Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.

The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.

The STAT3 Target Mettl8 Regulates Mouse ESC Differentiation via Inhibiting the JNK Pathway.

The capacity of embryonic stem cells (ESCs) to differentiate into all lineages of mature organism is precisely regulated by cellular signaling factors. STAT3 is a crucial transcription factor that plays a central role in maintaining ESC identity. However, the underlying mechanism by which STAT3 directs differentiation is still not completely understood. Here, we show that STAT3 positively regulates gene expression of methyltransferase-like protein 8 (Mettl8) in mouse ESCs. We found that METTL8 is dispensable for pluripotency but affects ESC differentiation. Subsequently, we discovered that METTL8 interacts with Mapkbp1's mRNA, which is an intermediate factor in c-Jun N-terminal kinase (JNK) signaling, and inhibits the translation of the mRNA. Thereby, METTL8 prohibits the activation of JNK signaling and enhances the differentiation of mouse ESCs. Collectively, our study uncovers a STAT3 target, Mettl8, which regulates mouse ESC differentiation via JNK signaling.