The Lipid Transfer Protein StarD7: Structure, Function, and Regulation

Abstract

The steroidogenic acute regulatory (StAR) protein-related lipid transfer (START) domain proteins constitute a family of evolutionarily conserved and widely expressed proteins that have been implicated in lipid transport, metabolism, and signaling. The 15 well-characterized mammalian START domain-containing proteins are grouped into six subfamilies. The START domain containing 7 mRNA encodes StarD7, a member of the StarD2/phosphatidylcholine transfer protein (PCTP) subfamily, which was first identified as a gene overexpressed in a choriocarcinoma cell line. Recent studies show that the StarD7 protein facilitates the delivery of phosphatidylcholine to the mitochondria. This review summarizes the latest advances in StarD7 research, focusing on the structural and biochemical features, protein-lipid interactions, and mechanisms that regulate StarD7 expression. The implications of the role of StarD7 in cell proliferation, migration, and differentiation are also discussed.

Figure 1

Schematic representation of the human StarD7 gene, mRNA, and protein. (a) Gene organization. The relative position and approximate sizes of eight exons spanning 23.96 kb on chromosome 2 is shown in a linear representation; (b) mRNA (NM_020151.3) schema. Putative translation initiation AUG codons encoding the StarD7-I of 370 (positions 402–1514) and StarD7-II of 295 (positions 627–1514) amino acid residues are shown. Light grey boxes represent 5′UTR and 3′UTR regions; (c) The StarD7 protein (370 aa). Putative ubiquitination (red) and phosphorylation (black) sites as well as the mitochondrial localization signal (grey box) and the steroidogenic acute regulatory protein-related lipid transfer (START) domain (black box) are indicated.

Figure 2

Steroidogenic factor 1 (SF-1)/β-catenin upregulates StarD7 expression in JEG-3 cells. The proposed model shows SF-1/β-catenin mechanisms involved in StarD7-induced expression, based on current data. The Wnt/β-catenin pathway is a conserved cell-cell signaling mechanism in animals that regulates gene expression via the TCF/LEF1 family to coordinate many cellular processes. In the absence of Wnt signaling, the destruction complex remains in the cytoplasm, where it binds, phosphorylates, and ubiquitinates β-catenin via the β-transducing repeat-containing protein (βTrCP). Finally, the proteasome recycles the complex by degrading β-catenin (Wnt off). In the presence of Wnt signaling, the destruction complex captures and phosphorylates β-catenin but ubiquitination by β-TrCP is blocked. This results in accumulation and nuclear localization of the newly synthesized β-catenin. In the nucleus, β-catenin regulates target gene expression by interacting with TCF/LEF1 transcription factors [69]. Free β-catenin interacts with SF-1 to increase StarD7 transcription [65]. In addition, the cAMP response element-binding protein (CREB) may bind putative cAMP response elements that modulate gene expression. StarD7 mediates PC intracellular trafficking to the mitochondria [26] and possibly to the plasma membrane [24] and lipid droplets [34]. APC, adenomatous polyposis coli; CK1, casein kinase 1; Dvl, Dishevelled; LrP, low density lipoprotein receptor-related protein.

Figure 3

The role of StarD7 in various cellular events in JEG-3 cells. StarD7 knockdown causes a reduction in ABCG2 and phospholipid synthesis, decreased cell migration and proliferation, and increased βhCG and syncytin-1 transcription [83]. High StarD7 levels have been found in several types of cancers (Table 1). StarD7 is induced by the Wnt/β-catenin pathway [64].