The acyltransferase lycat controls specific phosphoinositides and related membrane traffic and hormone receptor signaling
Bibliographic record
Abstract
Phosphoinositdes (PIPs) are a group of signaling phospholipids involved in regulating many cellular processes, including organelle dynamics, nutrient uptake, autophagy and apoptosis. Through the action of lipid kinases and phosphatases, phosphatidylinositol (PI) can be phosphorylated on three different positions of the inositol headgroup resulting in seven distinct PIP species. Substantial research has focused on elucidating the function and importance of headgroup phosphorylation while much less is known about the significance of the incorporation of specific acyl chains within PI. PI exhibits unique specificity of acyl chain composition, where majority contains 1-stearoyl-2-arachidonoyl acyl species. This unique acyl chain enrichment is, in part, controlled by the PI acyltransferase lysocardiolipin acyltransferase (LYCAT). How LYCAT and, in turn, incorporation of specific fatty acids, controls the function of PI and PIPs is poorly understood. Thus, I investigated the impact of LYCAT perturbation on PIP acyl profile and effects on PIP-dependent processes. Perturbation of LYCAT by siRNA gene silencing resulted in a shift in the acyl profile of PIP2 species to contain shorter species. Additionally, LYCAT silencing altered the cellular localization and levels of phosphatidylinositol-4,5-bisphosphate and phosphatidylinositol-3-phosphate but was without effect on other PI species examined. Consistent with this, silencing of LYCAT perturbed the membrane traffic of transferrin receptor dependent on these specific PIPs. I also observed changes in PI-dependent receptor tyrosine kinase signaling pathways that control cell survival and proliferation, which are regulated by phosphatidylinositol-3,4,5-trisphosphate. LYCAT perturbation altered activation of Akt1, which impacted a number of Akt substrates. Additionally, using fluorescence microscopy, I discovered that LYCAT is localized to peripheral ER vesicles that contain PI synthase enzyme, which is responsible for PI synthesis. These peripheral vesicles partially overlap with endoplasmic reticulum-plasma membrane contact sites marked by E-Syt2 but showed little overlap with the ER maker, KDEL. Collectively, my results show that the PI acyltransferase LYCAT controls the function of specific species of PIPs, which in turn selectively impacts specific stages of endomembrane traffic and hormone receptor signaling. Hence, the regulation of acyl content of PI is an important new dimension for the control of PI and PIP function.
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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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".