Jui Cho,Edoardo Muratore,Camille Soudée,Candice Lainé,Eric Delabesse,Claire Goulvestre,Cindy S Ma,Anne Puel,Stuart G Tangye,Isabelle André,Christine Bole-Feysot,Laurent Abel,Miriam Erlacher,Shen-Ying Zhang,Vivien Béziat,Chantal Lagresle-Peyrou,Emmanuelle Six,Marlène Pasquet,Laia Alsina,Alessandro Aiuti,Peng Zhang,Yanick J Crow,Nils Landegren,Riccardo Masetti,Danny T Huang,Jean-Laurent Casanova,Jacinta Bustamante","doi":"10.1172/jci181604","DOIUrl":"https://doi.org/10.1172/jci181604","url":null,"abstract":"Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"208 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439431","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":"HOPE springs eternal: lack of HIV superinfection in HIV Organ Policy Equity Act kidney transplants.","authors":"Christine M Durand,Andrew D Redd","doi":"10.1172/jci184326","DOIUrl":"https://doi.org/10.1172/jci184326","url":null,"abstract":"Kidney transplantation from donors with HIV to recipients with HIV (HIV D+/R+) is an emerging practice that has shown substantial clinical benefit. Sustained HIV superinfection, whereby a transplant recipient acquires a new strain of HIV from their organ donor, is a theoretical risk, which might increase chances of viral failure. In this issue of the JCI, Travieso, Stadtler, and colleagues present phylogenetic analysis of HIV from kidney tissue, urine, plasma, and cells from 12 HIV D+/R+ kidney transplants out to five years of follow-up. Early after transplant, donor HIV was transiently detected in five of 12 recipients, primarily from donors with untreated HIV and high-level viremia, consistent with a viral inoculum. Long-term, donor HIV was not detected in any recipients, demonstrating no sustained HIV superinfection. These reassuring data support earlier findings from South Africa and the United States and further confirm the safety of HIV D+/R+ transplantation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439429","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}