The Journal of Clinical Investigation最新文献_第9页

ST6GalNAc-I regulates tumor cell sialylation via NECTIN2/MUC5AC-mediated immunosuppression and angiogenesis in non-small cell lung cancer. 在非小细胞肺癌中，st6galnac - 1通过NECTIN2/ muc5ac介导的免疫抑制和血管生成调节肿瘤细胞唾液化。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci186863

Muthamil Iniyan Appadurai,Sanjib Chaudhary,Ashu Shah,Gopalakrishnan Natarajan,Zahraa W Alsafwani,Parvez Khan,Dhananjay D Shinde,Subodh M Lele,Lynette M Smith,Mohd Wasim Nasser,Surinder Kumar Batra,Apar Kishor Ganti,Imayavaramban Lakshmanan

{"title":"ST6GalNAc-I regulates tumor cell sialylation via NECTIN2/MUC5AC-mediated immunosuppression and angiogenesis in non-small cell lung cancer.","authors":"Muthamil Iniyan Appadurai,Sanjib Chaudhary,Ashu Shah,Gopalakrishnan Natarajan,Zahraa W Alsafwani,Parvez Khan,Dhananjay D Shinde,Subodh M Lele,Lynette M Smith,Mohd Wasim Nasser,Surinder Kumar Batra,Apar Kishor Ganti,Imayavaramban Lakshmanan","doi":"10.1172/jci186863","DOIUrl":"https://doi.org/10.1172/jci186863","url":null,"abstract":"Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I-deficient tumor cells cocultured with T cells were more susceptible to T cell-mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I-knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I-deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I-mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982469","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}

引用次数: 0

Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia. 泛素偶联酶UBE2N调节免疫蛋白酶体阳性急性髓性白血病的蛋白平衡。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci184665

Chiharu Ishikawa,Laura Barreyro,Avery M Sampson,Kathleen M Hueneman,Kwangmin Choi,Sophia Y Philbrook,Issac Choi,Lyndsey C Bolanos,Mark Wunderlich,Andrew G Volk,Stephanie S Watowich,Kenneth D Greis,Daniel T Starczynowski

{"title":"Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.","authors":"Chiharu Ishikawa,Laura Barreyro,Avery M Sampson,Kathleen M Hueneman,Kwangmin Choi,Sophia Y Philbrook,Issac Choi,Lyndsey C Bolanos,Mark Wunderlich,Andrew G Volk,Stephanie S Watowich,Kenneth D Greis,Daniel T Starczynowski","doi":"10.1172/jci184665","DOIUrl":"https://doi.org/10.1172/jci184665","url":null,"abstract":"Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif-containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin-mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"123 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982470","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}

引用次数: 0

TMEM219 signaling promotes intestinal stem cell death and exacerbates colitis. TMEM219信号通路促进肠道干细胞死亡并加重结肠炎。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci185783

Francesca D'Addio,Giovanni Amabile,Emma Assi,Anna Maestroni,Adriana Petrazzuolo,Cristian Loretelli,Ahmed Abdelasalam,Moufida Ben Nasr,Ida Pastore,Maria Elena Lunati,Vera Usuelli,Monica Zocchi,Andy Joe Seelam,Domenico Corradi,Stefano La Rosa,Virna Marin,Monique Zangarini,Marta Nardini,Stefano Porzio,Filippo Canducci,Claudia Nardini,Basset El Essawy,Manuela Nebuloni,Jun Yang,Massimo Venturini,Giovanni Maconi,Franco Folli,Silvio Danese,Gianvincenzo Zuccotti,Gianluca M Sampietro,Sandro Ardizzone,Paolo Fiorina

{"title":"TMEM219 signaling promotes intestinal stem cell death and exacerbates colitis.","authors":"Francesca D'Addio,Giovanni Amabile,Emma Assi,Anna Maestroni,Adriana Petrazzuolo,Cristian Loretelli,Ahmed Abdelasalam,Moufida Ben Nasr,Ida Pastore,Maria Elena Lunati,Vera Usuelli,Monica Zocchi,Andy Joe Seelam,Domenico Corradi,Stefano La Rosa,Virna Marin,Monique Zangarini,Marta Nardini,Stefano Porzio,Filippo Canducci,Claudia Nardini,Basset El Essawy,Manuela Nebuloni,Jun Yang,Massimo Venturini,Giovanni Maconi,Franco Folli,Silvio Danese,Gianvincenzo Zuccotti,Gianluca M Sampietro,Sandro Ardizzone,Paolo Fiorina","doi":"10.1172/jci185783","DOIUrl":"https://doi.org/10.1172/jci185783","url":null,"abstract":"Mechanisms by which mucosal regeneration is abrogated in inflammatory bowel disease (IBD) are still under investigation, and a role for an intestinal stem cell (ISC) defect is now emerging. Herein, we report an abnormal ISC death that occurs in Crohn's disease, which exacerbates colitis, limits ISC-dependent mucosal repair, and is controlled through the death factor Transmembrane protein 219 (TMEM219). Large alterations in TMEM219 expression were observed in patients with Crohn's disease, particularly in those with active disease and/or those who were nonresponders to conventional therapy, confirming that TMEM219 signaling is abnormally activated and leads to failure of the mucosal regenerative response. Mechanistic studies revealed a proapoptotic TMEM219-mediated molecular signature in Crohn's disease, which associates with Caspase-8 activation and ISC death. Pharmacological blockade of the IGFBP3/TMEM219 binding/signal with the recombinant protein ecto-TMEM219 restored the self-renewal abilities of miniguts generated from patients with Crohn's disease in vitro and ameliorated DSS-induced and T cell-mediated colitis in vivo, ultimately leading to mucosal healing. Genetic tissue-specific deletion of TMEM219 in ISCs in newly generated TMEM219fl/flLGR5cre mice revived their mucosal regenerative abilities both in vitro and in vivo. Our findings demonstrate that a TMEM219-dependent ISC death exacerbates colitis and that TMEM219 blockade reestablishes intestinal self-renewal properties in IBD.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992058","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}

