Sorting through the extensive and confusing roles of sortilin in metabolic disease

Abstract

Sortilin is a post-Golgi trafficking receptor homologous to the yeast vacuolar protein sorting receptor 10 (VPS10). The VPS10 motif on sortilin is a 10-bladed β-propeller structure capable of binding more than 50 proteins, covering a wide range of biological functions including lipid and lipoprotein metabolism, neuronal growth and death, inflammation, and lysosomal degradation. Sortilin has a complex cellular trafficking itinerary, where it functions as a receptor in the trans-Golgi network, endosomes, secretory vesicles, multivesicular bodies, and at the cell surface. In addition, sortilin is associated with hypercholesterolemia, Alzheimer's disease, prion diseases, Parkinson's disease, and inflammation syndromes. The 1p13.3 locus containing SORT1, the gene encoding sortilin, carries the strongest association with LDL-C of all loci in human genome-wide association studies. However, the mechanism by which sortilin influences LDL-C is unclear. Here, we review the role sortilin plays in cardiovascular and metabolic diseases and describe in detail the large and often contradictory literature on the role of sortilin in the regulation of LDL-C levels.

Keywords: CVD; LDL/metabolism; SORT1; VPS10; cellular trafficking; cholesterol/metabolism; cholesterol/trafficking; dyslipidemias; lipoproteins/metabolism; sortilin.

Fig. 1

Sortilin is a member of the VPS10 family. A: Sortilin is a member of the mammalian VPS10 family of receptors along with SorLA, SorCS1, SorCS2, and SorCS3, which have a large luminal/extracellular segment containing a VPS10 domain, a transmembrane domain, and a short cytoplasmic/intracellular tail. Diagram adapted from Malik and Willnow (21). B: The VPS10 domain folds into a 10-bladed β-propeller and cysteine-rich 10CC module, as determined by Quistgaard et al. (25). Protein Data Bank ID: 3F6K.

Fig. 2

Cellular trafficking of sortilin. A: 1) Sortilin is converted from its proform to its mature form in the TGN by furin cleavage of its propeptide. Mature sortilin can exit the TGN through three different routes, depending on the cell type, 2) through anterograde sorting to endosomes, which requires binding of APs GGA and/or AP-1 to its cytoplasmic tail, 3) through the constitutive secretory pathway, or 4) through the regulated secretory pathway in specialized cell types. Sortilin does not localize to mature secretory granules, and it is unclear how it exits immature secretory granules, indicated by dotted arrows. When sortilin reaches the cell surface, it can be 5) shed from the surface, or 6) endocytosed, which requires AP-2 binding. The majority of sortilin at the plasma membrane is rapidly endocytosed. 7) Sortilin is returned from endosomes to the TGN by retrograde sorting, which requires interaction with the retromer complex and PACS-1. 8) Sortilin is also involved in sorting cargo to multivesicular bodies and can itself be secreted from the cell in exosomes. Highlighted box indicates a process that occur in specialized cell types. Diagram adapted from Malik and Willnow et al. (21). B: Important sorting motifs located in the cytoplasmic tails of sortilin, CI-MPR, CD-MPR, and yeast VPS10 include a tyrosine-based motif (YXXΦ) and an acidic cluster dileucine motif (DXXLL) that overlaps with an acidic cluster motif ([DE]XXXL[LI]), which are important for AP binding. Thickness of the underline indicates relative potency of the motif for the transport and AP binding indicated. MVB, multivesicular body; PACS-1, phosphofurin acidic cluster sorting protein 1.

Fig. 3

Models of sortilin function in lipoprotein metabolism in the liver. Model 1: Sortilin facilitates the secretion of VLDL, increasing circulating VLDL and LDL through lipolysis. Model 2: Sortilin promotes LDL internalization, decreasing circulating LDL. Model 3: Sortilin traffics VLDL from the TGN toward the endolysosomal system for degradation, decreasing circulating VLDL and LDL. Diagram adapted from Schmidt and Willnow (175). LDL, red shaded; VLDL, gray shaded.

Fig. 4

Sortilin contributes to many aspects of cardiovascular risk. Human GWAS, physiological studies in mice, and biochemical studies in cells have revealed a role for sortilin in several aspects of cardiovascular risk. Sortilin regulates LDL-C level by trafficking apoB-100-containing lipoproteins in hepatocytes, inflammation, and foam cell formation by regulating cytokine secretion and lipid uptake in macrophages, vascular calcification, and arterial remodeling by trafficking TNAP and p75NTR-induced apoptosis in smooth muscle cells, and glucose tolerance by trafficking GLUT4 storage vesicles in fat and muscle cells. Diagram adapted from Goettsch et al. (314).

Fig 5

List of several key questions that remain about the function of sortilin and the role that it plays in metabolic disease.