The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP

Abstract

Lysosomes are major sites for intracellular, acidic hydrolase-mediated proteolysis and cellular degradation. The export of low-molecular-weight catabolic end-products is facilitated by polytopic transmembrane proteins mediating secondary active or passive transport. A number of these lysosomal transporters, however, remain enigmatic. We present a detailed analysis of MFSD1, a hitherto uncharacterized lysosomal family member of the major facilitator superfamily. MFSD1 is not N-glycosylated. It contains a dileucine-based sorting motif needed for its transport to lysosomes. Mfsd1 knockout mice develop splenomegaly and severe liver disease. Proteomics of isolated lysosomes from Mfsd1 knockout mice revealed GLMP as a critical accessory subunit for MFSD1. MFSD1 and GLMP physically interact. GLMP is essential for the maintenance of normal levels of MFSD1 in lysosomes and vice versa. Glmp knockout mice mimic the phenotype of Mfsd1 knockout mice. Our data reveal a tightly linked MFSD1/GLMP lysosomal membrane protein transporter complex.

eLife digest

Lysosomes are specialized, enclosed compartments within cells with harsh chemical conditions where enzymes break down large molecules into smaller component parts. The products of these reactions are then transported out of the lysosome by transporter proteins so that they can be used to build new molecules that the cell needs.

Despite their importance, only a few lysosomal transporters have been thoroughly studied. A protein called MFSD1 had previously been identified as a potential lysosomal transporter, but its precise role has not been described.

Now, Massa López et al. have characterized the role of MFSD1, by genetically modifying mice so they could no longer make the transporter. These mice developed severe liver damage. In particular, a specific type of cell that is important for lining blood vessels in the liver, seemed to be lost in these mice. Older MFSD1 deficient mice also had more tumors in their livers compared to normal mice.

Massa López et al. next examined what happened to other lysosomal proteins in the MFSD1 deficient mice, and found that these mice had strikingly low levels of a protein called GLMP. To better understand the relationship between GLMP and MFSD1, another strain of genetically modified mice was analyzed, this time missing GLMP. Mice without GLMP were found to have very similar liver problems to those observed in the mice lacking MFSD1. Moreover, the GLMP deficient mice had low levels of the MFSD1 protein.

Further experiments demonstrated that MFSD1 and GLMP physically interact with each other: GLMP seemed to protect MFSD1 from being degraded in the harsh internal environment of the lysosome. Thus both GLMP and MFSD1 were needed to form a stable lysosomal transporter.

Characterizing MFSD1 is important for scientists attempting to understand how the lysosomal membrane and transporters work. Moreover, these findings may shed light on how defects in lysosomal transporters contribute to metabolic disease.