Salmonella Typhimurium manipulates macrophage cholesterol homeostasis through the SseJ-mediated suppression of the host cholesterol transport protein ABCA1.
Salmonella Typhimurium manipulates macrophage cholesterol homeostasis through the SseJ-mediated suppression of the host cholesterol transport protein ABCA1.
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DOI：
10.1111/cmi.13329
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发表时间：
2021-08
影响因子：
3.4
通讯作者：
Casanova JE
中科院分区：
文献类型：
--
作者：
Greene AR;Owen KA;Casanova JE
在宿主细胞感染后，肠沙门氏菌血清型鼠伤寒沙门氏菌驻留在被称为含沙门氏菌液泡（SCV）的改良内体隔室中。SCV的生物发生是由多个效应蛋白通过两个III型分泌系统（T3SS-1和T3SS-2）易位驱动的。虽然这些效应蛋白靶向的许多宿主蛋白已经被表征，但宿主脂质在SCV动力学中的作用仍然知之甚少。先前的研究表明，鼠伤寒沙门氏菌感染巨噬细胞导致细胞内胆固醇积聚，其中一些胆固醇集中在scv内和周围；然而，其潜在机制尚不清楚。在这里，我们发现鼠伤寒沙门氏菌利用T3SS-2效应物SseJ下调巨噬细胞中宿主胆固醇转运体ABCA1的表达，导致细胞胆固醇增加约45%。机制上，SseJ激活涉及宿主激酶FAK和Akt的信号级联，抑制Abca1的表达。SseJ酰基转移酶活性的突变失活、FAK沉默或抑制Akt可阻止感染期间Abca1下调和相应的胆固醇积累。重要的是，rnai介导的ABCA1沉默挽救了fak缺陷巨噬细胞中的细菌存活，这表明ABCA1下调和胆固醇积累对细胞内存活很重要。
Upon infection of host cells, Salmonella enterica serovar Typhimurium resides in a modified endosomal compartment referred to as the Salmonella-containing vacuole (SCV). SCV biogenesis is driven by multiple effector proteins translocated through two type III secretion systems (T3SS-1 and T3SS-2). While many host proteins targeted by these effector proteins have been characterized, the role of host lipids in SCV dynamics remains poorly understood. Previous studies have shown that S. Typhimurium infection in macrophages leads to accumulation of intracellular cholesterol, some of which concentrates in and around SCVs; however, the underlying mechanisms remain unknown. Here, we show that S. Typhimurium utilizes the T3SS-2 effector SseJ to downregulate expression of the host cholesterol transporter ABCA1 in macrophages, leading to a ~45% increase in cellular cholesterol. Mechanistically, SseJ activates a signaling cascade involving the host kinases FAK and Akt to suppress Abca1 expression. Mutational inactivation of SseJ acyltransferase activity, silencing FAK, or inhibiting Akt prevents Abca1 downregulation and the corresponding accumulation of cholesterol during infection. Importantly, RNAi-mediated silencing of ABCA1 rescued bacterial survival in FAK-deficient macrophages, suggesting that Abca1 downregulation and cholesterol accumulation are important for intracellular survival.
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影响因子：
13.3
作者：
Dai S;Dulcey AE;Hu X;Wassif CA;Porter FD;Austin CP;Ory DS;Marugan J;Zheng W
通讯作者：
Zheng W
影响因子：
3.4
作者：
Garner, MJ;Hayward, RD;Koronakis, V
通讯作者：
Koronakis, V
影响因子：
6.5
作者：
Cox, Brian E.;Griffin, Evelyn E.;Jerome, W. Gray
通讯作者：
Jerome, W. Gray
影响因子：
11.4
作者：
Fraldi, Alessandro;Annunziata, Fabio;Ballabio, Andrea
通讯作者：
Ballabio, Andrea
影响因子：
64.5
作者：
Bonham KS;Orzalli MH;Hayashi K;Wolf AI;Glanemann C;Weninger W;Iwasaki A;Knipe DM;Kagan JC
通讯作者：
Kagan JC