Electrostatic influence on IL-1 transport through the GSDMD pore.
Electrostatic influence on IL-1 transport through the GSDMD pore.
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DOI：
10.1073/pnas.2120287119
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发表时间：
2022-02-08
影响因子：
11.1
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Xie WJ;Xia S;Warshel A;Wu H
Gasdermin D(GSDMD)形成大的毛孔，引导活细胞释放包括白细胞介素1(IL-1)家族的细胞因子。IL-1被合成为一种非活性的胞浆前体，称为前-IL-1，在炎性小体激活或其他生理或病理刺激下，它被蛋白质分解为活性的成熟IL-1。GSDMD孔优先释放成熟的IL-1，而不是原IL-1，尽管它们的分子尺寸相似，都明显小于孔，表明大小以外的因素可能会影响转运。我们对静电在这种优先释放中的作用的研究揭示了GSDMD气孔的电荷选通机制。我们的研究对GSDMD介导的炎症有广泛的影响，并有助于理解大的跨膜孔如何实现货物偏好。多种信号，包括炎性小体的激活，触发Gasdermin D(GSDMD)形成大的跨膜孔。GSDMD毛孔主要有两个功能，驱动溶解细胞死亡，即所谓的上睑下垂，以及允许释放无领导的白介素1(IL-1)家族细胞因子，这一过程不需要下睑下垂。我们对GSDMD孔道从活细胞释放IL-1的机制很感兴趣。最近的研究表明，除了货物大小外，静电相互作用在GSDMD依赖的蛋白质释放中起着关键作用。在这里，我们通过计算确定，为了使静电过滤能够对抗前IL-1β，膜中的酸性脂质需要有效地中和GSDMD孔中面向膜的斑块中的正电荷。此外，我们预测了盐对静电过滤的减弱作用，然后用脂质体渗漏试验验证了这一预测。一个校准的静电屏蔽因子是必要的，以解释实验观察，这表明离子在孔内的分布可能不同于整体溶液。我们的发现证实了GSDMD孔对IL-1运输的静电影响，并揭示了影响静电环境的外部因素，包括脂和盐。
Gasdermin D (GSDMD) forms large pores that channel the release of alarmins, including interleukin-1 (IL-1) family cytokines, from living cells. IL-1 is synthesized as an inactive cytosolic precursor known as pro-IL-1, which is proteolytically processed into the active mature IL-1 in response to inflammasome activation or other physiological or pathological stimuli. GSDMD pores preferentially release mature IL-1 over pro-IL-1 despite their similar molecular dimensions, both markedly smaller than the pore, indicating that factors beyond size may affect the transport. Our investigation into the role of electrostatics in this preferential release revealed a charge-based gating mechanism for GSDMD pores. Our studies have broad implications in GSDMD-mediated inflammation and contribute to understanding of how large transmembrane pores may achieve cargo preference. A variety of signals, including inflammasome activation, trigger the formation of large transmembrane pores by gasdermin D (GSDMD). There are primarily two functions of the GSDMD pore, to drive lytic cell death, known as pyroptosis, and to permit the release of leaderless interleukin-1 (IL-1) family cytokines, a process that does not require pyroptosis. We are interested in the mechanism by which the GSDMD pore channels IL-1 release from living cells. Recent studies revealed that electrostatic interaction, in addition to cargo size, plays a critical role in GSDMD-dependent protein release. Here, we determined computationally that to enable electrostatic filtering against pro-IL-1β, acidic lipids in the membrane need to effectively neutralize positive charges in the membrane-facing patches of the GSDMD pore. In addition, we predicted that salt has an attenuating effect on electrostatic filtering and then validated this prediction using a liposome leakage assay. A calibrated electrostatic screening factor is necessary to account for the experimental observations, suggesting that ion distribution within the pore may be different from the bulk solution. Our findings corroborate the electrostatic influence of IL-1 transport exerted by the GSDMD pore and reveal extrinsic factors, including lipid and salt, that affect the electrostatic environment.
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DOI：
10.1038/s41573-021-00154-z
发表时间：
2021-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Liu X;Xia S;Zhang Z;Wu H;Lieberman J
通讯作者：
Lieberman J
形成孔的蛋白质加油D可以调节白细胞介素-1的巨噬细胞分泌。
影响因子：
32.4
作者：
Evavold CL;Ruan J;Tan Y;Xia S;Wu H;Kagan JC
通讯作者：
Kagan JC
Gasdermin A3膜孔的冷冻EM结构。
影响因子：
64.8
作者：
Ruan J;Xia S;Liu X;Lieberman J;Wu H
通讯作者：
Wu H
影响因子：
64.8
作者：
Shi, Jianjin;Zhao, Yue;Shao, Feng
通讯作者：
Shao, Feng
影响因子：
64.8
作者：
Zhang, Zhibin;Zhang, Ying;Lieberman, Judy
通讯作者：
Lieberman, Judy