CD73/NT5E-mediated ubiquitination of AURKA regulates alcohol-related liver fibrosis via modulating hepatic stellate cell senescence.

CD73/NT5E-mediated ubiquitination of AURKA regulates alcohol-related liver fibrosis via modulating hepatic stellate cell senescence.
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CD73/NT5E介导的AURKA泛素化通过调节肝星状细胞衰老来调节酒精性肝纤维化。

DOI:
10.7150/ijbs.80461
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发表时间:
2023
影响因子:
9.2
通讯作者:
Lv X
Lv X
中科院分区:
生物学2区
文献类型:
--
作者:
Liu Z;Wu B;Liu X;Wu X;Du J;Xia G;Cai J;Zhu H;Sheng X;Zhang M;Xu J;Xu T;Lv X

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酒精相关性肝病(ALD)是全世界最常见的慢性肝病;然而,目前还没有有效的治疗方法来预防酒精相关性肝纤维化(ALF)的进展。 CD73/NT5E 是一种核苷酸酶,通过将细胞外嘌呤能信号传导与细胞内激酶活性和基因转录相结合来控制细胞稳态,并与细胞增殖、分化和死亡相关。在本研究中,我们证明与CD39/ENTPD1相比,CD73/NT5E对HSC的活化、增殖和凋亡具有更显着的调节作用。我们检测了正常和纤维化人类肝脏中 CD73/NT5E 的表达。 CD73/NT5E 的缺失对 ALF 小鼠模型具有保护作用。此外,京都基因与基因组百科全书(KEGG)通路分析显示,CD73/NT5E过表达与p53信号通路有关,调节细胞衰老。使用 STRING 数据库预测与 p53 相互作用的蛋白质。蛋白质组分析和 STRING 数据库之间的重叠部分是极光激酶 A (AURKA),一种细胞周期调节激酶。免疫共沉淀 (co-IP) 测定和分子对接证实 CD73/NT5E 直接与 AURKA 相互作用。我们发现 CD73/NT5E 的过度表达抑制 AURKA 泛素化,而 p53 信号传导被下调。从机制上讲,CD73/NT5E 通过与 AURKA 结合来调节 ALF 以及星状细胞的激活和衰老。这些发现表明 CD73/NT5E 是 ALF 的潜在治疗靶点。
Alcohol-related liver disease (ALD) is the most common chronic liver disease worldwide; however, no effective treatment to prevent the progression of alcohol-related liver fibrosis (ALF) is available. CD73/NT5E, a nucleotidase, controls cellular homeostasis by combining extracellular purinergic signaling with intracellular kinase activity and gene transcription and is associated with cell proliferation, differentiation, and death. In this study, we demonstrated that CD73/NT5E had a more significant regulatory effect on the activation, proliferation, and apoptosis of HSCs compared with that of CD39/ENTPD1. We examined the expression of CD73/NT5E in the normal and fibrotic human livers. The absence of CD73/NT5E was protective in mouse models of ALF. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that CD73/NT5E overexpression was related to the p53 signaling pathway, which regulates cell senescence. Proteins interacting with p53 were predicted using the STRING database. The overlap between proteomic analysis and STRING databases was for Aurora kinase A (AURKA), a cell cycle-regulated kinase. Coimmunoprecipitation (co-IP) assay and molecular docking confirmed that CD73/NT5E directly interacted with AURKA. We found that overexpression of CD73/NT5E inhibited AURKA ubiquitination, whereas p53 signaling was downregulated. Mechanistically, CD73/NT5E regulated ALF and the activation and senescence of stellate cells by binding to AURKA. These findings indicate that CD73/NT5E is a potential therapeutic target for ALF.
DOI: 10.7150/thno.22010
发表时间: 2018
期刊: Theranostics
影响因子: 12.4
作者:
Li X;Xu W;Kang W;Wong SH;Wang M;Zhou Y;Fang X;Zhang X;Yang H;Wong CH;To KF;Chan SL;Chan MTV;Sung JJY;Wu WKK;Yu J
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发表时间: 2014-05-15
期刊: Nature
影响因子: 64.8
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DOI: 10.1002/hep.25744
发表时间: 2012-09
期刊: HEPATOLOGY
影响因子: 13.5
作者:
Kong, Xiaoni;Feng, Dechun;Wang, Hua;Hong, Feng;Bertola, Adeline;Wang, Fu-Sheng;Gao, Bin
通讯作者: Gao, Bin
DOI: 10.1016/j.addr.2017.05.007
发表时间: 2017-11-01
影响因子: 16.1
作者:
Higashi T;Friedman SL;Hoshida Y
通讯作者: Hoshida Y
DOI: 10.1016/s0140-6736(22)00847-9
发表时间: 2022-07-16
期刊: LANCET
影响因子: 168.9
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M.;Shivarov, Velizar;Shobeiri, Parnian;Shrestha, Roman;Sidemo, Negussie Boti;Sigfusdottir, Inga Dora;Silva, Diego Augusto Santos;da Silva, Natacha Torres;Singh, Jasvinder A.;Singh, Surjit;Skryabin, Valentin Yurievich;Skryabina, Anna Aleksandrovna;Sleet, David A.;Solmi, Marco;Solomon, Yonatan;Song, Suhang;Song, Yimeng;Sorensen, Reed J. D.;Soshnikov, Sergey;Soyiri, Ireneous N.;Stein, Dan J.;Subba, Sonu Hangma;Szocska, Miklos;Seisdedos, Rafael Tabares;Tabuchi, Takahiro;Taheri, Majid;Tan, Ker Kan;Tareke, Minale;Tarkang, Elvis Enowbeyang;Temesgen, Gebremaryam;Temesgen, Worku Animaw;Temsah, Mohamad Hani;Thankappan, Kavumpurathu Raman;Thapar, Rekha;Thomas, Nikhil Kenny;Tiruneh, Chalachew;Todorovic, Jovana;Torrado, Marco;Touvier, Mathilde;Palone, Marcos Roberto Tovani;Mai Thi Ngoc Tran;Llimos, Sergi Trias;Tripathy, Jaya Prasad;Vakilian, Alireza;Valizadeh, Rohollah;Varmaghani, Mehdi;Varthya, Shoban Babu;Vasankari, Tommi Juhani;Vos, Theo;Wagaye, Birhanu;Waheed, Yasir;Walde, Mandaras Tariku;Wang, Cong;Wang, Yanzhong;Wang, Yuan Pang;Westerman, Ronny;Wickramasinghe, Nuwan Darshana;Wubetu, Abate Dargie;Xu, Suowen;Yamagishi, Kazumasa;Yang, Lin;Yesera, Gesila Endashaw E.;Yigit, Arzu;Yigit, Vahit;Yimaw, Ayenew Engida;Yon, Dong Keon;Yonemoto, Naohiro;Yu, Chuanhua;Zadey, Siddhesh;Zahir, Mazyar;Zare, Iman;Zastrozhin, Mikhail Sergeevich;Zastrozhina, Anasthasia;Zhang, Zhi Jiang;Zhong, Chenwen;Zmaili, Mohammad;Zuniga, Yves Miel H.;Gakidou, Emmanuela;Madureira-Carvalho, Aurea M.
通讯作者: Madureira-Carvalho, Aurea M.