Sphingolipids, essential membrane components and signaling molecules in cells, have ceramides at the core of their metabolic pathways. Initially termed as "longevity assurance genes", the encoding genes of ceramide synthases are closely associated with individual aging and stress responses, although the mechanisms remain unclear. This study aims to explore the alterations and underlying mechanisms of three ceramide synthases, HYL-1, HYL-2, and LAGR-1, in the aging and stress responses of . Our results showed the knockdown of HYL-1 extends the lifespan and enhance stress resistance in worms, whereas the loss of HYL-2 function significantly impairs tolerances to heat, oxidation, and ultraviolet stress. Stress intolerance induced by HYL-2 deficiency may result from intracellular mitochondrial dysfunction, accumulation of reactive oxygen species, and abnormal nuclear translocation of DAF-16 under stress conditions. Loss of HYL-2 led to a significant reduction of predominant ceramides (d17:1/C20∼C23) as well as corresponding complex sphingolipids. Furthermore, the -acyl chain length composition of sphingolipids underwent dramatic modifications, characterized by a decrease in C22 sphingolipids and an increase in C24 sphingolipids. Extra d18:1-ceramides resulted in diminished stress resilience in wild-type worms, while supplementation of d18:1/C16 ceramide to HYL-2-deficient worms marginally improved stress tolerance to heat and oxidation. These findings indicate the importance of appropriate ceramide content and composition in maintaining subcellular homeostasis and nuclear-cytoplasmic signal transduction during healthy aging and stress responses.

中文翻译：

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秀丽隐杆线虫神经酰胺合酶 HYL-2 的缺失会损害应激反应并改变鞘脂组成


鞘脂是细胞中必需的膜成分和信号分子，神经酰胺是其代谢途径的核心。神经酰胺合酶的编码基因最初被称为“长寿保证基因”，与个体衰老和应激反应密切相关，但其机制尚不清楚。本研究旨在探讨三种神经酰胺合酶 HYL-1、HYL-2 和 LAGR-1 在衰老和应激反应中的变化和潜在机制。我们的结果表明，HYL-1 的敲低可延长蠕虫的寿命并增强其抗逆性，而 HYL-2 功能的丧失会显着损害对热、氧化和紫外线应激的耐受性。 HYL-2 缺陷引起的应激不耐受可能是由于应激条件下细胞内线粒体功能障碍、活性氧的积累以及 DAF-16 的异常核转位所致。 HYL-2 的缺失导致主要神经酰胺 (d17:1/C20∼C23) 以及相应的复合鞘脂显着减少。此外，鞘脂的α-酰基链长度组成发生了巨大的改变，其特征是C22鞘脂减少和C24鞘脂增加。额外的 d18:1-神经酰胺会导致野生型线虫的应激恢复能力下降，而向 HYL-2 缺陷线虫补充 d18:1/C16 神经酰胺则略微提高了对热和氧化的应激耐受性。这些发现表明适当的神经酰胺含量和成分在健康衰老和应激反应过程中维持亚细胞稳态和核细胞质信号转导中的重要性。