Dynamic ER-PM Contact Sites and their Impact on Lipid Homeostasis of Phosphotyrosine Signaling
Bibliographic record
Abstract
Membrane contact sites (MCS) are specialized cellular structures where two opposed membranes of intracellular organelles form a close gap (~20nm). These regions serve as communication hubs for various cellular processes such as inter-organellar exchange of lipids, calcium homeostasis, and phosphatase activity. The endoplasmic reticulum (ER) extends to the cell periphery and contacts the plasma membrane (PM) to form metastable ER-PM contact sites maintained by membrane tethering factors linking the two membranes. Cellular functions of ER-PM MCS depend on membrane tether proteins and distinct enzymes in the vicinity, but unsolved questions remain as to how ER-PM MCS is dynamically regulated. In this dissertation, I investigate the mechanism of ER-PM MCS formation and the functional role in physiological contexts. Specifically, the study aims to i) dissect the intrinsic properties of one of ER-PM contact/tether proteins, oxysterol-binding protein – related protein 8 (ORP8), to determine the deciding factors for its membrane targeting and ii) describe the role of cortical actin in regulating ER-PM contacts during phagocytosis and determine the physiological function of rapidly formed ER-PM contacts. In the first study, I found that both the N-terminal polybasic region and the PH domain of ORP8 are required for proper targeting of the short splice variant ORP8S to the PM-ER contact site. ORP8 localization is responsive to PM phosphatidylinositol phosphate (PIP) and phosphatidylserine (PtdSer) levels and its capability to bind PtdSer. Together, I describe that electrostatic interaction, PH domain binding of PIPs, and PtdSer ligand all play a role in defining ORP8 localization. In the second study, I characterize that depletion of cortical actin at the phagocytic cup leads to rapid ER-PM/early phagosome contact site formation. PTP1B accumulates in this region and acts in trans to dephosphorylate Syk. By modulating Syk signaling at ER-phagosome contacts, PTP1B regulates phagosomal superoxide production. In addition, my thesis includes a separate chapter investigating the role of lipid post-modification in SARS-CoV2 infectivity. I characterize that CoV-2 Spike protein is palmitoylated on multiple juxtamembrane cysteine residues and is required for efficient syncytium formation. Next, TVB-3166, a FASN inhibitor, significantly reduces Spike palmitoylation that reduces viral infectivity and grants protection against CoV infection.
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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 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".