Diversification of DNA binding specificities enabled SREBP transcription regulators to expand the repertoire of cellular functions that they govern in fungi.

The Sterol Regulatory Element Binding Proteins (SREBPs) are basic-helix-loop-helix transcription regulators that control the expression of sterol biosynthesis genes in higher eukaryotes and some fungi. Surprisingly, SREBPs do not regulate sterol biosynthesis in the ascomycete yeasts (Saccharomycotina) as this role was handed off to an unrelated transcription regulator in this clade. The SREBPs, nonetheless, expanded in fungi such as the ascomycete yeasts Candida spp., raising questions about their role and evolution in these organisms. Here we report that the fungal SREBPs diversified their DNA binding preferences concomitantly with an expansion in function. We establish that several branches of fungal SREBPs preferentially bind non-palindromic DNA sequences, in contrast to the palindromic DNA motifs recognized by most basic-helix-loop-helix proteins (including SREBPs) in higher eukaryotes. Reconstruction and biochemical characterization of the likely ancestor protein suggest that an intrinsic DNA binding promiscuity in the family was resolved by alternative mechanisms in different branches of fungal SREBPs. Furthermore, we show that two SREBPs in the human commensal yeast Candida albicans drive a transcriptional cascade that inhibits a morphological switch under anaerobic conditions. Preventing this morphological transition enhances C. albicans colonization of the mammalian intestine, the fungus' natural niche. Thus, our results illustrate how diversification in DNA binding preferences enabled the functional expansion of a family of eukaryotic transcription regulators.

SREBPs: physiology and pathophysiology of the SREBP family.

Sterol regulatory element-binding proteins (SREBPs) have been established as physiological regulators of lipid synthesis. The molecular mechanisms by which cellular sterol balance and nutritional states regulate SREBP activities are the current research focus of this field. Meanwhile, it has been shown that overnutrition or disturbed energy balance causes accumulation of tissue lipids, leading to metabolic disorders, often referred to as 'lipotoxicity'. In this overview, I discuss the pathological aspects of SREBPs, which contribute to lipotoxicity in a wide variety of organs, including hepatic insulin resistance in hepatosteatosis, impaired insulin secretion in pancreatic beta-cells, diabetic nephropathy, cardiac arrythmiasis, and obesity.