更新于：2024-09-19

TRIM33

更新于：2024-09-19

基本信息

别名

E3 ubiquitin-protein ligase TRIM33、Ectodermin homolog、FLJ11429

+ [18]

简介

Acts as an E3 ubiquitin-protein ligase. Promotes SMAD4 ubiquitination, nuclear exclusion and degradation via the ubiquitin proteasome pathway. According to PubMed:16751102, does not promote a decrease in the level of endogenous SMAD4. May act as a transcriptional repressor. Inhibits the transcriptional response to TGF-beta/BMP signaling cascade. Plays a role in the control of cell proliferation. Its association with SMAD2 and SMAD3 stimulates erythroid differentiation of hematopoietic stem/progenitor (By similarity). Monoubiquitinates SMAD4 and acts as an inhibitor of SMAD4-dependent TGF-beta/BMP signaling cascade (Monoubiquitination of SMAD4 hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade).

关联

100 项与 TRIM33 相关的临床结果

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100 项与 TRIM33 相关的转化医学

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0 项与 TRIM33 相关的专利（医药）

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310

项与 TRIM33 相关的文献（医药）

2024-10-01·Seminars in Arthritis and Rheumatism

Differences in the autoantibody phenotypes and long-term outcomes between juvenile- and adult-idiopathic inflammatory myopathies

Article

作者: Onishi, Akira ; Kitagori, Koji ; Onizawa, Hideo ; Yoshifuji, Hajime ; Okiyama, Naoko ; Nakashima, Ran ; Akizuki, Shuji ; Morinobu, Akio ; Tanaka, Masao ; Shirakashi, Mirei ; Hiwa, Ryosuke ; Ichimura, Yuki ; Mimori, Tsuneyo ; Sasai, Tsuneo ; Tsuji, Hideaki ; Yasumi, Takahiro

OBJECTIVETo investigate differences in autoantibodies, clinical features, and long-term outcomes between juvenile-idiopathic inflammatory myopathy (IIM) and adult-IIM METHODS: Autoantibodies, clinical characteristics, and drug-free conditions for a maximum of 20 years were retrospectively analyzed in 320 Japanese IIM patients (juvenile-IIM, n = 34; adult-IIM, n = 286) using the Kyoto University Registry.RESULTSAutoantibodies observed in juvenile-IIM were anti-TIF1-γ (15 %), anti-MDA-5 (15 %), anti-ARS (9 %), and anti-NXP-2 (6 %). Those observed in adult-IIM were anti-ARS (32 %), anti-MDA-5 (23 %), anti-TIF1-γ (8 %), anti-SRP (8 %), anti-Mi-2 (2 %), and anti-NXP-2 (1 %). The cumulative drug-free condition rate was higher in juvenile-IIM than in adult-IIM up to 20 years (juvenile-IIM vs. adult-IIM, 34 % vs. 18 %, p = 0.0016). Anti-TIF1-γ was associated with lesser muscle symptoms (60 % vs. 90 %), malignancy (0 % vs. 57 %), and glucocorticoid use (40 % vs. 86 %) in juvenile-IIM compared to adult-IIM, while juvenile-IIM more achieved drug-free conditions (60 % vs. 25 %). Both juvenile-IIM and adult-IIM with anti-MDA-5 demonstrated a high frequency of amyopathic dermatomyositis, interstitial lung disease (ILD), and multi-immunosuppressive therapy, with high drug-free conditions (50 % vs. 49 %). Both juvenile-IIM and adult-IIM with anti-ARS showed frequent skin rashes, muscle symptoms, and ILD, frequent need for multi-immunosuppressive therapy, and low drug-free condition rates (0 % vs. 3 %). Both juvenile-IIM and adult-IIM with anti-NXP-2 showed frequent skin rashes and muscle symptoms, low ILD frequency, and frequent use of methotrexate and glucocorticoids, which did not achieve drug-free conditions (0 % vs. 0 %).CONCLUSIONSDrug-free condition was achieved more frequently in juvenile-IIM patients than adult-IIM patients. Specific autoantibodies were associated with different clinical characteristics and outcomes between juvenile-IIM and adult-IIM.

