Dynamic Characterization of Protein and Posttranslational Modification Levels in Mycobacterial Cholesterol Catabolism
Dynamic Characterization of Protein and Posttranslational Modification Levels in Mycobacterial Cholesterol Catabolism
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分枝杆菌胆固醇分解代谢中蛋白质和翻译后修饰水平的动态表征
DOI：
10.1128/msystems.00424-19
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发表时间：
2020-01
期刊：
影响因子：
6.4
通讯作者：
Ye Bang-Ce
中科院分区：
文献类型：
--
作者：
Xu Jun-Yu;Zhao Lei;Xu Ying;Li Bolin;Zhai Linhui;Tan Minjia;Ye Bang-Ce
胆固醇同化是分枝杆菌慢性感染的关键步骤。然而，关于分枝杆菌在蛋白表达和PTM水平上胆固醇代谢的动态特性的知识仍然有限。我们的研究揭示了在分枝杆菌从葡萄糖到胆固醇的代谢变化过程中蛋白质表达、赖氨酸乙酰化、赖氨酸丙酰化和S/T/Y磷酸化的景观。数据显示，胆固醇诱导的碳转移导致参与胆固醇降解的多种代谢酶的蛋白质表达和赖氨酸酰化升高，胆固醇的存在也促进了分枝杆菌激酶系统磷酸化水平的扰动。本研究系统表征了几个不同水平的胆固醇分解代谢调控，为分枝杆菌蛋白质组学和潜在的抗分枝杆菌策略提供了详细的参考。宿主巨噬细胞膜的胆固醇对分枝杆菌感染、复制和持久性至关重要。在宿主肺组织慢性感染期间，胆固醇促进分枝杆菌吞噬成巨噬细胞。胆固醇降解导致乙酰辅酶A （CoA）和丙酰辅酶A的通量增加，为毒力大分子提供能量和构建块，并为全局蛋白质酰化提供供体。赖氨酸酰化的潜在功能在细菌的生存和发病机制中逐渐被揭示出来。然而，分枝杆菌蛋白质组和翻译后修饰（PTM）的变化参与胆固醇分解代谢的生物过程尚不清楚。在这里，我们使用非致病性耻垢分枝杆菌作为模型，同时监测在葡萄糖和胆固醇存在下分枝杆菌蛋白质组和乙酰组的变化。我们发现，在从葡萄糖到胆固醇的代谢转变过程中，胆固醇代谢酶在蛋白质表达水平和赖氨酸酰化水平方面都上调。在此之后，与胆固醇代谢相关的腺苷化酶被证实在丙酰化水平上被分枝杆菌酰基转移酶M. smegmatis Kat （MsKat）精确调节，以响应细胞丙酰辅酶a的积累。此外，激酶的表达和磷酸化水平也随着胆固醇水平的波动而变化。我们的结果扩大了目前对分支杆菌胆固醇分解代谢的酰化调控的认识，并为可能的抗分枝杆菌策略提供了参考。胆固醇同化是分枝杆菌慢性感染的关键步骤。然而，关于分枝杆菌在蛋白表达和PTM水平上胆固醇代谢的动态特性的知识仍然有限。我们的研究揭示了在分枝杆菌从葡萄糖到胆固醇的代谢变化过程中蛋白质表达、赖氨酸乙酰化、赖氨酸丙酰化和S/T/Y磷酸化的景观。数据显示，胆固醇诱导的碳转移导致参与胆固醇降解的多种代谢酶的蛋白质表达和赖氨酸酰化升高，胆固醇的存在也促进了分枝杆菌激酶系统磷酸化水平的扰动。本研究系统表征了几个不同水平的胆固醇分解代谢调控，为分枝杆菌蛋白质组学和潜在的抗分枝杆菌策略提供了详细的参考。
Cholesterol assimilation is a critical step in mycobacterial chronic infection. However, knowledge from the dynamic characterization of cholesterol metabolism in mycobacteria at the protein expression and PTM levels remains limited. Our study uncovered the landscape of protein expression, lysine acetylation, lysine propionylation, and S/T/Y phosphorylation during the metabolic changes from glucose to cholesterol in mycobacteria. The data showed that cholesterol-induced carbon shift resulted in the elevation of protein expression and lysine acylation in diverse metabolic enzymes involved in cholesterol degradation and that the presence of cholesterol also promoted the perturbations at the phosphorylation level in the kinase system in mycobacteria. This study systematically characterized the regulation of cholesterol catabolism at several different levels, which provided the detailed references in mycobacterial proteome and potential antimycobacterial strategies. ABSTRACT Cholesterol of the host macrophage membrane is vital for mycobacterial infection, replication, and persistence. During chronic infection within host lung tissues, cholesterol facilitates the phagocytosis of mycobacteria into macrophages. Cholesterol degradation leads to increased flux of acetyl-coenzyme A (CoA) and propionyl-CoA, providing energy and building blocks for virulence