Abstract
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.
Highlights
Serine palmitoyltransferase catalyses the condensation of serine and palmitoyl CoA to form 3-ketosphinganine, the rate limiting step in the de novo synthesis of ceramide [1].Cell Biochemistry and Biophysics (2021) 79:461–4753-Ketosphinganine is converted into sphinganine, by 3-ketosphinganine reductase, which is acylated by ceramide synthases (CerS) to form dihydroceramide
The increase in dihydroceramide levels in response to 4-HPR is consistent with elevated levels of dihydrosphingomyelin species, that are synthesised from dihydroceramides (Fig. 1A)
The increase in C16:0 ceramide in response to 4-HPR is associated with an elevation in the corresponding C34:1 (d18:1/16:0) sphingomyelin (Fig. 1A), while the decrease in C24:0 ceramide is associated with a reduction in C42:1 (d18:1/24:0) sphingomyelin levels (Fig. 1A)
Summary
Serine palmitoyltransferase catalyses the condensation of serine and palmitoyl CoA to form 3-ketosphinganine, the rate limiting step in the de novo synthesis of ceramide [1].Cell Biochemistry and Biophysics (2021) 79:461–4753-Ketosphinganine is converted into sphinganine, by 3-ketosphinganine reductase, which is acylated by ceramide synthases (CerS) to form dihydroceramide. Dihydroceramide desaturase (Degs1) catalyses the introduction of a trans 4,5 double bond to form ceramide. Degs deficiency in mouse embryonic fibroblasts is linked to increased dihydroceramide levels and AKT/protein kinase B (PKB) signalling that opposes apoptosis [6]. We have previously proposed that these opposing effects might involve native and polyubiquitinated forms of Degs1 [7, 8]. Native Degs is involved in induction of ceramidedependent apoptosis that might be linked with the inhibition of pro-survival AKT signalling. Polyubiquitinated forms of Degs confer pro-survival signaling via activation of p38 MAPK and XBP-1s in HEK293T cells and inhibition of autophagy [8]. Other studies have shown that inhibition of Degs promotes cell death, which may involve autophagy or apoptosis [4, 9]
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