The Lysosomal Trafficking of Acid Sphingomyelinase is Mediated by Sortilin and Mannose 6‐phosphate Receptor
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Bibliographic record
Abstract
Acid sphingomyelinase (ASM), a member of the saposin-like protein (SAPLIP) family, is a lysosomal hydrolase that converts sphingomyelin to ceramide. Deficiency of ASM causes a variant form of Niemann-Pick disease. The mechanism of lysosomal targeting of ASM is poorly known. Previous studies suggest that ASM could use in part the mannose 6-phosphate receptor (M6P-Rc). Sortilin, a type I transmembrane glycoprotein that belongs to a novel family of receptor proteins, presents structural features of receptors involved in lysosomal targeting. In this study we examined the hypothesis that sortilin may be implicated in the trafficking of ASM to the lysosomes. Using a dominant-negative sortilin construct lacking the cytoplasmic tail, which is essential to recruit adaptor proteins and clathrin, we demonstrated that sortilin is also involved in the lysosomal targeting of ASM. Confocal microscopy revealed that truncated sortilin partially inhibited the lysosomal trafficking of ASM in COS-7 cells and abolished the lysosomal targeting of ASM in I-cells. Pulse-chase experiments corroborated that sortilin is involved in normal sorting of newly synthesized ASM. Furthermore, over-expression of truncated sortilin accelerated and enhanced the secretion of ASM from COS-7 cells and I-cells. Co-immunoprecipitation assays confirmed the interaction between sortilin and ASM. In conclusion, ASM uses sortilin as an alternative receptor to be targeted to the lysosomes.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it