mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Abstract Mannose-6-phosphate receptor (M6PR) that facilitates cellular uptake of M6P-bearing proteins, including serine-protease granzyme-B (Gzm-B) has an important role in T-cell activation, migration and contraction. However, molecular mechanisms controlling M6PR expression in T cells remain poorly understood. Here, we show that M6PR expression on T cells is distinctively controlled by two common γ-chain cytokines interleukin-2 (IL-2) and IL-7, and the differential M6PR expression is not caused by an altered synthesis of M6PR protein, but is a result of distinct regulation of kinesin-3 motor-protein KIF13A that transport M6PR onto cell surfaces. Using signaling pathway-specific inhibitors, we determine that IL-2 and IL-7 distinctly regulate KIF13A and β1-adaptin and cell-surface M6PR by controlling a kinase mammalian target of rapamycin complex-1 (mTORC1). Inflammatory cytokine IL-2 and prosurvival cytokine IL-7 induce strong and weak activation of mTORC1, leading to up- and downregulation of motor-protein KIF13A and KIF13A-motorized M6PR on T cells, and formation of IL-2 and IL-7 effectors with M6PR high and M6PR low cell-surface expression, respectively. Inhibition of mTORC1 by rapamycin reduces T-cell expression of KIF13A and cell-surface M6PR, and increases T-cell survival in Listeria monocytogenes- infected mice. Using regulatory T (T reg )-cell-enriched mouse tumor model, we determine that M6PR high IL-2 effectors but not M6PR low IL-7 effectors adoptively transferred into tumors are vulnerable to T reg Gzm-B-mediated cell apoptosis. Inhibition of mTORC1 or small interfering RNA-mediated knockdown of KIF13A or M6PR renders IL-2 effectors refractory to T reg Gzm-B lethal hit. Overall, our data offer novel mechanistic insights into T-cell M6PR regulation, and T reg -resistant/T reg -susceptible phenomenon. Furthermore, regulation of T-cell fate vis-à-vis T reg suppression via the mTORC1-KIF13A-M6PR axis provides a proof of concept for therapeutic strategies to target cancer, infectious and autoimmune diseases.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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