期刊
TRAFFIC
卷 15, 期 12, 页码 1390-1405出版社
WILEY
DOI: 10.1111/tra.12227
关键词
AP-3; autophagy; beige; cathepsin B; CHS; CI-MPR; CtxB; EGFR; endocytosis; LC3; LLPD; lysosome; LYST; ricin; transferrin
类别
资金
- Research Council of Norway
Mutations in the large BEACH domain-containing protein LYST causes Chediak-Higashi syndrome. The diagnostic hallmark is enlarged lysosomes and lysosome-related organelles in various cell types. Dysfunctional secretion of enlarged lysosome-related organelles has been observed in cells with mutations in LYST, but the capacity of the enlarged lysosomes to degrade endogenous proteins has not been studied. Here, we show for the first time that small interfering RNA-depletion of LYST in human cell lines recapitulates the LYST mutant phenotype of enlarged lysosomes. We found no evidence for an effect of LYST depletion on autophagy or endocytic degradation. Autophagosomes are formed in normal size and quantities and are able to fuse to the enlarged lysosomes, leading to normal rates of degradation. Degradation of the epidermal growth factor receptor (EGFR) was similarly not affected, indicating that the enlarged lysosomes are fully functional in degrading endogenous proteins. Retrograde trafficking of toxins as well as the localization of transporters of lysosomal proteins, adaptor protein-3 (AP-3) and cation-independent mannose-6-phosphate receptor (CI-MPR), were all found to be unaffected by LYST. Quantitative analysis of the enlarged lysosomes shows that LYST depletion causes a reduction in vesicle quantity per cell, while the total enzymatic content and vesicular pH are unaffected, supporting a role for LYST in lysosomal fission and/or fusion events.
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