Characterisation of the Major Facilitator Superfamily Domain Containing 1 Protein (MFSD1) and study of its physiological role in the mouse

In this study, a recently identified putative lysosomal transporter, Major Facilitator Superfamily Domain containing 1 (MFSD1), was biochemically characterized and its physiological role in mice was investigated. MFSD1 is expressed ubiquitously in mouse tissues. A dileucine-based lysosomal sorting motif necessary for the transport of MFSD1 to lysosomes was identified. GLMP, a highly glycosylated lysosomal membrane protein, was identified as an interaction partner of MFSD1. The stability of GLMP and MFSD1 depends on each other. In the absence of GLMP, the levels of MFSD1 in tissues and cells were decreased below 10 % of normal levels. A thorough study of newly generated MFSD1-deficient mice revealed a complex phenotype, pointing towards a critical and essential role of MFSD1 in the physiology of the liver, the bone, the kidney and the immune system. MFSD1-deficient mice suffer from a liver insult characterized by loss of sinusoids, extravasation of erythrocytes, fibrosis and neocapillarization, a pathology that resembles that of human patients suffering from sinusoidal obstructive syndrome (SOS). SOS patients with genetic mutations in the transcription factor sp110 show an immunodeficiency. Interestingly, MFSD1-konockout mice are also immunodeficient due to impaired maturation of B lymphocytes, suggesting a possible role of MFSD1 in the pathology of SOS patients with immunodeficiency. Additionally, the mineralization ability of MFSD1-deficient osteoblasts in vertebrae is impaired, leading to decreased bone mineral density. Furthermore, the absence of MFSD1 also leads to an increase of the size of lysosomes in the proximal tubules of the kidney, suggesting a potential accumulation of the substrate(s) normally transported by MFSD1. A prove of the interdependence between MFSD1 and GLMP is that the phenotype of GLMP-deficient mice is a phenocopy of MFSD1 knockout mice.