The Journal of Clinical Investigation最新文献_第3页

Uromodulin modulates mitochondria and kidney tubule resilience. 尿调素调节线粒体和肾小管弹性。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci193829

Ronak Lakhia,Chunzi Song,Vishal Patel

引用次数: 0

RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression. rsk1驱动的TRIM28/E2F1反馈回路促进去势抵抗性前列腺癌的进展。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci185119

Miyeong Kim,Jinpeng Liu,Yanquan Zhang,Ruixin Wang,Ryan Goettl,Jennifer Grasso,Derek B Allison,Chi Wang,Tianyan Gao,Xiaoqi Liu,Ka-Wing Fong

{"title":"RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression.","authors":"Miyeong Kim,Jinpeng Liu,Yanquan Zhang,Ruixin Wang,Ryan Goettl,Jennifer Grasso,Derek B Allison,Chi Wang,Tianyan Gao,Xiaoqi Liu,Ka-Wing Fong","doi":"10.1172/jci185119","DOIUrl":"https://doi.org/10.1172/jci185119","url":null,"abstract":"Castration-resistant prostate cancer (CRPC) marks the advanced and lethal stage of prostate cancer (PCa). TRIM28, also known as KAP1, is a transcriptional regulator recently shown to promote CRPC cell proliferation and xenograft tumor growth. Nonetheless, knowledge gaps persist regarding the mechanisms underlying TRIM28 upregulation in CRPC as well as the genomic targets regulated by TRIM28. Here, we report that TRIM28 is a E2F1 target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcriptional activation and genomic function of E2F1 independent of retinoblastoma (Rb) status. Furthermore, we identified RSK1 as a kinase that directly phosphorylates TRIM28 at S473, and, as such, RSK1 drives the TRIM28/E2F1 feedback loop. Accordingly, pS473-TRIM28 promotes CRPC progression, which is mitigated by RSK inhibition. In summary, our study reveals a critical role of the RSK1-TRIM28-E2F1 axis in CRPC progression, which may be exploited as a vulnerability in treating Rb-deficient CRPC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295966","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

Regular meals matter: bone growth and beyond. 规律饮食很重要：骨骼生长和其他方面。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci194079

Rhonda D Kineman,Shoshana Yakar

引用次数: 0

Gestational hypertension increases risk of seizures in children and mice. 妊娠期高血压增加儿童和小鼠癫痫发作的风险。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci183393

Baojian Xue,Serena B Gumusoglu,Grant Tiarks,Brittany P Todd,Angela Wong,Donna A Santillan,Chin-Chi Kuo,Hsiu-Yin Chiang,Rohith Ravindranath,Sophia Y Wang,Vinit B Mahajan,Alan Kim Johnson,Heath A Davis,Polly Ferguson,Elizabeth A Newell,Mark K Santillan,Jason M Misurac,Alexander G Bassuk

{"title":"Gestational hypertension increases risk of seizures in children and mice.","authors":"Baojian Xue,Serena B Gumusoglu,Grant Tiarks,Brittany P Todd,Angela Wong,Donna A Santillan,Chin-Chi Kuo,Hsiu-Yin Chiang,Rohith Ravindranath,Sophia Y Wang,Vinit B Mahajan,Alan Kim Johnson,Heath A Davis,Polly Ferguson,Elizabeth A Newell,Mark K Santillan,Jason M Misurac,Alexander G Bassuk","doi":"10.1172/jci183393","DOIUrl":"https://doi.org/10.1172/jci183393","url":null,"abstract":"Gestational hypertension (GH) is prevalent, with life-long health burdens for mothers and their children exposed in utero. We analyzed the nation-wide Epic Cosmos dataset and found significantly higher rates of seizures in children of mothers with GH than in children of normotensive mothers. Complementary studies of nested Iowa and Stanford cohorts and a large Taiwanese cohort also revealed significantly increased seizure risk after covariate adjustments. We modeled this association in an angiotensin (ANG) II mouse model of GH. Maternal ANG II significantly increased seizure grade and deaths elicited by pilocarpine among male but not female offspring. Electrical stimulation increased seizure grade and death across sexes in offspring from ANG II-treated dams. Proinflammatory and microglial gene expression in the brain were upregulated only in male offspring from ANG II-treated dams. Chronic phenylephrine, a GH model lacking the maternal proinflammatory aspects of ANG II, induced similar offspring seizure phenotypes. PLX5622-induced depletion of microglia or antiinflammatory pentoxifylline abolished this sensitized seizure response and lowered mortality in the ANG II model. These results suggest that GH programs offspring risk for seizures in a sex-dependent manner in humans and mice. Neuroinflammatory mechanisms may contribute to the elevated sensitivity and mortality from seizures elicited by GH exposure in utero.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295962","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

