Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1
Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1
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DOI：
10.1021/acsinfecdis.0c00011
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发表时间：
2020-05-08
影响因子：
5.3
通讯作者：
Volkman, Brian F.
中科院分区：
文献类型：
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作者：
Dishman, Acacia F.;Lee, Michelle W.;Volkman, Brian F.
抗菌肽 (AMP) 是一类分子，通常通过优先破坏细胞膜来杀死病原体。趋化因子是信号蛋白家族，可指导免疫细胞迁移并具有保守的 α-β 三级结构。最近，人们发现趋化因子的一个子集也可以起到 AMP 的作用，包括 CCL20、CXCL4 和 XCL1。因此，令人惊讶的是，基于机器学习的分析预测 CCL20 和 CXCL4 的 α 螺旋具有膜破坏性，而 XCL1 的螺旋则不会。然而，XCL1 是唯一已知的变态蛋白趋化因子，它可以在两种不同的天然结构（β-片层二聚体和 α-β 趋化因子结构）之间可逆地相互转化。在这里，我们研究了 XCL1 的抗菌作用机制，重点关注变质折叠的作用。我们证明 XCL1 是一把分子“瑞士军刀”，可以重新折叠成不同的结构，以实现不同的上下文相关功能：而 α-β 趋化因子结构通过与 G 蛋白偶联受体 (GPCR) 结合来控制细胞迁移，我们发现使用小角 X 射线散射 (SAXS)，只有 β-片层和未折叠的 XCL1 结构才能在膜中诱导负高斯曲率 (NGC)，这是膜拓扑所需的曲率类型渗透。此外，XCL1 β-折叠结构的膜重塑活性强烈依赖于膜组成：XCL1 选择性地重塑细菌模型膜，但不重塑哺乳动物模型膜。有趣的是，XCL1 还能渗透真菌模型膜并在体外表现出抗念珠菌活性，这与需要 Th17 介导的细胞反应的常用抗真菌防御模式相反。这些观察结果表明，变质 XCL1 能够实现多种多模式形式的抗菌防御。
Antimicrobial peptides (AMPs) are a class of molecules which generally kill pathogens via preferential cell membrane disruption. Chemokines are a family of signaling proteins that direct immune cell migration and share a conserved alpha-beta tertiary structure. Recently, it was found that a subset of chemokines can also function as AMPs, including CCL20, CXCL4, and XCL1. It is therefore surprising that machine learning based analysis predicts that CCL20 and CXCL4's alpha-helices are membrane disruptive, while XCL1's helix is not. XCL1, however, is the only chemokine known to be a metamorphic protein which can interconvert reversibly between two distinct native structures (a beta-sheet dimer and the alpha-beta chemokine structure). Here, we investigate XCL1's antimicrobial mechanism of action with a focus on the role of metamorphic folding. We demonstrate that XCL1 is a molecular "Swiss army knife" that can refold into different structures for distinct context-dependent functions: whereas the alpha-beta chemokine structure controls cell migration by binding to G-Protein Coupled Receptors (GPCRs), we find using small angle X-ray scattering (SAXS) that only the beta-sheet and unfolded XCL1 structures can induce negative Gaussian curvature (NGC) in membranes, the type of curvature topologically required for membrane permeation. Moreover, the membrane remodeling activity of XCL1's beta-sheet structure is strongly dependent on membrane composition: XCL1 selectively remodels bacterial model membranes but not mammalian model membranes. Interestingly, XCL1 also permeates fungal model membranes and exhibits anti-Candida activity in vitro, in contrast to the usual mode of antifungal defense which requires Th17 mediated cell-based responses. These observations suggest that metamorphic XCL1 is capable of a versatile multimodal form of antimicrobial defense.