2.A.1.49.2
The spinster homologue, Spin1 or Spns1 (SLC63A1) of 528 aas and 12 TMSs. It interacts with Bc1-2/Bc1-XL to induce a caspase-independent autophagic cell death (Yanagisawa et al., 2003). It is a spingosine-1-phosphate (S1P) (or sphingolipid) exporter (Nijnik et al. 2012). S1P is important for lymphocyte trafficking, immune responses, vascular and embryonic development, cancer, and bone homeostasis (Zhu et al. 2018). S1P is produced intracellularly and then secreted into the circulation to engage in the above physiological or pathological processes by regulating the proliferation, differentiation and survival of target cells. SPNS2 acts as a mediator of intracellular S1P release. The SPNS1-dependent lysosomal lipid transport pathway enables cell survival under choline limitation (Scharenberg et al. 2023). The orphan lysosomal transmembrane protein SPNS1 is critical for cell survival under choline limitation. SPNS1 loss leads to intralysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). SPNS1 is a proton gradient-dependent transporter of LPC species from the lysosome for their re-esterification into phosphatidylcholine in the cytosol (Scharenberg et al. 2023). Beenken et al. 2024 have reported that Spns1 is an iron transporter essential for megalin-dependent endocytosis. Proximal tubule endocytosis is essential to produce protein free urine as well as to regulate system-wide metabolic pathways, such as the activation of Vitamin D. Beenken et al. 2024 have shown that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules. The endocytic defect was accompanied by changes in megalin phosphorylation as well as enlargement of lysosomes confirming previous findings in Drosophila and Zebrafish. The endocytic defect was also accompanied by iron overload in proximal tubules. Iron levels regulated the Spns1 phenotypes, because feeding an iron deficient diet or mating Spns1 knockout with divalent metal transporter1 (DMT1) knockout rescued the phenotypes. Conversely, iron loading wild type mice reproduced the endocytic defect, These data demonstrate a reversible, negative feedback for apical endocytosis, and raise the possibility that regulation of endocytosis, pinocytosis, megalin activation, and organellar size and function is nutrient-responsive (Beenken et al. 2024).