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2019 1

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Deubiquitinases as pivotal regulators of T cell functions

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《医学前沿（英文）》 2018年第12卷第4期页码 451-462 doi: 10.1007/s11684-018-0651-y

摘要：

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases (DUBs). DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.

关键词： deubiquitinase ubiquitination T cell activation T cell differentiation T cell tolerance

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Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

《医学前沿（英文）》 2022年第16卷第3期页码 442-458 doi: 10.1007/s11684-021-0877-y

摘要： T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

关键词： T-cell acute lymphoblastic leukemia HDAC inhibitor chidamide NOTCH1 MYC ubiquitination

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Regulation of NLR stability in plant immunity

Tao WANG, Jiaxin LI, Qian-Hua SHEN

《农业科学与工程前沿（英文）》 2019年第6卷第2期页码 97-104 doi: 10.15302/J-FASE-2018248

摘要：

Plant nucleotide binding domain and leucine-rich repeat (NLR) receptors recognize pathogen effectors directly or indirectly and mediate innate immune responses. NLR-mediated immunity also has direct impacts on plant growth and development, as well as yield and survival. The levels of NLR proteins are therefore intricately controlled in plants to balance defense responses and other processes. In recent years, the ubiquitination-26S proteasome system and the HSP90 chaperones have emerged as having key functions in the regulation of NLR stability. The N-end rule pathway of protein degradation is also directly linked to NLR stability. Recent progress in the regulation of NLR stability and turnover is summarized here, focusing on the key components and pathways.

关键词： E3 ubiquitin ligase degradation nucleotide-binding leucine-rich repeat receptor plant immunity proteasome protein stability ubiquitination

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时间序列多组学整合分析揭示原代肝细胞体外培养去分化过程伴随非降解性泛素化修饰的增加 Article

姜正一, 孙泽宇, 欧阳晓希, 赵亚磊, 周梦豪, 王保红, 李启睿, 范林骁, 张赛男, 李兰娟

《工程（英文）》 2020年第6卷第11期页码 1302-1314 doi: 10.1016/j.eng.2020.02.011

摘要：

目前，原代肝细胞（PHC）在各个研究领域被广泛使用，但是由于在体外培养过程中肝细胞特异性功能的迅速退化（即去分化），严重限制了它的应用范围。尽管学者已经对PHC的转录调控和全细胞蛋白质组（WCP）进行了广泛研究，但只有为数不多的研究考虑了蛋白质翻译后修饰（PTM）在这一过程中的作用。为了揭示引起PHC去分化的潜在机制，我们收集了在体外培养0 h、6 h、12 h、24 h和48 h的大鼠原代肝细胞样本，对各个时间点细胞样本的转录组、WCP、泛素化蛋白质组和磷酸化蛋白质组进行了定量分析。我们的数据包含了原代肝细胞体外培养去分化过程中详细的多组学分析结果，包括2196个蛋白质、2056个泛素化修饰位点和4932个磷酸化修饰位点。这项研究表明，PHC去分化过程中基因转录水平和蛋白质表达量之间的相关性较低。泛素化修饰组和对应的WCP联合分析表明，PHC去分化伴随着非降解性K27泛素化修饰位点的增加。对差异表达的磷酸化修饰蛋白进行功能富集分析，表明该过程中有铁死亡参与。其中，有404种蛋白质同时具有泛素化修饰位点和磷酸化修饰位点，被鉴定为与去分化事件有关的关键蛋白。最终，Ptbp1、Hnrpd、Hnrnpu和Srrm2被鉴定为PHC去分化过程中的hub分子。综上所述，我们的数据为抑制原代肝细胞体外培养去分化提供了潜在靶点分子及新的见解。

关键词：去分化原代肝细胞翻译后修饰泛素化蛋白质组学磷酸化蛋白质组学转录组学