Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK.
SLING, Singapore Lipidomics Incubator, Life Sciences Institute and Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore, Singapore.
Cell Biochem Biophys. 2021 Sep;79(3):461-475. doi: 10.1007/s12013-021-00990-1. Epub 2021 May 15.
Dihydroceramide desaturase (Degs1) catalyses the introduction of a 4,5-trans double bond into dihydroceramide to form ceramide. We show here that Degs1 is polyubiquitinated in response to retinol derivatives, phenolic compounds or anti-oxidants in HEK293T cells. The functional predominance of native versus polyubiquitinated forms of Degs1 appears to govern cytotoxicity. Therefore, 4-HPR or celecoxib appear to stimulate the de novo ceramide pathway (with the exception of C24:0 ceramide), using native Degs1, and thereby promote PARP cleavage and LC3B-I/II processing (autophagy/apoptosis). The ubiquitin-proteasomal degradation of Degs1 is positively linked to cell survival via XBP-1s and results in a concomitant increase in dihydroceramides and a decrease in C24:0 ceramide levels. However, in the case of 4-HPR or celecoxib, the native form of Degs1 functionally predominates, such that the apoptotic programme is sustained. In contrast, 4-HPA or AM404 do not produce apoptotic ceramide, using native Degs1, but do promote a rectifier function to induce ubiquitin-proteasomal degradation of Degs1 and are not cytotoxic. Therefore, Degs1 appears to function both as an 'inducer' and 'rectifier' of apoptosis in response to chemical cellular stress, the dynamic balance for which is dependent on the nature of chemical stress, thereby determining cytotoxicity. The de novo synthesis of ceramide or the ubiquitin-proteasomal degradation of Degs1 in response to anti-oxidants, retinol derivatives and phenolic compounds appear to involve sensors, and for rectifier function, this might be Degs1 itself.
二氢神经酰胺去饱和酶 (Degs1) 催化二氢神经酰胺中 4,5-顺式双键的引入，形成神经酰胺。我们在这里表明 Degs1 在 HEK293T 细胞中对视黄醇衍生物、酚类化合物或抗氧化剂的反应会发生多泛素化。天然形式与多泛素化形式的 Degs1 的功能优势似乎决定了细胞毒性。因此，4-HPR 或塞来昔布似乎通过使用天然 Degs1 刺激从头合成神经酰胺途径（除了 C24:0 神经酰胺），从而促进 PARP 切割和 LC3B-I/II 加工（自噬/凋亡）。Degs1 的泛素-蛋白酶体降解通过 XBP-1s 与细胞存活呈正相关，导致二氢神经酰胺增加和 C24:0 神经酰胺水平降低。然而，在 4-HPR 或塞来昔布的情况下，天然形式的 Degs1 具有功能优势，使凋亡程序得以维持。相比之下，4-HPA 或 AM404 不会使用天然 Degs1 产生促凋亡的神经酰胺，但会促进整流功能，诱导 Degs1 的泛素-蛋白酶体降解，且无细胞毒性。因此，Degs1 似乎在响应化学细胞应激时既是凋亡的“诱导剂”又是“整流器”，其动态平衡取决于化学应激的性质，从而决定了细胞毒性。抗氧化剂、视黄醇衍生物和酚类化合物对神经酰胺的从头合成或 Degs1 的泛素-蛋白酶体降解的反应似乎涉及传感器，对于整流功能，这可能是 Degs1 本身。
