Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in <i>C. elegans</i>

The maintenance of lysosome membrane integrity is vital for cell homeostasis and viability, but the underlying mechanisms are not well understood. In this study, we identified a novel role of SPHK-1, the sole <i>Caenorhabditis elegans</i> sphingosine kinase, in protecting lysosome membrane integrity. Loss of SPHK-1 affects lysosomal integrity and degradative function, causing cargo accumulation and lysosome membrane rupture. <i>sphk-1(lf)</i> mutants show severe defects in embryonic and larval development and have significantly shortened lifespan. We found that <i>sphk-1(lf)</i> mutants accumulate high levels of sphingosine, predominantly in lysosomes. Accordingly, sphingosine supplementation leads to the appearance of damaged lysosomes in wild-type worms. We identified <i>sptl-1</i> and <i>sptl-3</i> mutations that fully suppress the lysosomal integrity defects in <i>sphk-1(lf)</i> mutants. <i>sptl-1</i> and <i>sptl-3</i> encode serine palmitoyltransferases that catalyze the first and rate-limiting step of <i>de novo</i> sphingolipid synthesis. Loss of <i>sptl-1</i> alleviates sphingosine accumulation, reverses lysosomal integrity and degradation defects, and restores normal development and longevity in <i>sphk-1(lf)</i> mutants. Our study indicates that sphingolipid metabolism via sphingosine kinase is important for maintaining lysosome membrane integrity and function, and is essential for animal development and longevity.