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Pathogenesis

Bien CM, Espenshade PJ. Eukaryotic Cell 2010;9:352–9.

Similar to mammalian sterol regulatory element-binding proteins (SREBPs), characterized fungal SREBPs are transcriptional activators of sterol biosynthesis and are required for maintenance of cellular sterol homeostasis. Fungal SREBPs are not only regulated by cellular sterol concentrations (as in the mammalian SREBP pathway), but are also regulated by oxygen levels. SREBPs are functionally conserved in fungi and are required for adaptation in hypoxic environments, for virulence, and for resistance to antifungal drugs. Inhibitors of fungal SREBPs may act synergistically with currently available antifungal drugs to more effectively and rapidly clear fungal infections.

 

The present authors present a mini-review of fungal sterol regulatory element-binding protein (SREBP) pathways and their importance in correlation to human disease. SREBPs are transcription factors that belong to the basic-helix-loop-helix (bHLH) leucine zipper family and regulate sterol synthesis. SREBPs are synthesized as inactive proteins that are bound to the endoplasmic reticulum (ER) and require cleavage for activation. SREBP cleavage-activating protein (Scap) is another ER membrane protein that is bound to SREBP on the ER; this protein consists of eight transmembrane segments and is a component of the sterol sensor. In sterol-depleted cells, Scap escorts SREBP from the ER to the Golgi apparatus, where the site-1 and site-2 proteases cleave SREBP and release the N-terminal transcription factor domain into the cytosol. The soluble N-terminus of SREBP enters the nucleus and activates genes required for the synthesis and uptake of sterols. When membrane sterol levels are sufficient, Scap binds to sterols, leading to a conformational change and SREBP remains inactive on the ER membrane [1].

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