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Sterol regulatory element-binding protein (SREBP), a highly conserved family of membrane-bound transcription factors, is an essential regulator for cellular cholesterol and lipid homeostasis in mammalian cells. Sre1, the homolog of SREBP in the fission yeast  Schizosaccharomyces pombe  ( S .  pombe ), regulates genes involved in the transcriptional responses to low sterol as well as low oxygen. Previous study reported that casein kinase 1 family member Hhp2 phosphorylated the Sre1 N-terminal transcriptional factor domain (Sre1N) and accelerated Sre1N degradation, and other kinases might exist for regulating the Sre1 function. To gain insight into the mechanisms underlying the Sre1 activity and to identify additional kinases involved in regulation of Sre1 function, we developed a luciferase reporter system to monitor the Sre1 activity through its binding site called SRE2 in living yeast cells. Here we showed that both ergosterol biosynthesis inhibitors and hypoxia-mimic CoCl 2  caused a dose-dependent increase in the Sre1 transcription activity, concurrently, these induced transcription activities were almost abolished in Δ sre1  cells. Surprisingly, either AMPKα Subunit Ssp2 deletion or Glycogen Synthase Kinases Gsk3/Gsk31 double deletion significantly suppressed ergosterol biosynthesis inhibitors- or CoCl 2 -induced Sre1 activity. Notably, the Δ ssp2 Δ gsk3 Δ gsk31  mutant showed further decreased Sre1 activity when compared with their single or double deletion. Consistently, the Δ ssp2 Δ gsk3 Δ gsk31  mutant showed more marked temperature sensitivity than any of their single or double deletion. Moreover, the fluorescence of GFP-Sre1N localized at the nucleus in wild-type cells, but significantly weaker nuclear fluorescence of GFP-Sre1N was observed in Δ ssp2 , Δ gsk3 Δ gsk31 , Δ ssp2 Δ gsk3 , Δ ssp2 Δ gsk31  or Δ ssp2 Δ gsk3 Δ gsk31  cells. On the other hand, the immunoblot showed a dramatic decrease in GST-Sre1N levels in the Δ gsk3 Δ gsk31  or the Δ ssp2 Δ gsk3 Δ gsk31  cells but not in the Δ ssp2  cells. Altogether, our findings suggest that Gsk3/Gsk31 may regulate Sre1N degradation, while Ssp2 may regulate not only the degradation of Sre1N but also its translocation to the nucleus.

plos one

AMPKα Subunit Ssp2 and Glycogen Synthase Kinases Gsk3/Gsk31 are involved in regulation of sterol regulatory element-binding protein (SREBP) activity in fission yeast