TY - JOUR
T1 - Dihydroceramide Desaturase Functions as an Inducer and Rectifier of Apoptosis
T2 - Effect of Retinol Derivatives, Antioxidants and Phenolic Compounds
AU - Alsanafi, Mariam
AU - Brown, Ryan D. R.
AU - Oh, Jeongah
AU - Adams, David R.
AU - Torta, Federico
AU - Pyne, Nigel J.
AU - Pyne, Susan
N1 - Funding Information:
RDRB acknowledges the University of Strathclyde for a scholarship award. JO was supported by the NRF2019-NRF-ISF003-3172 grant. We would like to thank Professor Al Merrill for suggesting 4-HPA, acetaminophen and AM404 for comparison with 4-HPR.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Dihydroceramide desaturase
KW - Fenretinide
KW - Polubiquitination
UR - http://www.scopus.com/inward/record.url?scp=85106285059&partnerID=8YFLogxK
U2 - 10.1007/s12013-021-00990-1
DO - 10.1007/s12013-021-00990-1
M3 - Article
C2 - 33991313
SN - 1085-9195
VL - 79
SP - 461
EP - 475
JO - Cell Biochemistry and Biophysics
JF - Cell Biochemistry and Biophysics
IS - 3
ER -