Granulysin, a T cell product, kills bacteria by altering membrane permeability
Granulysin, a T cell product, kills bacteria by altering membrane permeability
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DOI：
10.4049/jimmunol.165.12.7102
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发表时间：
2000-12-15
影响因子：
4.4
通讯作者：
Modlin, RL
中科院分区：
文献类型：
--
作者：
Ernst, WA;Thoma-Uszynski, S;Modlin, RL
颗粒溶素是一种位于人类 NK 细胞和细胞毒性 T 细胞酸性颗粒中的蛋白质，对多种微生物病原体具有抗菌活性。根据相关蛋白质 NK 赖氨酸的核磁共振结构生成的预测模型表明，颗粒溶素含有四个 α 螺旋束基序，其中 α 螺旋富集带正电荷的氨基酸，包括精氨酸和赖氨酸残基。多肽变性将 α 螺旋含量从 49% 降低至 18%，导致抗菌活性完全抑制。精氨酸（而非赖氨酸）残基的化学修饰也会阻断抗菌活性，并干扰颗粒溶素粘附大肠杆菌和结核分枝杆菌的能力。颗粒溶素增加了细菌膜的通透性，这是通过其允许胞质β-半乳糖苷酶进入其不渗透底物的能力来判断的。通过电子显微镜观察，颗粒溶素引发结核分枝杆菌周质中的液体积聚，与渗透压扰动一致。这些数据表明颗粒溶素杀死微生物病原体的能力取决于与微生物细胞壁和/或细胞膜的直接相互作用，导致渗透性增加和裂解。
Granulysin, a protein located in the acidic granules of human NK cells and cytotoxic T cells, has antimicrobial activity against a broad spectrum of microbial pathogens. A predicted model generated from the nuclear magnetic resonance structure of a related protein, NK lysin, suggested that granulysin contains a four alpha helical bundle motif, with the alpha helices enriched for positively charged amino acids, including arginine and lysine residues, Denaturation of the polypeptide reduced the a helical content from 49 to 18% resulted in complete inhibition of antimicrobial activity. Chemical modification of the arginine, but not the lysine, residues also blocked the antimicrobial activity and interfered with the ability of granulysin to adhere to Escherichia coli and Mycobacterium tuberculosis. Granulysin increased the permeability of bacterial membranes, as judged by its ability to allow access of cytosolic beta -galactosidase to its impermeant substrate. By electron microscopy, granulysin triggered fluid accumulation in the periplasm of M, tuberculosis, consistent with osmotic perturbation, These data suggest that the ability of granulysin to kill microbial pathogens is dependent on direct interaction with the microbial cell wall and/or membrane, leading to increased permeability and lysis.