CG4928 Is Vital for Renal Function in Fruit Flies and Membrane Potential in Cells: A First In-Depth Characterization of the Putative Solute Carrier UNC93A

Abstract

The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK 1 channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.

The Fly Homologue of MFSD11 Is Possibly Linked to Nutrient Homeostasis and Has a Potential Role in Locomotion: A First Characterization of the Atypical Solute Carrier CG18549 in Drosophila Melanogaster

“…It is also possible that CG18549 does not have a specific role in starvation, but rather its expression is regulated by other genes. The results suggest that CG18549 is a more stable gene during starvation than other atypical SLCs such as CG4928, the orthologue to human UNC93A [27].…”

“…MFSD11 is an evolutionary-conserved protein and related proteins are identified in both prokaryotes and eukaryotes [17,27], but still the expression and function of MFSD11 is not fully known. A couple of years ago, MFSD11 was identified as an "atypical" SLC [16], where CG18549 was suggested to be the orthologue to MFSD11.…”

“…A couple of years ago, MFSD11 was identified as an "atypical" SLC [16], where CG18549 was suggested to be the orthologue to MFSD11. The closest relatives to MFSD11 in the human proteome are the UNC93 proteins (UNC93A and UNC93B1) [27], two proteins with very different function. UNC93A is believed to be involved in potassium fluxes [27,41,42], while UNC93B1 is established to be a transporter of toll-like receptors [43][44][45].…”

“…The closest relatives to MFSD11 in the human proteome are the UNC93 proteins (UNC93A and UNC93B1) [27], two proteins with very different function. UNC93A is believed to be involved in potassium fluxes [27,41,42], while UNC93B1 is established to be a transporter of toll-like receptors [43][44][45]. MFSD11 has also been showed to cluster with the SLC45 (proton:sugar cotransporter) and the SLC46 (folate transporter) superfamilies of the SLCs [17].…”

“…MFSD11 is known to be evolutionary conserved and is found in several other species. Phylogenetic analyses and amino acid alignments have been performed previously, revealing that the closest homologue to MFSD11 is CG18549 and that they have been reported to have 41.5% identical amino acid residues when performing a global pair-wise alignment [17,27]. Herein, we wanted to study the secondary and tertiary structures to look at similarities in the 2D and 3D structures, which could tell us more about their relationship and how well the results can be translational.…”