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.

Figure 1.

SREBP evolution. An evolutionary tree was constructed for the SREBP homologs from different species. Only a subset of species within each major category is shown for simplicity. (Cele) Caenorhabditis elegans; (Calb) Candida albicans; (Spom) Schizosaccharomyces pombe; (Cint) Ciona intestinalis; (Dme) Drosophila melanogaster; (Aaeg) Aedes aegypti; (Xtro) Xenopus tropicalis; (Mdom) Musca domesticus; (Rnor) Rattus norvegicus; (Mmus) Mus musculus; (Hsap) Homo sapiens; (Cfam) Canis familiaris; (Fcat) Felis catus; (Ggal) Gallus gallus; (Oana) Ornithorhynchus anatinus.

Figure 2.

Multiple pathways for SREBP regulation in the ER. SCAP is a polytopic ER membrane protein (blue), and its cytoplasmic C terminus interacts with the C terminus of the two-pass ER precursor form of SREBP (black). The bHLH-LZ DNA-binding domain (DBD) and N-terminal activation domain (AD) of SREBP are also shown. When bound to cholesterol, SCAP interacts with INSIG. This association keeps the SCAP–SREBP complex in the ER membrane. SREBP–SCAP movement to the Golgi apparatus is regulated by at least two pathways: (1) When cholesterol levels are depleted, a conformational change occurs in SCAP, decreasing its interaction with INSIG and exposing the MELADL COPII targeting signal. (2) Insulin–AKT and ER stress also result in INSIG dissociating from SCAP, and SCAP–SREBP moves to the Golgi presumably through the same pathway. (3) Once free of SCAP, INSIG interacts with the membrane-bound E3 ubiquitin ligase GP78 and, following ubiquitination, INSIG is degraded by the proteasome. (4) Once free of INSIG, SCAP escorts SREBP to the Golgi apparatus through interaction with the Sec24 subunit of COPII. The fate of SREBPs in the Golgi are discussed in the text.

Figure 3.

Oxygen regulates the active, cleaved Sre1N transcription factor by two mechanisms. (A, step 1) Oxygen-dependent ergosterol synthesis inhibits Sre1 proteolysis and production of Sre1N. (Step 2) Oxygen positively regulates Ofd1, which accelerates the proteasomal degradation of Sre1N. (B) In the presence of oxygen, Sre1 cleavage is low, and Ofd1-dependent degradation is high. Under low oxygen, these two mechanisms are reversed, and Sre1N accumulates.