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UBR-1缺陷导致（此处原文不完整，未明确具体对象）对伊维菌素产生耐药性。

UBR-1 deficiency leads to ivermectin resistance in .

作者信息

Li Yi, Gong Long, Wu Jing, Hung Wesley, Zhen Mei, Gao Shangbang

机构信息

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

出版信息

Elife. 2025 Apr 1;13:RP103718. doi: 10.7554/eLife.103718.

DOI:10.7554/eLife.103718
PMID:40167441
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11961118/
Abstract

Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in . Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca activity is diminished in . Additionally, enhancing glutamate uptake in mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in .

摘要

对抗蠕虫药，尤其是大环内酯类伊维菌素（IVM）的耐药性，对全球寄生虫控制构成了重大挑战。我们发现，一种进化上保守的E3泛素连接酶UBR-1的功能丧失会导致秀丽隐杆线虫产生IVM耐药性。在各种秀丽隐杆线虫突变体中，包括活力、体型、咽部抽动和运动能力在内的多种IVM抑制活性都得到了显著改善。有趣的是，外源施用谷氨酸会在野生型动物中诱导IVM耐药性。通过消除与谷氨酸代谢或信号传导相关的蛋白质：GOT-1（一种将天冬氨酸转化为谷氨酸的转氨酶）和EAT-4（一种囊泡谷氨酸转运体），秀丽隐杆线虫所有受IVM影响的表型的敏感性得以恢复。我们证明，IVM靶向的谷氨酸门控氯离子通道（GluCls）被下调，并且在秀丽隐杆线虫中IVM介导的对5-羟色胺激活的咽部钙活性的抑制作用减弱。此外，通过头孢曲松增强秀丽隐杆线虫突变体中的谷氨酸摄取，完全恢复了它们对IVM的敏感性。因此，UBR-1缺陷介导的异常谷氨酸信号传导导致秀丽隐杆线虫产生伊维菌素耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/0cd3a20b1bba/elife-103718-sa4-fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/7c9e961565b5/elife-103718-fig4-figsupp2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/4f2b869af88d/elife-103718-sa4-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/0cd3a20b1bba/elife-103718-sa4-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/6a08445039f7/elife-103718-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/1d839aeb6701/elife-103718-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/b959e5c82803/elife-103718-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/e3e1a255a0da/elife-103718-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/fff0227dc579/elife-103718-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/7821fca4dcd2/elife-103718-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/e2cea4940fa3/elife-103718-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/77dca660c72c/elife-103718-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/38889f7c3c4f/elife-103718-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/7c9e961565b5/elife-103718-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/97136225aaed/elife-103718-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/6f8f171e4fed/elife-103718-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/4f2b869af88d/elife-103718-sa4-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4396/11961118/0cd3a20b1bba/elife-103718-sa4-fig2.jpg

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