Suppr超能文献

CLAG3 基因中的表观遗传开关介导疟原虫对博莱霉素 S 的抗性。

Epigenetic switches in clag3 genes mediate blasticidin S resistance in malaria parasites.

机构信息

Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Catalonia, Spain.

出版信息

Cell Microbiol. 2013 Nov;15(11):1913-23. doi: 10.1111/cmi.12162. Epub 2013 Jul 19.

Abstract

Malaria parasites induce changes in the permeability of the infected erythrocyte membrane to numerous solutes, including toxic compounds. In Plasmodium falciparum, this is mainly mediated by PSAC, a broad-selectivity channel that requires the product of parasite clag3 genes for its activity. The two paralogous clag3 genes, clag3.1 and clag3.2, can be silenced by epigenetic mechanisms and show mutually exclusive expression. Here we show that resistance to the antibiotic blasticidin S (BSD) is associated with switches in the expression of these genes that result in altered solute uptake. Low concentrations of the drug selected parasites that switched from clag3.2 to clag3.1 expression, implying that expression of one or the other clag3 gene confers different transport efficiency to PSAC for some solutes. Selection with higher BSD concentrations resulted in simultaneous silencing of both clag3 genes, which severely compromises PSAC formation as demonstrated by blocked uptake of other PSAC substrates. Changes in the expression of clag3 genes were not accompanied by large genetic rearrangements or mutations at the clag3 loci or elsewhere in the genome. These results demonstrate that malaria parasites can become resistant to toxic compounds such as drugs by epigenetic switches in the expression of genes necessary for the formation of solute channels.

摘要

疟原虫诱导感染红细胞膜对多种溶质(包括有毒化合物)的通透性发生变化。在恶性疟原虫中,这主要是由 PSAC 介导的,PSAC 是一种广谱选择性通道,其活性需要寄生虫 clag3 基因产物的参与。两个平行的 clag3 基因,clag3.1 和 clag3.2,可以通过表观遗传机制沉默,并表现出相互排斥的表达。在这里,我们表明对抗生素硫酸博莱霉素 S(BSD)的抗性与这些基因表达的转换有关,这些转换导致溶质摄取的改变。低浓度的药物选择了从 clag3.2 切换到 clag3.1 表达的寄生虫,这意味着 clag3 基因的表达之一或另一个赋予 PSAC 对某些溶质不同的运输效率。用更高浓度的 BSD 选择导致两个 clag3 基因的同时沉默,这严重损害了 PSAC 的形成,如其他 PSAC 底物摄取受阻所证明的那样。clag3 基因表达的变化没有伴随着 clag3 基因座或基因组其他部位的大的遗传重排或突变。这些结果表明,疟原虫可以通过对形成溶质通道所必需的基因表达的表观遗传开关对有毒化合物(如药物)产生抗性。

相似文献

1
Epigenetic switches in clag3 genes mediate blasticidin S resistance in malaria parasites.
Cell Microbiol. 2013 Nov;15(11):1913-23. doi: 10.1111/cmi.12162. Epub 2013 Jul 19.
2
Identification of Antimalarial Compounds That Require CLAG3 for Their Uptake by -Infected Erythrocytes.
Antimicrob Agents Chemother. 2019 Apr 25;63(5). doi: 10.1128/AAC.00052-19. Print 2019 May.
3
Expression of the Plasmodium falciparum Clonally Variant clag3 Genes in Human Infections.
J Infect Dis. 2017 Mar 15;215(6):938-945. doi: 10.1093/infdis/jix053.
4
Solute restriction reveals an essential role for clag3-associated channels in malaria parasite nutrient acquisition.
Mol Pharmacol. 2012 Dec;82(6):1104-14. doi: 10.1124/mol.112.081224. Epub 2012 Sep 4.
7
Complex nutrient channel phenotypes despite Mendelian inheritance in a Plasmodium falciparum genetic cross.
PLoS Pathog. 2020 Feb 18;16(2):e1008363. doi: 10.1371/journal.ppat.1008363. eCollection 2020 Feb.
10
Deciphering the principles that govern mutually exclusive expression of Plasmodium falciparum clag3 genes.
Nucleic Acids Res. 2015 Sep 30;43(17):8243-57. doi: 10.1093/nar/gkv730. Epub 2015 Jul 21.