macromolecules as well as donors for global protein acylation. Potential functions of lysine acylation are gradually revealed in bacterial survival and pathogenesis. However, the mycobacterial proteome and posttranslational modification (PTM) changes involved in the cholesterol catabolism bioprocess remain unclear. Here, we used nonpathogenic Mycobacterium smegmatis as a model and simultaneously monitored mycobacterial proteome and acetylome changes in the presence of glucose and cholesterol. We discovered that cholesterol metabolic enzymes were upregulated with respect to both protein expression levels and lysine acylation levels during the metabolic shift from glucose to cholesterol. After that, adenylating enzymes related to cholesterol metabolism were proven to be precisely regulated at the propionylation level by mycobacterial acyltransferase M. smegmatis Kat (MsKat) in response to cellular propionyl-CoA accumulation. Furthermore, the kinase expression and phosphorylation levels were also changed along with fluctuations in cholesterol levels. Our results expanded current knowledge of acylation regulation in the cholesterol catabolism of mycobacteria and provided references for possible antimycobacterium strategy. IMPORTANCE Cholesterol assimilation is a critical step in mycobacterial chronic infection. However, knowledge from the dynamic characterization of cholesterol metabolism in mycobacteria at the protein expression and PTM levels remains limited. Our study uncovered the landscape of protein expression, lysine acetylation, lysine propionylation, and S/T/Y phosphorylation during the metabolic changes from glucose to cholesterol in mycobacteria. The data showed that cholesterol-induced carbon shift resulted in the elevation of protein expression and lysine acylation in diverse metabolic enzymes involved in cholesterol degradation and that the presence of cholesterol also promoted the perturbations at the phosphorylation level in the kinase system in mycobacteria. This study systematically characterized the regulation of cholesterol catabolism at several different levels, which provided the detailed references in mycobacterial proteome and potential antimycobacterial strategies.
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影响因子：
5.4
作者：
Dworkin J
通讯作者：
Dworkin J
影响因子：
5.6
作者：
Krishna K. Singh;Neerupma Bhardwaj;Gaurav D. Sankhe;N. Udaykumar;Rambir Singh;Vandana Malhotra;D. Saini
通讯作者：
Krishna K. Singh;Neerupma Bhardwaj;Gaurav D. Sankhe;N. Udaykumar;Rambir Singh;Vandana Malhotra;D. Saini
在补充有胆固醇、雄烯二酮或甘油的基本培养基中培养的耻垢分枝杆菌 MC² 155 的全基因组转录组分析。
影响因子：
5.6
作者：
Li Q;Ge F;Tan Y;Zhang G;Li W
通讯作者：
Li W
DOI：
10.1016/j.bbapap.2009.09.008
发表时间：
2010-03-01
影响因子：
3.2
作者：
Chao, Joseph;Wong, Dennis;Av-Gay, Yossef
通讯作者：
Av-Gay, Yossef
影响因子：
3.7
作者：
Thao S;Chen CS;Zhu H;Escalante-Semerena JC
通讯作者：
Escalante-Semerena JC