Phosphorylation of the Peptidoglycan Synthase PonA1 Governs the Rate of Polar Elongation in Mycobacteria.
Phosphorylation of the Peptidoglycan Synthase PonA1 Governs the Rate of Polar Elongation in Mycobacteria.
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DOI：
10.1371/journal.ppat.1005010
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发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Rubin EJ
中科院分区：
文献类型：
--
作者：
Kieser KJ;Boutte CC;Kester JC;Baer CE;Barczak AK;Meniche X;Chao MC;Rego EH;Sassetti CM;Fortune SM;Rubin EJ
细胞生长和分裂是细菌感染进展所必需的。大多数杆状细菌是通过沿着其中段插入新的细胞壁来生长的。然而，分枝杆菌，包括人类病原体结核分枝杆菌，在它们的两极产生新的细胞壁材料。分枝杆菌如何控制这种不同的生长模式还不完全清楚。在这里，我们发现，PonA 1，青霉素结合蛋白（PBP）能够转糖基化和转肽的细胞壁肽聚糖（PG），是一个主要的总督在分枝杆菌的极性生长。PonA 1是耻垢分枝杆菌生长所必需的，对M.结核病感染期间。在这两种情况下，PonA 1的催化活性都是正常细胞长度所必需的，尽管转糖基酶活性的丧失比转肽作用具有更显著的影响。改变PonA 1的数量或活性的突变导致细胞极的异常形成和细胞长度的变化。此外，PonA 1活性的改变导致抗生素敏感性的显著差异，这表明PonA 1的两种酶活性之间的平衡对生存至关重要。我们还发现PonA 1的胞质区域的磷酸化是正常活动所必需的。关键磷酸化残基的突变影响转糖基酶活性，并导致细胞伸长的异常速率。总之，我们的数据表明，PonA 1是分枝杆菌极性生长的核心决定因素，其对细胞伸长的控制是宿主诱导和抗生素应激期间细胞健康所必需的。细菌感染依赖于持续的细菌生长。研究细胞生长对于结核分枝杆菌等病原体特别重要，这些病原体的生长方式与模型生物不同。与大肠杆菌或枯草芽孢杆菌不同，它们通过沿着它们的身体结合细胞壁物质而生长，分枝杆菌从杆生长。分枝杆菌如何构建和延伸它们的杆仍然不清楚。我们的工作确定了细胞壁合成酶，PonA 1，作为分枝杆菌极性生长的关键决定因素。PonA 1通过构建细胞壁的肽聚糖（PG）的两种酶活性来控制极性生长;这两种活性都是正常细胞生长所必需的。PonA 1的量或活性的变化导致细胞两极错位和细胞增殖抑制。PonA 1是磷酸化的，这是PG脱氢酶的一种不寻常的修饰。这种磷酸化调节细胞伸长的速率。改变PonA 1的调节或酶活性会影响宿主中细胞的存活或用抗生素治疗时的存活。我们的工作显示了分枝杆菌细胞杆的建设和细胞健身是如何由一个主要的细胞壁合成酶，这些发现可能有其他细菌从他们的杆伸长的影响。
Cell growth and division are required for the progression of bacterial infections. Most rod-shaped bacteria grow by inserting new cell wall along their mid-section. However, mycobacteria, including the human pathogen Mycobacterium tuberculosis, produce new cell wall material at their poles. How mycobacteria control this different mode of growth is incompletely understood. Here we find that PonA1, a penicillin binding protein (PBP) capable of transglycosylation and transpeptidation of cell wall peptidoglycan (PG), is a major governor of polar growth in mycobacteria. PonA1 is required for growth of Mycobacterium smegmatis and is critical for M. tuberculosis during infection. In both cases, PonA1’s catalytic activities are both required for normal cell length, though loss of transglycosylase activity has a more pronounced effect than transpeptidation. Mutations that alter the amount or the activity of PonA1 result in abnormal formation of cell poles and changes in cell length. Moreover, altered PonA1 activity results in dramatic differences in antibiotic susceptibility, suggesting that a balance between the two enzymatic activities of PonA1 is critical for survival. We also find that phosphorylation of a cytoplasmic region of PonA1 is required for normal activity. Mutations in a critical phosphorylated residue affect transglycosylase activity and result in abnormal rates of cell elongation. Together, our data indicate that PonA1 is a central determinant of polar growth in mycobacteria, and its governance of cell elongation is required for robust cell fitness during both host-induced and antibiotic stress. Bacterial infections rely on continued bacterial growth. Studying cell growth is particularly important for pathogens such as Mycobacterium tuberculosis that grow differently than model organisms. Unlike Escherichia coli or Bacillus subtilis, which grow by incorporating cell wall material along their body, mycobacteria grow from the pole. It remains unclear how mycobacteria construct and extend their poles. Our work identifies a cell wall synthase, PonA1, as a key determinant of mycobacterial polar growth. PonA1 governs polar growth through two enzymatic activities that build the cell wall’s peptidoglycan (PG); both of these activities are required for normal cell growth. Changes in the amount or activity of PonA1 leads to misplaced cell poles and inhibition of cell proliferation. PonA1 is phosphorylated, an unusual modification for PG synthases. This phosphorylation tunes the rate of cell elongation. Changing PonA1’s regulatory or enzymatic activity impacts the survival of cells in the host or when treated with antibiotics. Our work shows how mycobacterial cell pole construction and cell fitness is governed by a major cell wall synthase; these findings may have implications for other bacteria that elongate from their poles.
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影响因子：
64.5
作者：
Paradis-Bleau C;Markovski M;Uehara T;Lupoli TJ;Walker S;Kahne DE;Bernhardt TG
通讯作者：
Bernhardt TG
影响因子：
3.2
作者：
Lavollay, Marie;Arthur, Michel;Mainardi, Jean-Luc
通讯作者：
Mainardi, Jean-Luc
影响因子：
6.7
作者：
Chao, Michael C.;Kieser, Karen J.;Rubin, Eric J.
通讯作者：
Rubin, Eric J.
影响因子：
3.1
作者：
Doerr, Tobias;Moell, Andrea;Waldor, Matthew K.
通讯作者：
Waldor, Matthew K.
影响因子：
5.6
作者：
Parikh, Amit;Verma, Sunil Kumar;Nandicoori, Vinay Kumar
通讯作者：
Nandicoori, Vinay Kumar