Rickettsia Lipid A Biosynthesis Utilizes the Late Acyltransferase LpxJ for Secondary Fatty Acid Addition.
Rickettsia Lipid A Biosynthesis Utilizes the Late Acyltransferase LpxJ for Secondary Fatty Acid Addition.
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DOI：
10.1128/jb.00334-18
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发表时间：
2018-10-01
影响因子：
3.2
通讯作者：
Azad AF
中科院分区：
文献类型：
--
作者：
Guillotte ML;Gillespie JJ;Chandler CE;Rahman MS;Ernst RK;Azad AF
脂多糖（LPS）通过TLR 4-MD 2受体复合物和炎症性半胱天冬酶触发炎症反应，这是一个由脂多糖的脂质A部分介导的过程。立克次体直接参与细胞外和细胞内的免疫监视，但对立克次体脂质A的了解甚少。在这里，我们证明了来自伤寒立克次体和R.立克次氏体催化将C16脂肪酸链添加到脂质A 3′-连接的初级酰基链中，这是相对于大肠杆菌的高度炎症性脂质A的主要结构差异。立克次体属的成员是专性细胞内革兰氏阴性球杆菌，感染哺乳动物和节肢动物宿主。几种立克次体是人类病原体，由吸血节肢动物传播。在革兰氏阴性寄生虫中，外膜（OM）位于宿主-病原体相互作用的节点，并且富含脂多糖（LPS）。LPS的脂质A组分将分子锚定到细菌表面，并且是Toll样受体4（TLR 4）的内毒素激动剂。尽管脂质A在维持OM完整性以及其在感染期间的炎症潜力方面具有明显的重要性，但该分子在立克次体病原体中的特征很差。在这项工作中，我们已经确定和特点的新成员，最近发现的LpxJ家族的脂质A酰基转移酶在伤寒立克次体和立克次体，鼠斑疹伤寒和落基山斑疹热的病原体，分别。我们的研究结果表明，这些酶催化添加的二级酰基链（C14/C16）的3′-连接的脂质A部分的主要酰基链在脂质A生物合成的Raetz途径的最后步骤。由于脂质A架构是细菌OM完整性的基础，我们认为，立克次体LpxJ可能是重要的，在维持膜动力学，以促进分子相互作用在宿主-病原体界面所需的粘附和入侵的哺乳动物细胞。这项工作有助于我们了解立克次体外膜的生理学，并为进一步探索包膜及其在发病机制中的作用奠定了基础。重要性脂多糖（LPS）通过TLR 4-MD 2受体复合物和炎性半胱天冬酶触发炎症反应，该过程由LPS的脂质A部分介导。立克次体直接参与细胞外和细胞内的免疫监视，但对立克次体脂质A的了解甚少。在这里，我们证明了来自伤寒立克次体和R.立克次氏体催化将C16脂肪酸链添加到脂质A 3′-连接的初级酰基链中，这是相对于大肠杆菌的高度炎症性脂质A的主要结构差异。
Lipopolysaccharide (LPS) triggers an inflammatory response through the TLR4-MD2 receptor complex and inflammatory caspases, a process mediated by the lipid A moiety of LPS. Species of Rickettsia directly engage both extracellular and intracellular immunosurveillance, yet little is known about rickettsial lipid A. Here, we demonstrate that the alternative lipid A acyltransferase, LpxJ, from Rickettsia typhi and R. rickettsii catalyzes the addition of C16 fatty acid chains into the lipid A 3′-linked primary acyl chain, accounting for major structural differences relative to the highly inflammatory lipid A of Escherichia coli. Members of the Rickettsia genus are obligate intracellular, Gram-negative coccobacilli that infect mammalian and arthropod hosts. Several rickettsial species are human pathogens and are transmitted by blood-feeding arthropods. In Gram-negative parasites, the outer membrane (OM) sits at the nexus of the host-pathogen interaction and is rich in lipopolysaccharide (LPS). The lipid A component of LPS anchors the molecule to the bacterial surface and is an endotoxic agonist of Toll-like receptor 4 (TLR4). Despite the apparent importance of lipid A in maintaining OM integrity, as well as its inflammatory potential during infection, this molecule is poorly characterized in Rickettsia pathogens. In this work, we have identified and characterized new members of the recently discovered LpxJ family of lipid A acyltransferases in both Rickettsia typhi and Rickettsia rickettsii, the etiological agents of murine typhus and Rocky Mountain spotted fever, respectively. Our results demonstrate that these enzymes catalyze the addition of a secondary acyl chain (C14/C16) to the 3′-linked primary acyl chain of the lipid A moiety in the final steps of the Raetz pathway of lipid A biosynthesis. Since lipid A architecture is fundamental to bacterial OM integrity, we believe that rickettsial LpxJ may be important in maintaining membrane dynamics to facilitate molecular interactions at the host-pathogen interface that are required for adhesion and invasion of mammalian cells. This work contributes to our understanding of rickettsial outer membrane physiology and sets a foundation for further exploration of the envelope and its role in pathogenesis. IMPORTANCE Lipopolysaccharide (LPS) triggers an inflammatory response through the TLR4-MD2 receptor complex and inflammatory caspases, a process mediated by the lipid A moiety of LPS. Species of Rickettsia directly engage both extracellular and intracellular immunosurveillance, yet little is known about rickettsial lipid A. Here, we demonstrate that the alternative lipid A acyltransferase, LpxJ, from Rickettsia typhi and R. rickettsii catalyzes the addition of C16 fatty acid chains into the lipid A 3′-linked primary acyl chain, accounting for major structural differences relative to the highly inflammatory lipid A of Escherichia coli.