The sterol regulatory element-binding proteins (SREBPs), a family of endoplasmic reticulum (ER) membrane-bound transcription factors that, in mammals, stimulate the transcription of genes involved in cholesterol and fatty acid synthesis, are regulated by feedback inhibition. SREBP is activated through proteolytic cleavage in the Golgi; high concentrations of sterols promote formation of a complex between SREBP and its binding partner SREBP cleavage activating protein (SCAP) and the ER protein Insig, trapping SREBP-SCAP in the ER. Hughes et al. identified a gene (sre1+) in Schizosaccharomyces pombe with 59% sequence identity to human SREBP-1a in its DNA binding domain and similar overall topology. They also identified a yeast homolog of SCAP (scp1+) and of Insig-1 (ins1+). Yeast Sre1 formed a complex with Scp1 and underwent proteolysis when sterol synthesis was pharmacologically inhibited. Microarray analysis of mRNA isolated from sterol-depleted wild-type yeast and yeast lacking scp1 indicated that Sre1 promoted the transcription of genes involved in sterol biosynthesis and also that of genes required for the shift from aerobic to anaerobic growth. Yeast lacking sre1 or scp1 were unable to grow in the absence of oxygen; moreover, low oxygen promoted Sre1 cleavage in wild-type cells and stimulated the expression of its target genes. Shifting to low oxygen reduced ergosterol synthesis; after several hours, wild-type cells were able to adapt and increase ergosterol synthesis, whereas cells lacking sre1 could not. Thus, the authors propose that Sre1 monitors oxygen availability through oxygen-dependent sterol synthesis and may play a role in the response to hypoxia in mammals as well as in yeast.
A. L. Hughes, B. L. Todd, P. J. Espenshade, SREBP pathway responds to sterols and functions as an oxygen sensor in fission yeast. Cell 120, 831-842 (2005). [Online Journal]