Coxiella burnetii Sterol-Modifying Protein Stmp1 Regulates Cholesterol in the Intracellular Niche.
Coxiella burnetii Sterol-Modifying Protein Stmp1 Regulates Cholesterol in the Intracellular Niche.
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伯氏柯克斯体修饰蛋白Stmp1调节细胞内的胆固醇。
DOI：
10.1128/mbio.03073-21
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发表时间：
2022-02-22
期刊：
影响因子：
6.4
通讯作者：
Gilk SD
中科院分区：
文献类型：
--
作者：
Clemente TM;Ratnayake R;Samanta D;Augusto L;Beare PA;Heinzen RA;Gilk SD
贝氏柯克斯体在一个吞噬溶酶体样的空泡中复制，称为含柯克斯体的空泡（CCV）。虽然宿主胆固醇很容易转移到CCV，但胆固醇积累会导致CCV酸化和细菌死亡。因此，细菌对CCV胆固醇含量的调节对于柯克斯体的发病是必不可少的。柯克斯体表达一种固醇修饰蛋白，Stmp 1，可能通过酶修饰降低CCV胆固醇。使用Stmp 1敲除（Δ stmp 1），我们确定Stmp 1对于无菌生长不是必需的。然而，在宿主细胞内，Δ stmp 1突变细菌形成较小的CCV，其积累胆固醇，优先与溶酶体融合，并变得更加酸性，与显著的生长缺陷相关。然而，在无胆固醇的细胞中，Δ stmp 1突变细菌的生长与野生型细菌相似，但对胆固醇补充剂过敏。为了更好地理解Δ stmp 1突变表型背后的潜在机制，我们进行了固醇分析。令人惊讶的是，我们发现Δ stmp 1 muclide感染的巨噬细胞积累了有效的胆固醇稳态调节剂25-羟基胆固醇（25-HC）。我们接下来通过用25-HC处理野生型柯克斯体感染的细胞来确定失调的25-HC是否改变柯克斯体感染。与Δ stmp 1突变表型相似，25-HC增加CCV蛋白水解活性并抑制细菌生长。总的来说，这些数据表明，Stmp 1改变宿主胆固醇代谢，是建立一个成熟的CCV，支持柯克斯体生长所必需的。
Coxiella burnetii replicates in a phagolysosome-like vacuole called the Coxiella-containing vacuole (CCV). While host cholesterol readily traffics to the CCV, cholesterol accumulation leads to CCV acidification and bacterial death. Thus, bacterial regulation of CCV cholesterol content is essential for Coxiella pathogenesis. Coxiella expresses a sterol-modifying protein, Stmp1, that may function to lower CCV cholesterol through enzymatic modification. Using an Stmp1 knockout (Δstmp1), we determined that Stmp1 is not essential for axenic growth. Inside host cells, however, Δstmp1 mutant bacteria form smaller CCVs which accumulate cholesterol, preferentially fuse with lysosomes, and become more acidic, correlating with a significant growth defect. However, in cholesterol-free cells, Δstmp1 mutant bacteria grow similarly to wild-type bacteria but are hypersensitive to cholesterol supplementation. To better understand the underlying mechanism behind the Δstmp1 mutant phenotype, we performed sterol profiling. Surprisingly, we found that Δstmp1 mutant-infected macrophages accumulated the potent cholesterol homeostasis regulator 25-hydroxycholesterol (25-HC). We next determined whether dysregulated 25-HC alters Coxiella infection by treating wild-type Coxiella-infected cells with 25-HC. Similar to the Δstmp1 mutant phenotype, 25-HC increased CCV proteolytic activity and inhibited bacterial growth. Collectively, these data indicate that Stmp1 alters host cholesterol metabolism and is essential to establish a mature CCV which supports Coxiella growth.
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影响因子：
6.7
作者：
Carey KL;Newton HJ;Lührmann A;Roy CR
通讯作者：
Roy CR
影响因子：
6.4
作者：
Beare PA;Gilk SD;Larson CL;Hill J;Stead CM;Omsland A;Cockrell DC;Howe D;Voth DE;Heinzen RA
通讯作者：
Heinzen RA
DOI：
10.1007/978-94-007-4315-1_13
发表时间：
2012-01-01
期刊：
COXIELLA BURNETII: RECENT ADVANCES AND NEW PERSPECTIVES IN RESEARCH OF THE Q FEVER BACTERIUM
影响因子：
--
作者：
Beare, Paul A.
通讯作者：
Beare, Paul A.
影响因子：
3.4
作者：
Howe, D;Melnicáková, J;Heinzen, RA
通讯作者：
Heinzen, RA
DOI：
10.1073/pnas.1309195110
发表时间：
2013-12-03
影响因子：
11.1
作者：
Larson, Charles L.;Beare, Paul A.;Heinzen, Robert A.
通讯作者：
Heinzen, Robert A.