Casein Kinase 1 Regulates Sterol Regulatory Element-binding Protein (SREBP) to Control Sterol Homeostasis

Background: SREBP transcription factor controls sterol homeostasis. Results: Fission yeast casein kinase 1 (CK1) binds and accelerates degradation of active SREBP, inhibiting expression of target genes and decreasing ergosterol. Conclusion: CK1 controls nuclear SREBP stability to regulate sterol homeostasis in fission yeast. Significance: CK1 is the first kinase shown to regulate fungal SREBP and functions in the control of SREBP and sterol homeostasis. Sterol homeostasis is tightly controlled by the sterol regulatory element-binding protein (SREBP) transcription factor that is highly conserved from fungi to mammals. In fission yeast, SREBP functions in an oxygen-sensing pathway to promote adaptation to decreased oxygen supply that limits oxygen-dependent sterol synthesis. Low oxygen stimulates proteolytic cleavage of the SREBP homolog Sre1, generating the active transcription factor Sre1N that drives expression of sterol biosynthetic enzymes. In addition, low oxygen increases the stability and DNA binding activity of Sre1N. To identify additional signals controlling Sre1 activity, we conducted a genetic overexpression screen. Here, we describe our isolation and characterization of the casein kinase 1 family member Hhp2 as a novel regulator of Sre1N. Deletion of Hhp2 increases Sre1N protein stability and ergosterol levels in the presence of oxygen. Hhp2-dependent Sre1N degradation by the proteasome requires Hhp2 kinase activity, and Hhp2 binds and phosphorylates Sre1N at specific residues. Our results describe a role for casein kinase 1 as a direct regulator of sterol homeostasis. Given the role of mammalian Hhp2 homologs, casein kinase 1 and 1E, in regulation of the circadian clock, these findings may provide a mechanism for coordinating circadian rhythm and lipid metabolism.