PDF(Pubmed)
Abstract：
Human defensins are cysteine-rich peptides (Cys-rich peptides) of the innate immune system. Defensins contain an ancestral structural motif (i.e., γ-core motif) associated with the antimicrobial activity of natural Cys-rich peptides. In this study, low concentrations of human α- and β-defensins showed microbicidal activity that was not associated with cell membrane permeabilization. The cell death pathway was similar to that previously described for human lactoferrin, also an immunoprotein containing a γ-core motif. The common features were (1) cell death not related to plasma membrane (PM) disruption, (2) the inhibition of microbicidal activity via extracellular potassium, (3) the influence of cellular respiration on microbicidal activity, and (4) the influence of intracellular pH on bactericidal activity. In addition, in yeast, we also observed (1) partial K+-efflux mediated via Tok1p K+-channels, (2) the essential role of mitochondrial ATP synthase in cell death, (3) the increment of intracellular ATP, (4) plasma membrane depolarization, and (5) the inhibition of external acidification mediated via PM Pma1p H+-ATPase. Similar features were also observed with BM2, an antifungal peptide that inhibits Pma1p H+-ATPase, showing that the above coincident characteristics were a consequence of PM H+-ATPase inhibition. These findings suggest, for the first time, that human defensins inhibit PM H+-ATPases at physiological concentrations, and that the subsequent cytosolic acidification is responsible for the in vitro microbicidal activity. This mechanism of action is shared with human lactoferrin and probably other antimicrobial peptides containing γ-core motifs.
摘要：
人防御素是先天免疫系统的富含半胱氨酸的肽(富含Cys的肽)。防御素包含祖先的结构基序(即，γ-核心基序）与天然富含Cys的肽的抗微生物活性相关。在这项研究中,低浓度的人α-和β-防御素显示出与细胞膜透化无关的杀微生物活性。细胞死亡途径类似于先前描述的人类乳铁蛋白，也是含有γ-核心基序的免疫蛋白。共同特征是(1)细胞死亡与质膜(PM)破坏无关，（2）通过细胞外钾抑制杀菌活性，(3)细胞呼吸对杀菌活性的影响,(4)细胞内pH对杀菌活性的影响。此外,在酵母中，我们还观察到(1)通过Tok1pK+通道介导的部分K+外排，(2)线粒体ATP合酶在细胞逝世亡中的根本感化，(3)细胞内ATP的增加,（4）质膜去极化，（5）通过PMPma1pH-ATPase介导的外部酸化抑制作用。BM2也观察到类似的特征，BM2是一种抑制Pma1pH+-ATP酶的抗真菌肽，表明上述一致特征是PMH-ATPase抑制的结果。这些发现表明,第一次,人类防御素在生理浓度下抑制PMH+-ATP酶，并且随后的胞质酸化负责体外杀菌活性。这种作用机制与人乳铁蛋白以及可能包含γ-核心基序的其他抗微生物肽共享。
