Ros Uris, Pedrera Lohans, Garcia-Saez Ana J
Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
Int J Mol Sci. 2020 Mar 31;21(7):2412. doi: 10.3390/ijms21072412.
Pyroptosis, necroptosis, and ferroptosis are well-characterized forms of regulated necrosis that have been associated with human diseases. During regulated necrosis, plasma membrane damage facilitates the movement of ions and molecules across the bilayer, which finally leads to cell lysis and release of intracellular content. Therefore, these types of cell death have an inflammatory phenotype. Each type of regulated necrosis is mediated by a defined machinery comprising protein and lipid molecules. Here, we discuss how the interaction and reshaping of these cellular components are essential and distinctive processes during pyroptosis, necroptosis, and ferroptosis. We point out that although the plasma membrane is the common target in regulated necrosis, different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Current efforts are focused on new therapies that target critical protein and lipid molecules on these pathways to fight human pathologies associated with inflammation.
焦亡、坏死性凋亡和铁死亡是特征明确的程序性坏死形式，与人类疾病相关。在程序性坏死过程中，质膜损伤促进离子和分子跨双层膜移动，最终导致细胞裂解并释放细胞内物质。因此，这些类型的细胞死亡具有炎症表型。每种类型的程序性坏死都由包含蛋白质和脂质分子的特定机制介导。在此，我们讨论这些细胞成分的相互作用和重塑在焦亡、坏死性凋亡和铁死亡过程中是如何成为必不可少且独特的过程。我们指出，尽管质膜是程序性坏死的共同靶点，但根据细胞死亡形式出现了不同的通透化机制。gasdermin（GSDM）形成孔道是焦亡的标志，而混合谱系激酶结构域样（MLKL）蛋白促进坏死性凋亡中的膜通透化，磷脂过氧化导致铁死亡中的膜损伤。这种导致膜通透化的多种机制有助于确定每种类型程序性坏死的特定炎症和免疫结果。目前的努力集中在针对这些途径上关键蛋白质和脂质分子的新疗法，以对抗与炎症相关的人类疾病。
