Oxygen‐dependent regulation of sterol regulatory element binding protein (SREBP) in fission yeast

Abstract

Sre1, the fission yeast Sterol Regulatory Element Binding Protein (SREBP), is a principal regulator of low oxygen gene expression whose activation is required for low oxygen growth. Oxygen regulates the activity of Sre1 by two independent mechanisms: Sre1 proteolysis is stimulated by inhibition of oxygen-dependent sterol synthesis; and oxygen accelerates the degradation of nuclear Sre1. Here, we report the identification of 4-methyl sterols as a signal for activation of Sre1 proteolysis. These sterols accumulate under low oxygen and activate Sre1 processing when added exogenously. In addition, we describe the identification of an uncharacterized 2-oxoglutarate, iron-dependent dioxygenase that is required for the oxygen-dependent degradation of nuclear Sre1. This bivalent regulation of Sre1 permits the rapid activation of gene expression and adaptation to fluctuations in environmental oxygen. These studies have important implications for our understanding of sterol-sensing domain proteins and for regulation of SREBP degradation in mammalian cells. Research was funded by a grant from the NIH HL-077588, a Burroughs Wellcome Fund Career Award in the Biomedical Sciences (PJE), and American Heart Association Predoctoral Fellowships (ALH and BTH).