EMBO REPORTS
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2021
·Vol. 22
·期 2
·e51162
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IF 8.807
Jia Song,Tongtong Liu,Yue Yin,Wei Zhao,Zhiqiang Lin,Yuxin Yin,Dan Lu,Fuping You
Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage-associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T-cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2023
·
IF 8.2
Wang Meng-yang,Yu Tian-xiang,Wang Qin-yan,Han Xue,Hu Xiang,Ye Shi-ju,Long Xiao-hong,Wang Yi,Zhu Hong,Luo Wu,Liang Guang
Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 μg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 μM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.
研究领域:
肾病学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2023
·
IF 12.4
Mengyang Wang,Xue Han,Tianxiang Yu,Minxiu Wang,Wu Luo,Chunpeng Zou,Xiuyun Li,Gao Li,Gaojun Wu,Yi Wang,Guang Liang
Rationale: Understanding the molecular mechanisms of deleterious cardiac remodeling is important for the development of treatments for heart failure. Recent studies have highlighted a role of deubiquitinating enzymes in cardiac pathophysiology. In the present study, we screened for alteration of deubiquitinating enzymes in experimental models of cardiac remodeling, which indicated a potential role of OTU Domain-Containing Protein 1 (OTUD1). Methods: Wide-type or OTUD1 knockout mice with chronic angiotensin II infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodeling and heart failure. We also overexpressed OTUD1 in mouse heart with AAV9 vector to validate the function of OTUD1. LC-MS/MS analysis combined with Co-IP was used to identify the interacting proteins and substrates of OTUD1. Results: We found that OTUD1 is elevated in mouse heart tissues following chronic angiotensin II administration. OTUD1 knockout mice were significantly protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis and inflammatory response. Similar results were obtained in the TAC model. Mechanistically, OTUD1 bounds to the SH2 domain of STAT3 and causes deubiquitination of STAT3. Cysteine at position 320 of OTUD1 exerts K63 deubiquitination to promote STAT3 phosphorylation and nuclear translocation, thereby increasing STAT3 activity to induce inflammatory responses, fibrosis, and hypertrophy in cardiomyocytes. Finally, OTUD1 overexpression by AAV9 vector increases Ang II-induced cardiac remodeling in mice and OTUD1-regulated responses can be inhibited by blocking STAT3. Conclusion: Cardiomyocyte OTUD1 promotes pathological cardiac remodeling and dysfunction by deubiquitinating STAT3. These studies have highlighted a novel role of OTUD1 in hypertensive heart failure and identified STAT3 as a target of OTUD1 in mediating these actions.
研究领域:
心脏病学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
CELLULAR ONCOLOGY
·
2023
·Vol. 46
·期 4
·1001-1014
·
IF 6.6
Zhang Qi,Li Jinglei,Chen Zihan,Jiang Ke,Yang Kunyu,Huang Fang,Huang Ai,Zhang Xiaodong,Zhang Jinxiang,Wang Hui
Background The deubiquitinase ovarian tumor domain-containing 1 (OTUD1) has been considered as a tumor suppressor in many tumors, but there is minimal research on the role of OTUD1 in lung adenocarcinoma (LUAD) pathogenesis. Methods Bioinformatics analyses and western blot were applied for investigating OTUD1 expression in lung cancer and the drug that upregulated OTUD1. Kaplan–Meier analysis with log-rank test was used for survival analyses. IP-MS and co-IP were performed for identifying potential protein interactions with OTUD1. In vitro and in vivo assays were used for exploring the function of OTUD1 during the progression of LUAD. Results OTUD1 was dramatically downregulated in tumors and cell lines of human lung cancer. OTUD1 inhibited proliferation and migration of lung cancer cells in vitro. Moreover, OTUD1 inhibited growth of xenografts in nude mice and formation of primary lung tumors in urethane-induced lung cancer model. Mechanistically, we showed that OTUD1 deubiquitinated and stabilized FHL1. Furthermore, we listed and identified VE-822 as a candidate agonist for OTUD1. VE-822 inhibited proliferation of lung adenocarcinoma both in vitro and in vivo. Conclusion These results indicated that the deubiquitinase OTUD1, which was upregulated by VE-822, inhibited the progression of LUAD in vitro and in vivo by deubiquitinating and stabilizing FHL1.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
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