Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Abstract

Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factors that are conserved from fungi to humans and are defined by two key features: a signature tyrosine residue in the DNA-binding domain, and a membrane-tethering domain that is a target for regulated proteolysis. Recent studies including genome-wide and model organism approaches indicate SREBPs coordinate cellular lipid metabolism with other cellular physiologic processes. These functions are broadly related as cellular adaptation to environmental changes ranging from nutrient fluctuations to toxin exposure. This review integrates classic features of the SREBP pathway with newer information regarding the regulation and sensing mechanisms that serve to assimilate different cellular physiologic processes for optimal function and growth.

Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1

“…Analysis of the effects of cholesterol and fatty acids on hepatic gene expression led to the discovery of a family of membrane-bound transcription factors named SREBPs and identifi ed them as the master regulators of lipid homeostasis ( 54 ). Family members SREBP1a and SREBP1c are known to activate genes involved in regulating general lipid metabolism, whereas SREBP2 regulates expression of genes involved in cholesterol homeostasis ( 53,54 ). Although numerous transcriptional targets of SREBPs have been identifi ed, little is known about their effects on expression of genes in extrahepatic tissues or genes not directly associated with lipid homeostasis.…”

“…The transcriptionally active bHLH-LZ domains translocate to the nucleus where they transactivate gene expression by binding to SREs within target promoters ( 51,53,54 ).…”

Yeast Sterol Regulatory Element-binding Protein (SREBP) Cleavage Requires Cdc48 and Dsc5, a Ubiquitin Regulatory X Domain-containing Subunit of the Golgi Dsc E3 Ligase

“…There, two sequential proteolytic cleavage events mediated by the Golgi-resident site-1 protease (S1P) and site-2 protease (S2P) release the N-terminal transcription factor domain of SREBP from the membrane. The soluble N-terminal SREBP transcription factor travels to the nucleus and up-regulates genes involved in sterol biosynthesis and uptake from the environment (3). Consequently, cellular sterols return to sufficient levels, SREBP activity is repressed, and cholesterol homeostasis is maintained.…”

Casein Kinase 1 Regulates Sterol Regulatory Element-binding Protein (SREBP) to Control Sterol Homeostasis

“…SREBPs are highly conserved from fungi to mammals, and under normal sterol conditions they exist as inactive endoplasmic reticulum transmembrane proteins. Depletion of cellular sterol results in translocation of SREBP to the Golgi where it undergoes proteolytic cleavage, liberating the N terminus which then localizes to the nucleus to function as a transcription factor (4,6). Once in the nucleus, active SREBP promotes expression of genes required for sterol homeostasis by binding to specific sterol regulatory elements (SREs) in the promoters of target genes.…”