2024-09-01·International Journal of Dermatology

Erythrodermic dermatomyositis with anti‐TIF1‐γ antibodies

Letter

作者: Jin, Hong‐zhong ; Tang, Ke‐yun

Erythroderma is a complex inflammatory disease in which erythema and scaling affect more than 90% of the body′s surface area.The underlying causes are grouped as dermatoses, drug-induced reactions, malignancies, infections, autoimmune diseases, and idiopathic disorders.

2024-09-01·Cellular Signalling

TRIM33 enhances the ubiquitination of TFRC to enhance the susceptibility of liver cancer cells to ferroptosis

Article

作者: Ji, Wenjing ; Zhang, Weibin ; Ke, Yue ; Zhang, Xin

BACKGROUNDHepatocellular carcinoma (HCC) is a common malignancy, and ferroptosis is a novel form of cell death driven by excessive lipid peroxidation. In recent years, ferroptosis has been widely utilized in cancer treatment, and the ubiquitination modification system has been recognized to play a crucial role in tumorigenesis and metastasis. Increasing evidence suggests that ubiquitin regulates ferroptosis-related substrates involved in this process. However, the precise mechanism of utilizing ubiquitination modification to regulate ferroptosis for HCC treatment remains unclear.METHODSIn this study, we detected the expression of TRIM33 in HCC using immunohistochemistry and western blotting techniques. The functional role of TRIM33 was verified through both in vitro and in vivo experiments. To evaluate the level of ferroptosis, mitochondrial superoxide levels, MDA levels, Fe2⁺ levels, and cell viability were assessed. Downstream substrates of TRIM33 were screened and confirmed via immunoprecipitation, immunofluorescence staining, and ubiquitination modification experiments.RESULTSOur findings demonstrate that TRIM33 inhibits the growth and metastasis of HCC cells both in vitro and in vivo while promoting their susceptibility to ferroptosis. Mechanistically speaking, TRIM33 induces cellular ferroptosis through E3 ligase-dependent degradation of TFRC-a known inhibitor of this process-thus elucidating the specific type and site at which TFRC undergoes modification by TRIM33.CONCLUSIONIn summary, our study reveals an important role for TRIM33 in HCC treatment while providing mechanistic support for its function. Additionally highlighted is the significance of ubiquitination modification leading to TFRC degradation-an insight that may prove valuable for future targeted therapies.