引用本文的文献

1
Overexpression in of an intrinsically disordered protein segment of UT impairs the parasite's proteostasis and reduces its growth rate.
Front Cell Infect Microbiol. 2025 May 13;15:1565814. doi: 10.3389/fcimb.2025.1565814. eCollection 2025.
2
The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels.
Cell Chem Biol. 2025 Jun 19;32(6):826-838.e13. doi: 10.1016/j.chembiol.2025.05.001. Epub 2025 May 23.
5
CLAG Paralogs All Traffic to the Host Membrane but Knockouts Have Distinct Phenotypes.
Microorganisms. 2024 Jun 8;12(6):1172. doi: 10.3390/microorganisms12061172.
6
Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle.
Int J Mol Sci. 2024 Jun 2;25(11):6145. doi: 10.3390/ijms25116145.
7
Genomics reveals heterogeneous Plasmodium falciparum transmission and selection signals in Zambia.
Commun Med (Lond). 2024 Apr 6;4(1):67. doi: 10.1038/s43856-024-00498-8.
8
Novel Ion Channel Genes in Malaria Parasites.
Genes (Basel). 2024 Feb 26;15(3):296. doi: 10.3390/genes15030296.
9
Genomics reveals heterogeneous transmission and population differentiation in Zambia and bordering countries.
medRxiv. 2024 Feb 11:2024.02.09.24302570. doi: 10.1101/2024.02.09.24302570.
10
Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum.
Malar J. 2024 Feb 12;23(1):44. doi: 10.1186/s12936-024-04855-9.

本文引用的文献

1
An epigenetic antimalarial resistance mechanism involving parasite genes linked to nutrient uptake.
J Biol Chem. 2013 Jul 5;288(27):19429-40. doi: 10.1074/jbc.M113.468371. Epub 2013 May 28.
2
Artemisinin resistance in Plasmodium falciparum: A process linked to dormancy?
Int J Parasitol Drugs Drug Resist. 2012 Dec 1;2:249-255. doi: 10.1016/j.ijpddr.2012.01.001. Epub 2012 Jan 27.
3
Silence, activate, poise and switch! Mechanisms of antigenic variation in Plasmodium falciparum.
Cell Microbiol. 2013 May;15(5):718-26. doi: 10.1111/cmi.12115. Epub 2013 Feb 21.
4
A view on the role of epigenetics in the biology of malaria parasites.
PLoS Pathog. 2012;8(12):e1002943. doi: 10.1371/journal.ppat.1002943. Epub 2012 Dec 13.
5
Solute restriction reveals an essential role for clag3-associated channels in malaria parasite nutrient acquisition.
Mol Pharmacol. 2012 Dec;82(6):1104-14. doi: 10.1124/mol.112.081224. Epub 2012 Sep 4.
6
Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases.
Nat Methods. 2012 Oct;9(10):993-8. doi: 10.1038/nmeth.2143. Epub 2012 Aug 26.
7
Ion and nutrient uptake by malaria parasite-infected erythrocytes.
Cell Microbiol. 2012 Jul;14(7):1003-9. doi: 10.1111/j.1462-5822.2012.01790.x. Epub 2012 Apr 19.
8
Outwitting evolution: fighting drug-resistant TB, malaria, and HIV.
Cell. 2012 Mar 16;148(6):1271-83. doi: 10.1016/j.cell.2012.02.021.
9
Transcriptional variation in the malaria parasite Plasmodium falciparum.
Genome Res. 2012 May;22(5):925-38. doi: 10.1101/gr.129692.111. Epub 2012 Mar 13.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验