Sterol regulatory element binding proteins in fungi: hypoxic transcription factors linked to pathogenesis

Abstract

Sterol regulatory element binding proteins (SREBPs) are membrane-bound transcription factors whose proteolytic activation is controlled by the cellular sterol concentration. Mammalian SREBPs are activated in cholesterol-depleted cells and serve to regulate cellular lipid homeostasis. Recent work demonstrates that SREBP is functionally conserved in fungi. While the ability to respond to sterols is conserved, fungal SREBPs are hypoxic transcription factors required for adaptation to a low-oxygen environment. In the fission yeast Schizosaccharomyces pombe, oxygen regulates the SREBP homolog Sre1 by independently controlling both its proteolytic activation and its degradation. SREBP is also required for adaptation to hypoxia in the human pathogens Cryptococcus neoformans and Aspergillus fumigatus. In these organisms, SREBP is required for virulence and resistance to antifungal drugs, making the SREBP pathway a potential target for antifungal therapy.

Fig. 1.

Mammalian SREBP pathway. Under sterol replete conditions, the SREBP-Scap complex is retained in the ER bound to INSIG. When sterol levels decrease, SREBP-Scap is transported to the Golgi apparatus, where SREBP is cleaved by the site 1 and site 2 proteases. The soluble N terminus of SREBP enters the nucleus and activates genes required for the synthesis and uptake of sterols and other lipids.

Fig. 2.

SREBP pathway in fungi. (A) S. pombe. In the presence of oxygen, sterols inhibit proteolysis of Sre1 and Ofd1 accelerates Sre1N degradation. In the absence of oxygen, both Sre1 proteolysis and stability increase, leading to upregulation of genes required for sterol synthesis and adaptation to low oxygen levels. How Sre1 is released from the membrane is unknown. (B) C. neoformans. Under low-oxygen conditions, CnSre1 is released from the membrane by the site 2 protease homolog Stp1 and CnSre1N activates genes required for sterol synthesis and metal homeostasis. Whether CnSre1N is regulated by Ofd1 is not known.