Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in C. elegans
Year: 2025
Type: article
Abstract: 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 Caenorhabditis elegans sphingosine kinase, in protecting lysosome membrane integrity. Loss of SPHK-1 affects lysosomal integrity and degradative function, causing cargo accumulation and lysosome membrane rupture. sphk-1(lf) mutants show severe defects in embryonic and larval development and have significantly shortened lifespan. We found that sphk-1(lf) 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 sptl-1 and sptl-3 mutations that fully suppress the lysosomal integrity defects in sphk-1(lf) mutants. sptl-1 and sptl-3 encode serine palmitoyltransferases that catalyze the first and rate-limiting step of de novo sphingolipid synthesis. Loss of sptl-1 alleviates sphingosine accumulation, reverses lysosomal integrity and degradation defects, and restores normal development and longevity in sphk-1(lf) 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.
Source: Molecular Biology of the Cell
Authors: Yuan Li, Jie Zhang, Meijiao Li, Lujia Yang, Xiaochen Wang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4415933315