Abstract
Characterization of orphan transporters is of importance due to their involvement in cellular homeostasis but also in pharmacokinetics and pharmacodynamics. The tissue and cellular localization, as well as function, is still unknown for many of the solute carriers belonging to the major facilitator superfamily (MFS) Pfam clan. Here, we have characterized two putative novel transporters MFSD14A (HIAT1) and MFSD14B (HIATL1) in the mouse central nervous system and found protein staining throughout the adult mouse brain. Both transporters localized to neurons and MFSD14A co-localized with the Golgi marker Giantin in primary embryonic cortex cultures, while MFSD14B staining co-localized with an endoplasmic retention marker, KDEL. Based on phylogenetic clustering analyses, we predict both to have organic substrate profiles, and possible involvement in energy homeostasis. Therefore, we monitored gene regulation changes in mouse embryonic primary cultures after amino acid starvations and found both transporters to be upregulated after 3 h of starvation. Interestingly, in mice subjected to 24 h of food starvation, both transporters were downregulated in the hypothalamus, while Mfsd14a was also downregulated in the brainstem. In addition, in mice fed a high fat diet (HFD), upregulation of both transporters was seen in the striatum. Both MFSD14A and MFSD14B were intracellular neuronal membrane-bound proteins, expressed in the Golgi and Endoplasmic reticulum, affected by both starvation and HFD to varying degree in the mouse brain.
Highlights
Membrane-bound transporter proteins play an important role in cell survival, as these proteins allow interaction between the external and internal environment of cells, importing and exporting substances across the lipid barrier
The outcome (Figure 1) placed MFSD14A and MFSD14B with a shared closest branching node with several solute carrier (SLC) families (15, 19, 22, 29, and 43). Both MFSD14A and MFSD14B had their own branch in the tree projecting out from their common node, meaning that they differed to such extent that they cannot be grouped into any existing major facilitator superfamily (MFS) family when classified according to the SLC tables1
We have characterized two putative transporters, MFSD14A and MFSD14B, which phylogenetically cluster to the SLCs of MFS type
Summary
Membrane-bound transporter proteins play an important role in cell survival, as these proteins allow interaction between the external and internal environment of cells, importing and exporting substances across the lipid barrier. Transporters are a class of proteins that are underrepresented in research (Cesar-Razquin et al, 2015) and many of the identified transporters remain orphans in that their localization and/or function remains unknown. The SLCs are facilitated or secondary active transporters (Fredriksson et al, 2003), working independently of ATP. In humans, they are a diverse group of proteins, consisting of 456 members divided into 52 subfamilies (Hediger et al, 2013; Cesar-Razquin et al, 2015), located in the outer plasma membrane or internal organelles membranes. Many are conserved in prokaryotes, invertebrates, and vertebrates indicating once again their importance, or at the very least, their important past
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