How sterols regulate protein sorting and traffic

Students of cell biology and physiology are in for a treat with the discoveries, reported in this issue of PNAS by Radhakrishnan et al. (1) and Sun et al. (2), that cholesterol and an enigmatic but potent derivative, 25-OH cholesterol, exert their effect on gene expression by changing the conformation of two membrane protein sensors that guide a transcription factor precursor into the machinery responsible for vesicular traffic from the endoplasmic reticulum (ER). Over the past dozen years or so, the prolific team of Michael Brown and Joseph Goldstein has elucidated a control pathway in which the production of a transcription factor responsible for the expression of HMG–CoA reductase, a key branch point enzyme in the biosynthesis of cholesterol, among other targets, is controlled by the cholesterol-regulated proteolytic maturation of a transcription factor precursor, sterol regulatory element-binding protein (SREBP) (3). In cells grown with excess exogenous cholesterol, SREBP is synthesized as a membrane protein precursor housed in the ER. On cholesterol starvation, SREBP precursor is mobilized and transported via a vesicle carrier to the Golgi apparatus, where two site-specific proteases act to liberate the N-terminal cytosolic domain of SREBP. This domain constitutes a transcription factor that is directed to the nucleus, where it engages genes controlled by the sterol regulatory element (SRE) promoter sequence. The key questions have been: how do cholesterol and 25-OH cholesterol cause SREBP precursor to be retained in the ER, and what happens to liberate SREBP when sterol levels decline? Control molecules that govern this sorting decision have been teased apart by an elegant combination of genetics and biochemistry. Two ER membrane proteins, Scap and Insig, appear to be the key regulators. Scap is a multispanning protein, of which a portion comprising transmembrane (TM) helices 2–6 was shown previously to bind rather specifically to cholesterol, but …