A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.
A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.
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DOI：
10.1172/jci161944
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发表时间：
2023-03-15
影响因子：
15.9
通讯作者：
Moody, D. Branch
中科院分区：
文献类型：
--
作者：
Bedard, Melissa;van der Niet, Sanne;Bernard, Elliott M.;Babunovic, Gregory;Cheng, Tan-Yun;Aylan, Beren;Grootemaat, Anita E.;Raman, Sahadevan;Botella, Laure;Ishikawa, Eri;O'Sullivan, Mary P.;Mayfield, Jacob A.;O'Leary, Seonadh;Buter, Jeffrey;Minnaard, Adriaan J.;Fortune, Sarah M.;Murphy, Leon O.;Ory, Daniel S.;Keane, Joseph;Yamasaki, Sho;Gutierrez, Maximiliano G.;van der Wel, Nicole;Moody, D. Branch
充满脂质的泡沫状巨噬细胞的诱导是结核病（TB）的细胞标志，其涉及感染的吞噬溶酶体从杀伤位点转化为营养丰富的复制小生境。在这里，我们表明，萜烯核苷脱落结核分枝杆菌，1-tuberculosinyladenosine（1-TbAd），引起溶酶体成熟停滞和自噬阻断，导致脂质储存在M1巨噬细胞。纯的1-TbAd，或用产生萜核苷的M.结核病引起的溶酶体内和细菌周围脂质储存模式与泡沫巨噬细胞中已知的分子和亚细胞位置相匹配。脂质组学显示，1-TbAd诱导甘油三酯和胆固醇酯的储存，1-TbAd增加M。在巨噬细胞中限制脂质进入的条件下结核生长。此外，脂质组学鉴定了1-TbAd诱导的脂质底物，其定义了戈谢病、沃尔曼病和其他先天性溶酶体贮积病。这些数据确定了M的遗传和分子原因。结核病诱导的溶酶体衰竭，导致成功测试TRPML 1钙通道激动剂，逆转细胞中的脂质储存。这些数据确立了促进巨噬细胞存活的孤儿效应分子的宿主定向细胞功能，提供了泡沫巨噬细胞中溶酶体失败的上游原因和详细情况。
Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside–producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd–induced lipid substrates that define Gaucher’s disease, Wolman’s disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis–induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.
DOI：
10.1021/acs.joc.6b01332
发表时间：
2016-08-05
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Buter J;Heijnen D;Wan IC;Bickelhaupt FM;Young DC;Otten E;Moody DB;Minnaard AJ
通讯作者：
Minnaard AJ
影响因子：
5.2
作者：
Mann FM;Xu M;Davenport EK;Peters RJ
通讯作者：
Peters RJ
DOI：
10.1084/jem.105.1.39
发表时间：
1957-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
SHEPARD CC
通讯作者：
SHEPARD CC