Distinct roles of two lipid kinases in lysosomal transport of the Gaucher disease enzyme glucocerebrosidase
Bibliographic record
Abstract
Lysosomal function in lipid metabolism relies on the efficient trafficking of glucocerebrosidase (GBA), a key enzyme in the breakdown of lysosomal glucosylceramide, through binding to its receptor LIMP2. Mutations in GBA result in mislocalization and onset of Gaucher disease. Surprisingly, the mechanism regulating GBA/LIMP2 transport to lysosomes remains elusive. In this study we have assessed the role of phosphatidylinositol 4‐phosphate (PtdIns4 P ), a key regulator of the Golgi sorting machinery, in LIMP2 transport. Compartment‐specific depletion of PtdIns4 P results in Golgi accumulation of LIMP2. However, PtdIns4 P synthesis at the Golgi has been attributed to more then one PtdIns4 P kinase, including PI4KIIIβ and PI4KIIα. Inhibition of the PI4KIIIβ kinase activity resulted in the decreased lysosomal delivery of LIMP2. Depletion of PI4KIIα, however, affected trafficking at a post‐Golgi compartment, resulting in LIMP2 accumulation on enlarged endosomal compartments. This effect was decreased following the PI4KIIIβ inhibition, as LIMP2 exit out of Golgi towards lysosomes became impaired. Collectively, LIMP2 exit was found to depend on the PI4KIIIβ activity at the Golgi, while transport at the late endosomal compartment requires PI4KIIα, demonstrating sequential roles of two kinases in lysosomal transport.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".