The Physiopathological Role of the Exchangers Belonging to the SLC37 Family

Abstract

The human SLC37 gene family includes four proteins SLC37A1-4, localized in the endoplasmic reticulum (ER) membrane. They have been grouped into the SLC37 family due to their sequence homology to the bacterial organophosphate/phosphate (Pi) antiporter. SLC37A1-3 are the less characterized isoforms. SLC37A1 and SLC37A2 are Pi-linked glucose-6-phosphate (G6P) antiporters, catalyzing both homologous (Pi/Pi) and heterologous (G6P/Pi) exchanges, whereas SLC37A3 transport properties remain to be clarified. Furthermore, SLC37A1 is highly homologous to the bacterial glycerol 3-phosphate permeases, so it is supposed to transport also glycerol-3-phosphate. The physiological role of SLC37A1-3 is yet to be further investigated. SLC37A1 seems to be required for lipid biosynthesis in cancer cell lines, SLC37A2 has been proposed as a vitamin D and a phospho-progesterone receptor target gene, while mutations in the SLC37A3 gene appear to be associated with congenital hyperinsulinism of infancy. SLC37A4, also known as glucose-6-phosphate translocase (G6PT), transports G6P from the cytoplasm into the ER lumen, working in complex with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to Pi and glucose. G6PT and G6Pase-β are ubiquitously expressed, whereas G6Pase-α is specifically expressed in the liver, kidney and intestine. G6PT/G6Pase-α complex activity regulates fasting blood glucose levels, whereas G6PT/G6Pase-β is required for neutrophil functions. G6PT deficiency is responsible for glycogen storage disease type Ib (GSD-Ib), an autosomal recessive disorder associated with both defective metabolic and myeloid phenotypes. Several kinds of mutations have been identified in the SLC37A4 gene, affecting G6PT function. An increased autoimmunity risk for GSD-Ib patients has also been reported, moreover, SLC37A4 seems to be involved in autophagy.

Keywords: G6PT deficiency; SLC37A1-4; endoplasmic reticulum; glucose-6-phosphate translocase; glycogen storage disease type Ib.

Figure 1

Alignment of the amino acid sequences of human SLC37A1, SLC37A2, SLC37A3, and SLC37A4 showing the location of nonsense and missense mutations identified in GSD-Ib patients. The aligned amino acid sequences are GENBANK accession numbers NP_061837.3 (SLC37A1), NP_938018.1 (SLC37A2), AAH46567.1 (SLC37A3), and CAG33014.1 (SLC37A4). Sequence conservation is indicated by an asterisk for identical residues, a dot for conserved substitutions, and a gap for non-conserved residues. The organo-phosphate/Pi antiporter family consensus sequence, ProSite PDOC00726, shared by the SLC37 family members is indicated by black double lines. Dashed black lines show lacking residues at the N- or C- terminal end in mutants MIV and R415X, respectively. Nonsense and missense mutations are highlighted in black or gray, respectively. Alignment has been performed by ClustalW.

Figure 2

Schematic topological model of human G6PT displaying nonsense and missense mutations identified in GSD-Ib patients. Nonsense and missense mutations are highlighted in black or gray, respectively. The extension of the consensus sequence is reported in an ellipse. White boxes represent mutations that eliminate the N- or C- terminal domain.

Figure 3

Primary metabolic pathways of G6P in the liver, kidney, and intestine, in normal (A) and defective G6PT (B) cells. Schematic cell harboring an extended endoplasmic reticulum (ER). G6Pase-α and G6PT are embedded in the ER membrane; the glucose transporter GLUT2 is embedded in the plasma membrane. Black arrows indicate metabolic changes due to defective SLC37A4. G6P, glucose-6-phosphate; G6Pase-α, glucose-6-phosphatase-α; G6PT, glucose-6-phosphate translocase; GLUT2, glucose transporter 2; P, phosphate; Pi, inorganic phosphate.

Figure 4

Main metabolic pathways of G6P in normal (A) and defective G6PT (B) neutrophils. Schematic cell showing an extended endoplasmic reticulum (ER) and the three major pathways (glycolysis, pentose phosphate pathway, and ER cycling) in which G6P is involved. G6Pase-β and G6PT are embedded in the ER membrane; GLUT 1 is embedded in the plasma membrane. Black arrows indicate metabolic changes due to defective SLC37A4.: G6P, glucose-6-phosphate; G6Pase-β, glucose-6-phosphatase-β; G6PT, glucose-6-phosphate translocase; GLUT 1, glucose transporter 1; P, phosphate; Pi, inorganic phosphate; ATP, adenosine triphosphate; NADPH, nicotinamide adenine dinucleotide phosphate.