Friend or foe: assessing the value of animal models for facilitating clinical breakthroughs in complement research. 朋友还是敌人：评估动物模型对促进补体研究临床突破的价值。

The Journal of Clinical Investigation Pub Date : 2025-06-16 DOI: 10.1172/jci188347

Felix Poppelaars,V Michael Holers,Joshua M Thurman

{"title":"Friend or foe: assessing the value of animal models for facilitating clinical breakthroughs in complement research.","authors":"Felix Poppelaars,V Michael Holers,Joshua M Thurman","doi":"10.1172/jci188347","DOIUrl":"https://doi.org/10.1172/jci188347","url":null,"abstract":"Animal experiments have long been a cornerstone of advancements in biomedical research, particularly in developing novel therapeutic strategies for inflammatory and autoimmune diseases. However, these historically important approaches are now facing growing scrutiny for ethical reasons, concerns about translational limitations to human biology, and the rising availability of animal-free research methods. This shift raises a critical question: How relevant and effective are animal models for driving future advancements in today's research landscape? This Review aims to explore this question within the field of biomedical research on the complement system, critically evaluating the contribution of animal models to the recent advancements and clinical successes of complement-targeted therapies. Specifically, we assess areas where animal studies have been indispensable for elucidating disease mechanisms and conducting preclinical evaluations, alongside instances where findings from animal models failed to translate successfully to human trials. Furthermore, we discuss similarities and differences in the complement system between animals and humans and explore innovations in animal research designed to improve translatability to human biology. By assessing the contributions of animal studies to complement therapeutics, this Review aims to provide insights into animal models' strengths, limitations, and evolving role in complement research.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295964","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

Myeloid cell genome-wide screen identifies variants associated with Mycobacterium tuberculosis-induced cytokine transcriptional responses. 髓系细胞全基因组筛选鉴定与结核分枝杆菌诱导的细胞因子转录反应相关的变异。

The Journal of Clinical Investigation Pub Date : 2025-05-22 DOI: 10.1172/jci179822

Joshua J Ivie,Kimberly A Dill-McFarland,Jason D Simmons,Glenna J Peterson,Penelope H Benchek,Harriet Mayanja-Kizza,Lily E Veith,Moeko Agata,Dang Tm Ha,Ho Dt Nghia,W Henry Boom,Catherine M Stein,Chiea C Khor,Guy E Thwaites,Hoang T Hai,Nguyen Tt Thuong,Xuling Chang,Sarah J Dunstan,Thomas R Hawn

{"title":"Myeloid cell genome-wide screen identifies variants associated with Mycobacterium tuberculosis-induced cytokine transcriptional responses.","authors":"Joshua J Ivie,Kimberly A Dill-McFarland,Jason D Simmons,Glenna J Peterson,Penelope H Benchek,Harriet Mayanja-Kizza,Lily E Veith,Moeko Agata,Dang Tm Ha,Ho Dt Nghia,W Henry Boom,Catherine M Stein,Chiea C Khor,Guy E Thwaites,Hoang T Hai,Nguyen Tt Thuong,Xuling Chang,Sarah J Dunstan,Thomas R Hawn","doi":"10.1172/jci179822","DOIUrl":"https://doi.org/10.1172/jci179822","url":null,"abstract":"Immune and clinical outcomes to Mycobacterium tuberculosis (Mtb) infection vary greatly between individuals yet the underlying genetic and cellular mechanisms driving this heterogeneity remain poorly understood. We performed a cellular genome-wide association study (GWAS) to identify genetic variants associated with Mtb-induced monocyte transcriptional expression of IL1B, IL6, TNF, and IFNB1 via RNA-seq in a Ugandan cohort. Significantly associated variants were assessed for transferability in an independent Seattle cohort, further validated in vitro, and assessed for clinical phenotype associations. We identified 77 loci suggestively associated with Mtb-induced cytokine expression in monocytes in Uganda. SNPs associated with Mtb-induced TNF were enriched within alpha-linolenic acid metabolism pathway genes which was validated in vitro using PLA2 inhibitors. Four loci maintained significant associations in Seattle. We validated cytokine effect with siRNA knockdown for two of these loci which mapped to the genes SLIT3 and SLC1A1. Furthermore, exogenous treatment of macrophages with SLIT3 enhanced Mtb intracellular replication. Finally, SLC1A1 and SLIT3 variants were associated with susceptibility to tuberculous meningitis (TBM) and subsequent survival in a Vietnamese cohort, respectively. In sum, we identified multiple variants and pathways associated with Mtb-induced cytokine transcriptional responses that validated in vitro and were associated with clinical TB susceptibility.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114264","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