引用次数: 0

Traffic jam in lung capillaries: inter-organ communication impedes gas exchange after acute kidney injury. 肺毛细血管堵塞：急性肾损伤后器官间通讯阻碍气体交换。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci192917

Ulrich Matt,Susanne Herold

引用次数: 0

Autophagy is an upstream mediator of chromatin dynamics in normal and autoimmune germinal centre B cells. 自噬是正常和自身免疫生发中心B细胞染色质动力学的上游介质。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci178920

Marta C Sallan,Filip Filipsky,Christina H Shi,Elena Pontarini,Manuela Terranova-Barberio,Gordon Beattie,Andrew Clear,Michele Bombardieri,Kevin Y Yip,Dinis Parente Calado,Mark S Cragg,Sonya James,Matthew J Carter,Jessica Okosun,John G Gribben,Tanya Klymenko,Andrejs Braun

引用次数: 0

Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis. 天冬酰胺内肽酶裂解载脂蛋白A1，加速动脉粥样硬化的发病。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci185128

Mengmeng Wang,Bowei Li,Shuke Nie,Xin Meng,Guangxing Wang,Menghan Yang,Wenxin Dang,Kangning He,Tucheng Sun,Ping Xu,Xifei Yang,Keqiang Ye

{"title":"Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis.","authors":"Mengmeng Wang,Bowei Li,Shuke Nie,Xin Meng,Guangxing Wang,Menghan Yang,Wenxin Dang,Kangning He,Tucheng Sun,Ping Xu,Xifei Yang,Keqiang Ye","doi":"10.1172/jci185128","DOIUrl":"https://doi.org/10.1172/jci185128","url":null,"abstract":"Atherosclerosis is a slowly progressing inflammatory disease characterized with cholesterol disorder and intimal plaques. Asparagine endopeptidase (AEP) is an endolysosomal protease that is activated under acidic conditions and is elevated substantially in both plasma and plaques of patients with atherosclerosis. However, how AEP accelerates atherosclerosis development remains incompletely understood, especially from the view of cholesterol metabolism. This project aims to reveal the crucial substrate of AEP during atherosclerosis plaque formation and to lay the foundation for developing novel therapeutic agents for Atherosclerosis. Here, we show that AEP is augmented in the atherosclerosis plaques obtained from patients and proteolytically cuts apolipoprotein A1 (APOA1) and impairs cholesterol efflux and high-density lipoprotein (HDL) formation, facilitating atherosclerosis pathologies. AEP is activated in the liver and aorta of apolipoprotein E-null (APOE-null) mice, and deletion of AEP from APOE-/- mice attenuates atherosclerosis. APOA1, an essential lipoprotein in HDL for cholesterol efflux, is cleaved by AEP at N208 residue in the liver and atherosclerotic macrophages of APOE-/- mice. Blockade of APOA1 cleavage by AEP via N208A mutation or its specific inhibitor, #11a, substantially diminishes atherosclerosis in both APOE-/- and LDLR-/- mice. Hence, our findings support that AEP disrupts cholesterol metabolism and accelerates the development of atherosclerosis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982463","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}

引用次数: 0

GALNT14 deficiency: connecting multiple links in the IgA nephropathy pathogenetic chain. GALNT14缺乏：连接IgA肾病发病链中的多个环节。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci192687

John Pell,Madhav C Menon

引用次数: 0

Promoting mucosal healing by targeting TMEM219-dependent intestinal epithelial stem cell defects in inflammatory bowel disease. 通过靶向炎症性肠病中tmem219依赖性肠上皮干细胞缺陷促进粘膜愈合

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci192640

Nicolas Schlegel

引用次数: 0

Endothelial dysfunction in patients with type 2 diabetes: the truth is in the blood. 2型糖尿病患者的内皮功能障碍：真相在血液中。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci193128

Sarah Costantino,Shafeeq A Mohammed,Francesco Paneni

引用次数: 0

Disease classification, diagnostic challenges, and evolving clinical trial design in MASLD. MASLD的疾病分类、诊断挑战和不断发展的临床试验设计。

The Journal of Clinical Investigation Pub Date : 2025-05-15 DOI: 10.1172/jci189953

Mette Munk Lauridsen,Kim Ravnskjaer,Lise Lotte Gluud,Arun J Sanyal

{"title":"Disease classification, diagnostic challenges, and evolving clinical trial design in MASLD.","authors":"Mette Munk Lauridsen,Kim Ravnskjaer,Lise Lotte Gluud,Arun J Sanyal","doi":"10.1172/jci189953","DOIUrl":"https://doi.org/10.1172/jci189953","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"121 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992067","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}

引用次数: 0