Inhibition of Salmonella enterica serovar Typhimurium lipopolysaccharide deacylation by aminoarabinose membrane modification
Inhibition of Salmonella enterica serovar Typhimurium lipopolysaccharide deacylation by aminoarabinose membrane modification
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DOI：
10.1128/jb.187.7.2448-2457.2005
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发表时间：
2005-04-01
影响因子：
3.2
通讯作者：
Miller, SI
中科院分区：
文献类型：
--
作者：
Kawasaki, K;Ernst, RK;Miller, SI
鼠伤寒沙门氏菌重塑脂多糖的脂类A成分，这是外膜的主要成分，以在动物体内生存。在宿主环境中，传感器激酶PhoQ的激活增加了脱酰化、棕榈酰化、羟化的酶的合成，并将氨基阿拉伯糖附着到脂A上，也称为内毒素。这些修饰促进了细菌对抗菌肽的耐药性，并降低了Toll样受体4对类脂A的宿主识别能力。沙门氏菌类脂A3-O-脱酰酶PagL是一种外膜蛋白，其表达受PhoQ调控。在鼠伤寒沙门氏菌中，尽管PhoQ诱导了PagL蛋白的表达，但在能够将氨基阿拉伯糖添加到脂质A中的菌株中，没有检测到3-O-脱酰基脂A物种。反之，不能修饰A类脂蛋白的菌株在体内表现出PagL活性，表明这种膜修饰抑制了PagL的酶活性。由于并不是所有的脂质A分子在PhoQ激活时都被氨基阿拉伯糖修饰，这些结果不能归因于PagL的底物专一性。在超声破碎膜和非离子去污剂N-辛基-β-D-吡喃葡萄糖苷处理的膜中检测到依赖于PagL的脱酰化，这表明对完整外膜的扰动释放了含有氨基阿拉伯糖膜的翻译后抑制。综上所述，这些结果表明，PagL的酶脱酰作用受到膜环境的抑制，膜环境要么将PagL从底物上隔离下来，要么改变其构象。
Salmonella enterica serovar Typhimurium remodels the lipid A component of lipopolysaccharide, a major component of the outer membrane, to survive within animals. The activation of the sensor kinase PhoQ in host environments increases the synthesis of enzymes that deacylate, palmitoylate, hydroxylate, and attach aminoarabinose to lipid A, also known as endotoxin. These modifications promote bacterial resistance to antimicrobial peptides and reduce the host recognition of lipid A by toll-like receptor 4. The Salmonella lipid A 3-O-deacylase, PagL, is an outer membrane protein whose expression is regulated by PhoQ. In S. enterica serovar Typhimurium strains that had the ability to add aminoarabinose to lipid A, 3-O-deacylated lipid A species were not detected, despite the PhoQ induction of PagL protein expression. In contrast, strains defective for the aminoarabinose modification of lipid A demonstrated in vivo PagL activity, indicating that this membrane modification inhibited PagL's enzymatic activity. Since not all lipid A molecules are modified with aminoarabinose upon PhoQ activation, these results cannot be ascribed to the substrate specificity of PagL. PagL-dependent deacylation was detected in sonically disrupted membranes and membranes treated with the nonionic detergent n-octyl-beta-D-glucopyranoside, suggesting that perturbation of the intact outer membrane releases PagL from posttranslational inhibition by aminoarabinose-containing membranes. Taken together, these results suggest that PagL enzymatic deacylation is posttranslationally inhibited by membrane environments, which either sequester PagL from its substrate or alter its conformation.