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利什曼原虫通过过度表达宿主 Rab18 和 TRAPPC9 并下调 miR-1914-3p 的表达，劫持宿主脂滴以供其在巨噬细胞中增殖。

Leishmania highjack host lipid body for its proliferation in macrophages by overexpressing host Rab18 and TRAPPC9 by downregulating miR-1914-3p expression.

机构信息

National Institute of Immunology, New Delhi, India.

Kusuma School of Biological Sciences, Indian Institute of Technology, Hauz Khas, New Delhi, India.

出版信息

PLoS Pathog. 2024 Feb 27;20(2):e1012024. doi: 10.1371/journal.ppat.1012024. eCollection 2024 Feb.

DOI:10.1371/journal.ppat.1012024
PMID:38412149
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10898768/
Abstract

Lipids stored in lipid-bodies (LBs) in host cells are potential sources of fatty acids for pathogens. However, the mechanism of recruitment of LBs from the host cells by pathogens to acquire fatty acids is not known. Here, we have found that Leishmania specifically upregulates the expression of host Rab18 and its GEF, TRAPPC9 by downregulating the expression of miR-1914-3p by reducing the level of Dicer in macrophages via their metalloprotease gp63. Our results also show that miR-1914-3p negatively regulates the expression of Rab18 and its GEF in cells. Subsequently, Leishmania containing parasitophorous vacuoles (Ld-PVs) recruit and retain host Rab18 and TRAPPC9. Leishmania infection also induces LB biogenesis in host cells and recruits LBs on Ld-PVs and acquires FLC12-labeled fatty acids from LBs. Moreover, overexpression of miR-1914-3p in macrophages significantly inhibits the recruitment of LBs and thereby suppresses the multiplication of parasites in macrophages as parasites are unable to acquire fatty acids. These results demonstrate a novel mechanism how Leishmania acquire fatty acids from LBs for their growth in macrophages.

摘要

储存在宿主细胞脂滴（LB）中的脂质是病原体获取脂肪酸的潜在来源。然而，病原体从宿主细胞中招募 LB 以获取脂肪酸的机制尚不清楚。在这里，我们发现利什曼原虫通过其金属蛋白酶 gp63 降低巨噬细胞中 Dicer 的水平，特异性地下调 miR-1914-3p 的表达，从而上调宿主 Rab18 和其鸟苷酸交换因子（GEF）TRAPPC9 的表达。我们的结果还表明，miR-1914-3p 负调控细胞中 Rab18 和其 GEF 的表达。随后，含有滋养液泡（Ld-PVs）的利什曼原虫招募并保留宿主 Rab18 和 TRAPPC9。利什曼原虫感染还诱导宿主细胞中 LB 的生物发生，并招募 Ld-PVs 上的 LB，并从 LB 中获取 FLC12 标记的脂肪酸。此外，巨噬细胞中 miR-1914-3p 的过表达显著抑制 LB 的募集，从而抑制巨噬细胞中寄生虫的增殖，因为寄生虫无法获取脂肪酸。这些结果表明了利什曼原虫从 LB 中获取脂肪酸以在巨噬细胞中生长的一种新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/84795e5cb9af/ppat.1012024.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/19fb603fc56e/ppat.1012024.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/055bcbdac0dc/ppat.1012024.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/ce032e5ee1ad/ppat.1012024.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/3069ad1f37ea/ppat.1012024.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/059f34fb6d14/ppat.1012024.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/84795e5cb9af/ppat.1012024.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/19fb603fc56e/ppat.1012024.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/055bcbdac0dc/ppat.1012024.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/ce032e5ee1ad/ppat.1012024.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/3069ad1f37ea/ppat.1012024.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/059f34fb6d14/ppat.1012024.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de6/10898768/84795e5cb9af/ppat.1012024.g006.jpg

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引用本文的文献

[1]
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ACS Omega. 2025-7-23

[2]
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[3]
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[4]
VAPA mediates lipid exchange between Leishmania amazonensis and host macrophages.

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本文引用的文献

[1]
Metabolic and immune-sensitive contacts between lipid droplets and endoplasmic reticulum reconstituted in vitro.

Proc Natl Acad Sci U S A. 2022-6-14

[2]
Hemoglobin Endocytosis and Intracellular Trafficking: A Novel Way of Heme Acquisition by .

Pathogens. 2022-5-16

[3]
Lipid droplet accumulation occurs early following Salmonella infection and contributes to intracellular bacterial survival and replication.

Mol Microbiol. 2022-2

[4]
Lipid and fatty acid metabolism in trypanosomatids.

Microb Cell. 2021-10-6

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An overview of the fatty acid biosynthesis in the protozoan parasite Leishmania and its relevance as a drug target against leishmaniasis.

Mol Biochem Parasitol. 2021-11

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Lipid droplets and the host-pathogen dynamic: FATal attraction?

J Cell Biol. 2021-8-2

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Biochim Biophys Acta Mol Cell Biol Lipids. 2021-7

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Nutrient sensing in Leishmania: Flagellum and cytosol.

Mol Microbiol. 2021-5

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Trends Parasitol. 2020-1-28

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