SREBP Pathway Responds to Sterols and Functions as an Oxygen Sensor in Fission Yeast

Abstract

Cholesterol and fatty acid synthesis in mammals are controlled by SREBPs, a family of membrane bound transcription factors. Our studies identified homologs of SREBP, its binding partner SCAP, and the ER retention protein Insig in Schizosaccharomyces pombe, named sre1+, scp1+, and ins1+. Like SREBP, Sre1 is cleaved and activated in response to sterol depletion in a Scp1-dependent manner. Microarray analysis revealed that Sre1 activates sterol biosynthetic enzymes as in mammals, and, surprisingly, Sre1 also stimulates transcription of genes required for adaptation to hypoxia. Furthermore, Sre1 rapidly activates these target genes in response to low oxygen and is itself required for anaerobic growth. Based on these findings, we propose and test a model in which Sre1 and Scp1 monitor oxygen-dependent sterol synthesis as an indirect measure of oxygen supply and mediate a hypoxic response in fission yeast.

Reactive oxygen species and cellular oxygen sensing

“…In yeast, decreased de novo synthesis of sterol and heme due to O 2 limitation affects the activities of multiple transcription factors, such as Hap1 and Sre1 [6,7]. In metazoans, O 2 sensing systems are more complicated.…”

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

“…However, the molecular components have been identified in many other distantly related species (Table 1). Although the key proteins are conserved, the SREBP pathway in the fission yeast system responds to sterol levels as a secondary response to limited oxygen supply (Hughes et al 2005), whereas in Drosophila and probably other invertebrates that are cholesterol auxotrophs (Karlson 1970), SREBP maturation does not respond to sterol concentrations, but rather to phosphatidylethanolamine (PE) ). An INSIG homolog has not been found in Drosophila (Rawson 2003) despite the fact that processing of the Drosophila SREBP homolog is regulated by sterols when expressed in mammalian cells (Rosenfeld and Osborne 1998).…”

“…Sequence database searches revealed homologs of SREBP, SCAP, and INSIG, called Sre1, Scp1, and Ins1, respectively (Table 1; Hughes et al 2005). As in mammalian cells, Sre1-Scp1 form a complex, and Sre1 is proteolytically cleaved and activated in response to cellular depletion of the fungal sterol ergosterol (Hughes et al 2005(Hughes et al , 2007.…”

“…This juxtaposes the N-terminal domain containing the transcriptional activation and DNA-binding domains with the C-terminal regulatory domain on the cytoplasmic side of the membrane (Brown and Goldstein 1999). In SREBPs from yeast to humans, the C-terminal domain interacts with the SREBP cleavage-activating protein (SCAP), which is an escort protein that carries SREBPs from the ER to the Golgi apparatus in response to metabolic regulatory cues (Hughes et al 2005). Once in the Golgi, the SREBPs are released from the membrane through a sequential two-step proteolytic process discussed in more detail below.…”

Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2

“…Part of this regulation involves the transcription control of genes encoding ergosterol biosynthetic enzymes and proteins that perform sterol processing and uptake 2 . In some fungal species, such as Schizosaccharomyces pombe, it is mediated by hypoxic regulatory proteins, Sre1 and Scp1, which share common features with the mammalian sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein 3,4 . However, many other fungal species, including Saccharomyces cerevisiae and Candida species, lack protein homologues of the mammalian cholesterol regulators and appear to have evolved distinct regulatory mechanism 5 .…”