项与 TRIM33 相关的新闻（医药）

2024-06-12

·生物探索

Cell Mol Immunol丨吴励课题组揭示调控树突状细胞发育与生存的重要机制

引言清华大学-北京大学生命联合中心吴励课题组近日在Cellular & Molecular Immunology期刊上在线发表了题为“TRIM33通过对Irf8与Bcl2l11转录的调控在树突状细胞的分化与稳态中发挥重要作用”（TRIM33 plays a critical role in regulating dendritic cell differentiation and homeostasis by modulating Irf8 and Bcl2l11 transcription）的研究论文。该研究首次报告了TRIM33通过促进Irf8表达以支持cDC1发育，同时通过抑制Bcl2l11在所有DC亚群及其前体中的表达，在维持DC的稳态中起到关键作用。作为免疫系统中重要的调控细胞，树突状细胞（dendritic cells，DC）的稳态对于维持机体的先天和适应性免疫反应至关重要【1】。本项研究在课题组既往鉴定的调控DC发育分化的关键转录因子和表观遗传修饰因子【2-5】的基础上，确定了TRIM33作为调控DC分化和生存的又一新的调节因子的重要功能。已有研究显示TRIM33通过转录及表观调控对红细胞、淋巴细胞、单核细胞和粒细胞系的谱系生成和功能具有显著影响【6-8】，但TRIM33在DC谱系中的作用仍不明确。此前研究显示TRIM33与转录因子PU.1，一个关键的DC命运调节因子之间具有相互作用【8】，进一步提示TRIM33可能参与了DC的谱系调控。为了研究TRIM33在DC分化及稳态中的作用，作者首先对Trim33fl/fl Cre-ERT2小鼠进行了表型分析，观察到诱导全身性Trim33敲除后，经典1型DC（conventional type 1 DC, cDC1）和浆细胞样DC（plasmacytoid DC, pDC）明显缺失，cDC2数量则显著减少，同时DC前体的数量和DC生成潜能也严重受损。为进一步解释这些发现的分子基础，作者检测了几种关键转录因子的表达，发现TRIM33缺失的DC前体中Irf8，一个调控cDC1分化的关键转录因子的表达显著下降。综合CUT&Tag、co-IP/MS等分子机制研究，作者证实TRIM33通过与Irf8基因体和增强子区域结合，通过影响CDK9和Ser2磷酸化RNA聚合酶II的招募直接调控Irf8的转录。这一发现解释了DC（尤其是cDC1）分化对TRIM33依赖性。此外，作者在DC前体中鉴定到了数百个TRIM33和PU.1的共结合位点，并证实TRIM33通过与促凋亡因子Bcl2l11（Bim）的一个增强子位点结合来抑制Bcl2l11（Bim）的转录，进而抑制DC及其前体的凋亡。同时进一步分析确定了在CD11c+条件性敲除的Trim33fl/fl Itgax-Cre小鼠中，大多数DC亚群的细胞数显著减少，这说明TRIM33的缺失导致了终末分化DC的生存缺陷。此外，研究还显示在DC前体中同时过表达irf8和敲低Bcl2l11可以恢复TRIM33缺失的DC前体产生cDC1的能力，但单一过表达Irf8或敲低Bcl2l11均不能产生此效果。因此，本研究鉴定了TRIM33在转录调控DC发育和维持其生存中的双重新功能，这些功能协同维持了DC的稳态。下图总结了TRIM33在DC谱系稳态中的关键作用。模式图（Credit: Cellular & Molecular Immunology）有意思的是，近期Tiniakou I. et al.发表的一篇文章也描述了非常相似的发现【9】，是对本研究结果的很好佐证。本研究成果为深入了解DC发育和稳态的关键转录调节因子提供了新对知识，今后基于DC的免疫调节和治疗新策略的制定将会从这项研究中受益。参考文献 1. Durai, V. & Murphy, Kenneth M. Functions of Murine Dendritic Cells. Immunity 45, 719-736, doi:https://doi.org/10.1016/j.immuni.2016.10.010 (2016). 2. Wu, L., Nichogiannopoulou, A., Shortman, K. & Georgopoulos, K. Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity 7, 483-492 (1997). 3. Wu, L. et al. RelB is essential for the development of myeloid-related CD8 alpha(-) dendritic cells but not of lymphoid-related CD8 alpha(+) dendritic cells. Immunity 9, 839-847, doi:10.1016/s1074-7613(00)80649-4 (1998). 4. Carotta, S. et al. The Transcription Factor PU.1 Controls Dendritic Cell Development and Flt3 Cytokine Receptor Expression in a Dose-Dependent Manner. Immunity 32, 628-641, doi:10.1016/j.immuni.2010.05.005 (2010). 5. Zhang, Y. et al. Regulation of pDC Fate Determination by Histone Deacetylase 3. eLife 12, e80477, doi:10.7554/eLife.80477 (2023). 6. Rossmann, M. P. et al. Cell-specific transcriptional control of mitochondrial metabolism by TIF1gamma drives erythropoiesis. Science 372, 716-721, doi:10.1126/science.aaz2740 (2021). 7. Wang, E. et al. The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer. eLife 4, e06377, doi:10.7554/eLife.06377 (2015). 8. Kusy, S. et al. Adult Hematopoiesis is Regulated by TIF1 gamma, a Repressor of TAL1 and PU.1 Transcriptional Activity. Cell Stem Cell 8, 412-425, doi:10.1016/j.stem.2011.02.005 (2011). 9. Tiniakou, I. et al. Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation. Science immunology 9, eadi1023, doi:10.1126/sciimmunol.adi1023 (2024). 责编|探索君排版|探索君文章来源|“BioArtMED” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床结果

