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伊维菌素通过与磷脂酰肌醇3激酶相关激酶的调节因子TELO2结合来抑制Wnt/β-连环蛋白信号通路。

Ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases.

作者信息

Yonezawa Honami, Ikeda Akari, Takahashi Ryo, Endo Haruka, Sugawara Yasuyo, Goto Mikako, Kanno Mirute, Ogawa Sosuke, Nakamura Karin, Ujiie Haruki, Iwatsuki Masato, Hirose Tomoyasu, Sunazuka Toshiaki, Uehara Yoshimasa, Nishiya Naoyuki

机构信息

Division of Integrated Information for Pharmaceutical Sciences, Department of Clinical Pharmacy, Iwate Medical University School of Pharmacy, Shiwa-gun, Yahaba-cho, Iwate 028-3694, Japan.

Ōmura Satoshi Memorial Institute and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Minato-ku 108-8641, Japan.

出版信息

iScience. 2022 Mar 7;25(3):103912. doi: 10.1016/j.isci.2022.103912. eCollection 2022 Mar 18.

DOI:10.1016/j.isci.2022.103912
PMID:35530256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9072907/
Abstract

Ivermectin (IVM), an avermectin-derivative anthelmintic, specifically binds to glutamate-gated chloride ion channels (GluCls), causing paralysis in invertebrates. IVM also exhibits other biological activities such as Wnt/β-catenin pathway inhibition in vertebrates that do not possess GluCls. This study showed that affinity purification using immobilized IVM B1a isolated TELO2, a cofactor of phosphatidylinositol 3-kinase-related kinases (PIKKs), as a specific IVM B1a-binding protein. knockdown reduced cytoplasmic β-catenin and the transcriptional activation of β-catenin/TCF. IVM B1a bound to TELO2 through the C-terminal α-helix, in which mutations conferred IVM resistance. IVM reduced the TELO2 and PIKK protein levels and the AKT and S6 kinase phosphorylation levels. The inhibition of mTOR kinase reduced the cytoplasmic β-catenin level. Therefore, IVM binds to TELO2, inhibiting PIKKs and reducing the cytoplasmic β-catenin level. In conclusion, our data indicate TELO2 as a druggable target for human diseases involving abnormalities of the Wnt/β-catenin pathway and PIKKs, including mTOR.

摘要

伊维菌素（IVM）是一种阿维菌素衍生物驱虫药，它特异性地与谷氨酸门控氯离子通道（GluCls）结合，导致无脊椎动物麻痹。IVM还表现出其他生物活性，如在不具有GluCls的脊椎动物中抑制Wnt/β-连环蛋白信号通路。本研究表明，使用固定化的IVM B1a进行亲和纯化，分离出了磷脂酰肌醇3激酶相关激酶（PIKKs）的辅助因子TELO2，作为一种特异性的IVM B1a结合蛋白。敲低TELO2可降低细胞质中的β-连环蛋白以及β-连环蛋白/TCF的转录激活。IVM B1a通过C端α螺旋与TELO2结合，其中的突变赋予了IVM抗性。IVM降低了TELO2和PIKK蛋白水平以及AKT和S6激酶的磷酸化水平。抑制mTOR激酶可降低细胞质中的β-连环蛋白水平。因此，IVM与TELO2结合，抑制PIKKs并降低细胞质中的β-连环蛋白水平。总之，我们的数据表明TELO2是涉及Wnt/β-连环蛋白信号通路和PIKKs（包括mTOR）异常的人类疾病的一个可成药靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/529784cef20f/sc14.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/e4f301bb18f8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/a78c6fe6e130/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/3c27d127ad66/sc2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/615248906e12/sc3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/84f681433f3a/sc4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/9b22e7726174/sc5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/55aa2b4595ec/sc6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/3e5daf9dc716/sc7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/3872eb919178/sc8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/2eb9cc1ca58c/sc9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/5e41730b6808/sc10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/c8473f380067/sc11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/b2d1e5ed3286/sc12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/fdcf9aa1c0e8/sc13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8150/9072907/529784cef20f/sc14.jpg

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