KSHV requires eIF3d for cholesterol biosynthesis to support lytic replication
Bibliographic record
Abstract
ABSTRACT Herpesvirus genomes are decoded by host RNA polymerase II, generating viral messenger ribonucleic acids (mRNAs) that are post-transcriptionally modified and exported to the cytoplasm. These viral mRNAs have 5□-m 7 GTP caps and poly(A) tails that enable assembly of host translation initiation factors (TIFs) required for viral protein synthesis. Here we show that maximal production of viral proteins during lytic replication requires both the canonical host TIF eukaryotic initiation factor 4F (eIF4F) and the alternative host TIF eIF3d. Despite this, production of infectious virions is largely dependent on eIF3d, with eIF4F playing a minor role. Investigating the effects of eIF3d silencing on the host proteome revealed that it is required for accumulation of proteins involved in cholesterol metabolism, as well as the accumulation of intracellular cholesterol during KSHV lytic replication. In KSHV infected and uninfected cells alike, eIF3d supports efficient translation of cholesterol biosynthesis enzymes, including squalene epoxidase (SQLE), whose function is required to support productive lytic replication during cholesterol scarcity. These findings position eIF3d as a critical TIF required to support translation of essential host mRNAs required for KSHV replication. AUTHOR SUMMARY Animal cells tightly regulate uptake, synthesis, storage, and export of cholesterol to ensure optimal membrane fluidity and permeability. Many enveloped viruses require cholesterol to support membrane fusion events during cell entry and cell surface budding events during assembly and egress. Herpesviruses like Kaposi’s sarcoma-associated virus (KSHV) require cholesterol to support entry, but its role in post-entry events, including budding and fusion at internal membranes, remains incompletely understood. Here, through our studies of KSHV protein synthesis, we uncovered a new mechanism of cellular control of cholesterol metabolism involving the host translation initiation factor (TIF) eIF3d. We demonstrated that eIF3d was required to support efficient translation of host mRNAs encoding key proteins required for cholesterol biosynthesis and uptake. Using a lytic reactivation model that bypasses the entry step, we observed that productive KSHV lytic replication is accompanied by eIF3d-dependent increases in intracellular cholesterol. Preventing cholesterol synthesis and uptake, or silencing eIF3d , strongly inhibited production of infectious virions. These studies shed new light on the importance of intracellular cholesterol to support KSHV replication, and provide motivation for future studies of how cholesterol influences discrete post-entry steps of KSHV 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".