Manhertz-Patterson Rojae, Atilla-Gokcumen G Ekin
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, U.S.A.
Biochem Soc Trans. 2025 Apr 29;53(2):BST20253012. doi: 10.1042/BST20253012.
Protein lipidation is a collection of important post-translational modifications that modulate protein localization and stability. Protein lipidation affects protein function by facilitating interactions with cellular membranes, changing the local environment of protein interactions. Among these modifications, S-acylation has emerged as a key regulator of various cellular processes, including different forms of cell death. In this mini-review, we highlight the role of S-acylation in apoptosis and its emerging contributions to necroptosis and pyroptosis. While traditionally associated with the incorporation of palmitic acid (palmitoylation), recent findings indicate that other fatty acids can also participate in S-acylation, expanding its functional repertoire. In apoptosis, S-acylation influences the localization and function of key regulators such as Bcl-2-associated X protein and other proteins modulating their role in mitochondrial permeabilization and death receptor signaling. Similarly, in necroptosis, S-acylation of mixed lineage kinase domain-like protein (MLKL) with palmitic acid and very long-chain fatty acids enhances membrane binding and membrane permeabilization, contributing to cell death and inflammatory responses. Recent studies also highlight the role of S-acylation in pyroptosis, where S-acylated gasdermin D facilitates membrane localization and pore assembly upon inflammasome activation. Blocking palmitoylation has shown to suppress pyroptosis and cytokine release, reducing inflammatory activity and tissue damage in septic models. Collectively, these findings underscore S-acylation as a shared and important regulatory mechanism across cell death pathways affecting membrane association of key signaling proteins and membrane dynamics, and offer insights into the spatial and temporal control of protein function.
蛋白质脂化是一系列重要的翻译后修饰，可调节蛋白质的定位和稳定性。蛋白质脂化通过促进与细胞膜的相互作用来影响蛋白质功能，改变蛋白质相互作用的局部环境。在这些修饰中，S-酰化已成为各种细胞过程的关键调节因子，包括不同形式的细胞死亡。在本综述中，我们重点介绍了S-酰化在细胞凋亡中的作用及其对坏死性凋亡和炎性小体介导的细胞死亡的新贡献。虽然传统上与棕榈酸的掺入（棕榈酰化）相关，但最近的研究结果表明，其他脂肪酸也可以参与S-酰化，扩大了其功能范围。在细胞凋亡中，S-酰化影响关键调节因子如Bcl-2相关X蛋白的定位和功能，以及其他调节其在线粒体通透性和死亡受体信号传导中作用的蛋白质。同样，在坏死性凋亡中，混合谱系激酶结构域样蛋白（MLKL）与棕榈酸和超长链脂肪酸的S-酰化增强了膜结合和膜通透性，导致细胞死亡和炎症反应。最近的研究还强调了S-酰化在炎性小体介导的细胞死亡中的作用，其中S-酰化的gasdermin D在炎性小体激活后促进膜定位和孔组装。阻断棕榈酰化已被证明可抑制炎性小体介导的细胞死亡和细胞因子释放，减少脓毒症模型中的炎症活性和组织损伤。总的来说，这些发现强调了S-酰化是影响关键信号蛋白膜结合和膜动力学的细胞死亡途径中的一种共同且重要的调节机制，并为蛋白质功能的时空控制提供了见解。
