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Ceramide kinase/ceramide 1-phosphate signaling regulates LC3B expression and autophagosome formation
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DOI：10.1016/j.jlr.2026.101077.png)
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Abstract
En 中文
Ceramide kinase (CerK) generates ceramide 1-phosphate (C1P), a bioactive sphingolipid involved in diverse cellular responses, but its role in autophagy is not fully understood. Here, we examined whether the CerK/C1P pathway regulates LC3B expression and autophagosome formation in HeLa cells. Proteomics analysis of cerebellum from Cerk-KO mice identified reduced levels of multiple autophagy-related proteins. In HeLa cells, genetic ablation, siRNA-mediated knockdown, and pharmacological inhibition of CerK consistently reduced LC3B-II levels. This effect was reversed by extracellular C1P and by re-expression of wild-type, but not kinase-dead, CerK, indicating that CerK-generated C1P is required for maintenance of LC3B-II. LC3B-II levels remained lower in CERK-KO cells in the presence of bafilomycin A1, and two-step flux analysis showed that disruption of the CerK/C1P pathway preferentially impaired the LC3B-associated autophagosome formation parameter. MAP1LC3B mRNA and Nrf2 protein levels were reduced in CERK-KO cells, and pharmacological activation of Nrf2 tended to restore MAP1LC3B mRNA levels and significantly increased LC3B-II protein levels. Finally, loss of the CerK/C1P pathway enhanced nutrient starvation-induced apoptotic responses and loss of viability. Together, these results identify the CerK/C1P pathway as a positive lipid signaling mechanism that maintains LC3B expression, supports LC3B-associated autophagosome formation, and promotes cell survival under nutrient-deprived conditions.
Keywords:
Sphingolipids
Ceramides
Cell signaling
Golgi apparatus
Proteomics
Ceramide kinase
Ceramide 1-phosphate
LC3B
Autophagosome formation
Nrf2
BafA
bafilomycin A1
C1P
ceramide 1-phosphate
CerK
ceramide kinase
CPTP
ceramide 1-phosphate transfer protein
DEM
diethyl maleate
NRF1
nuclear respiratory factor 1
Nrf1/NFE2L1
nuclear factor erythroid 2-related factor 1
Nrf2
nuclear factor erythroid 2-related factor 2
PARP
poly(ADP-ribose) polymerase
ULK1
unc-51-like autophagy activating kinase 1
WIPI2
WD repeat domain phosphoinositide-interacting protein 2
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