Regulation of lysosome biogenesis by phosphoinositides and phagocytosis
Bibliographic record
Abstract
Lysosomes are acidic organelles responsible for molecular degradation, energy balance, and pathogen clearance. Consequently, lysosome dysfunction is linked to numerous diseases, including lysosome storage diseases. Notably, enhancing lysosome biogenesis ameliorates cell function and helps clear metabolites. The transcription factor EB (TFEB) is a master regulator of lysosome biogenesis, and thus a potential therapeutic target. Among known regulators of TFEB, the mammalian target of rapamycin complex 1 (mTORC1) is best understood. In nutrient-rich cells, mTORC1 is activated and represses TFEB by phosphorylation. Upon starvation, mTORC1 is inactivated and TFEB enters the nucleus, upregulating lysosomal gene expression to enhance cellular degradation for energy recovery. Numerous other TFEB-dependent pathways have been identified. We aim to understand how TFEB is regulated in two additional contexts: in lysosome enlargement during phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] depletion and in phagocytosis. First, PtdIns(3,5)P2 is required for maintaining lysosome size by an incompletely understood mechanism. We hypothesized that TFEB-mediated lysosome biogenesis contributes de novo lysosomal material. Acute depletion of PtdIns(3,5)P2-synthesizing kinase PIKfyve induced TFEB nuclear accumulation. Despite increases in transcription, little to no protein translation was observed. Furthermore, tfeb-/-cells and cells blocked with cycloheximide were similar to wild-type cells, with regard to the number and size of lysosomes during PIKfyve inhibition cells, suggesting biosynthesis is not necessary for lysosome enlargement. However, TFEB still becomes active by an known mechanism. We show that TFEB nuclear localization during PIKfyve inhibition was not due to mTORC1 inactivation but may result from GSK3 inhibition. Secondly, phagocytosis allows immune cells to sequester potential pathogens by engulfing them into phagosomes. These phagosomes are then degraded by the lysosome. We postulated that phagocytosis would enhance TFEB-mediated lysosome biogenesis to promote pathogen killing. Fcγ receptor-mediated phagocytosis activated TFEB and increased biosynthesis of select lysosomal genes, augmenting existing lysosomes and enhancing proteolysis. To understand how TFEB was activated by the Fcγ receptor, we inhibited key signaling and trafficking mediators. Particle internalization, phagosome formation, and phagosome maturation appear to be necessary for TFEB activation. Overall, our work uncovers two additional mechanisms that may govern TFEBactivation.
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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 | 0.000 | 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 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".