2023-01-15

·生物谷

The EMBO Journal:揭示PML核体招募TRIM33在小鼠胚胎干细胞中调控基因转录的新机制

本研究首次发现TRIM33能够特异的在小鼠胚胎干细胞（mESC）中形成聚集体并与早幼粒细胞白血病核体(PML NBs)共定位转化生长因子β（transforming growth factor β, TGF-β）信号通路在组织稳态调节、免疫反应、肿瘤的发生和哺乳动物早期中内胚层分化中发挥着重要功能。已有研究表明TRIM家族成员TRIM33是TGF-β信号通路中的关键成员，在小鼠胚胎干细胞向中内胚层分化过程中调控相关标志基因的转录。在研究过程中发现TRIM33在小鼠胚胎干细胞及中内胚层分化状态下蛋白水平无显著差异，然而其在细胞内聚集状态及调控的基因截然不同。因此，在不同细胞状态下TRIM33发挥功能的机制仍然有待深入研究。清华大学郗乔然课题组及吝易课题组在《欧洲分子生物学组织期刊》（The EMBO Journal）杂志在线发表题为“细胞环境依赖的PML核体在小鼠胚胎干细胞中特异招募TRIM33调控基因转录”（Recruitment of TRIM33 to cell-context specific PML nuclear bodies regulates Nodal signaling in mESCs）的研究论文。本研究首次发现TRIM33能够特异的在小鼠胚胎干细胞（mESC）中形成聚集体并与早幼粒细胞白血病核体(PML NBs)共定位，显微成像结果显示，mESCs中TRIM33蛋白形成聚集体依赖于PML NBs，且只能在特定细胞状态下被招募进入PML NBs中。此外，基因组学及转录组学分析表明TRIM33和PML共同调控mESCs中Nodal信号通路下游靶基因Lefty1/2的转录。在干细胞状态下，TRIM33及PML NBs共同定位于靶基因Lefty1/2基因座上，促进基因转录；而在拟胚体分化及氧化应激状态下，PML NBs离开了Lefty1/2基因座，TRIM33聚集体解聚并难以结合在Lefty1/2基因启动子区域，导致Lefty1/2基因转录水平显著降低。最后，PML-TurboID邻近标记结合蛋白质谱分析证实了PML NBs的蛋白组成在不同细胞环境中发生动态变化，TRIM33仅在干细胞特异的PML NBs中高度富集。因此，本研究揭示了PML NBs在mESCs形成的转录调控中心，能够帮助TRIM33形成聚集体并调控Lefty1/2基因转录，同时论证了PML NBs作为转录调控中心，以细胞环境依赖的方式招募不同蛋白组分的调节功能。清华大学生命科学学院郗乔然副教授，吝易助理教授为本文共同通讯作者。清华大学2016级博士生孙宏瑶、2017级博士生陈昱彤为并列第一作者。清华大学生命科学学院张强锋课题组2017级已毕业博士生邵燕秋帮助分析了Hi-C数据。郗乔然课题组2016级已毕业博士生闫坤为本工作顺利开展作出重要贡献。本研究同时感谢清华大学流式分选平台、质谱分析平台、影像平台的大力支持与帮助。本工作获得国家自然科学基金、科技部国家重点研发计划、清华-北大生命科学联合中心、清华-IDG/麦戈文脑科学研究院的大力支持。图：PML NBs形成转录调控中心，能够调控一簇基因的转录，并招募TRIM33及其他转录因子结合在Lefty1/2基因座上，从而调控Lefty1/2基因的转录。