Integrin-mediated mTOR signaling drives TGF-β overactivity and myxomatous mitral valve degeneration in hypomorphic fibrillin-1 mice. 整合素介导的mTOR信号驱动TGF-β过度活性和二尖瓣黏液变性。

The Journal of Clinical Investigation Pub Date : 2025-05-20 DOI: 10.1172/jci183558

Fu Gao,Qixin Chen,Makoto Mori,Sufang Li,Giovanni Ferrari,Markus Krane,Rong Fan,George Tellides,Yang Liu,Arnar Geirsson

{"title":"Integrin-mediated mTOR signaling drives TGF-β overactivity and myxomatous mitral valve degeneration in hypomorphic fibrillin-1 mice.","authors":"Fu Gao,Qixin Chen,Makoto Mori,Sufang Li,Giovanni Ferrari,Markus Krane,Rong Fan,George Tellides,Yang Liu,Arnar Geirsson","doi":"10.1172/jci183558","DOIUrl":"https://doi.org/10.1172/jci183558","url":null,"abstract":"Mitral valve prolapse is often benign but progression to mitral regurgitation may require invasive intervention and there is no specific medical therapy. An association of mitral valve prolapse with Marfan syndrome resulting from pathogenic FBN1 variants supports the use of hypomorphic fibrillin-1 mgR mice to investigate mechanisms and therapy for mitral valve disease. mgR mice developed severe myxomatous mitral valve degeneration with mitral regurgitation by 12 weeks of age. Persistent activation of TGF-β and mTOR signaling along with macrophage recruitment preceded histological changes at 4 weeks of age. Short-term mTOR inhibition with rapamycin from 4 to 5 weeks of age prevented TGF-β overactivity and leukocytic infiltrates, while long-term inhibition of mTOR or TGF-β signaling from 4 to 12 weeks of age rescued mitral valve leaflet degeneration. Transcriptomic analysis identified integrins as key receptors in signaling interactions and serologic neutralization of integrin signaling or a chimeric integrin receptor altering signaling prevented mTOR activation. We confirmed increased mTOR signaling and a conserved transcriptome signature in human specimens of sporadic mitral valve prolapse. Thus, mTOR activation from abnormal integrin-dependent cell-matrix interactions drives TGF-β overactivity and myxomatous mitral valve degeneration, and mTOR inhibition may prevent disease progression of mitral valve prolapse.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"138 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103546","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

Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis. Trapα缺乏会损害胰岛素生物合成和葡萄糖稳态的早期事件。

The Journal of Clinical Investigation Pub Date : 2025-05-20 DOI: 10.1172/jci179845

Xin Li,Jingxin Hu,Yumeng Huang,Hai Zhang,Ning Xu,Yang Liu,Xuan Liu,Yuanyuan Ye,Xinxin Zhang,Xiaoxi Xu,Yuxin Fan,Ziyue Zhang,Weiping J Zhang,Shusen Wang,Wenli Feng,Peter Arvan,Ming Liu

{"title":"Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.","authors":"Xin Li,Jingxin Hu,Yumeng Huang,Hai Zhang,Ning Xu,Yang Liu,Xuan Liu,Yuanyuan Ye,Xinxin Zhang,Xiaoxi Xu,Yuxin Fan,Ziyue Zhang,Weiping J Zhang,Shusen Wang,Wenli Feng,Peter Arvan,Ming Liu","doi":"10.1172/jci179845","DOIUrl":"https://doi.org/10.1172/jci179845","url":null,"abstract":"Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Gene encoding TRanslocon-Associated Protein alpha (TRAPα) shows linkage to glycemic control in humans, although their pathophysiological role remains unknown. Here we found that β-cell specific TRAPα knockout (TRAPα-βKO) mice fed with chow diet or high fat diet (HFD) exhibit decreased circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-βKO not only causes inefficient PPI translocation, but also leads to PI misfolding and ER stress, selectively limiting PI ER export and β-cell compensatory potential. Importantly, decreased TRAPα expression was evident in islets of wild-type mice fed with high fat diet and in patients with type 2 diabetes (T2D). Furthermore, TRAPα expression was positively correlated with insulin content in human islet β cells, and decreased TRAPα was associated with PI maturation defects in T2D islets. Together, these data demonstrate that TRAPα deficiency in pancreatic β-cells impairs PPI translocation, PI folding, insulin production, and glucose homeostasis, contributing to its genetic linkage to T2D.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103545","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

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