Primary envelopment of Kaposi’s sarcoma-associated herpesvirus at the nucleoplasmic reticulum
Bibliographic record
Abstract
ABSTRACT Herpesvirus egress begins with primary envelopment of newly assembled capsids at the inner nuclear membrane (INM). Primary envelopment has been observed at the peripheral INM as well as nuclear infoldings. Nuclear infoldings from invaginations of the INM are Type-I nucleoplasmic reticulum (NR), whereas infoldings of both INM and outer nuclear membrane (ONM) are Type-II NR. Here, we report that Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation from latency and lytic cycle progression correlates with increases in both types of NR, but primary envelopment is restricted to peripheral INM and Type-I NR. These Type-I NR structures co-localized with puncta containing CTP:phosphocholine cytidylyltransferase (CCTα), the enzyme that catalyzes the rate-limiting step in phosphatidylcholine (PtdCho) synthesis that drives the de novo membrane biogenesis and membrane curvature required for NR expansion; CCTα recruitment may provide sufficient Type-I NR to facilitate nuclear egress. Despite the concurrent expansion of Type-II NR, primary envelopment involves a mechanism that specifically targets capsids to Type-I NR. Building upon our observation of capsids lacking envelopes in complex higher-order Type-I NR structures, we used polar lipid dyes, CLICK-labeled fluorescent viral genomes, and fluorescent KSHV capsids to track the fate of NR-associated capsids via live cell microscopy. These studies provide evidence for trafficking of NR-associated capsids toward the nuclear periphery and cytoplasm. Taken together, these findings suggest that nuclear egress occurs not only at the nuclear periphery but also at the Type-I NR. IMPORTANCE Herpesvirus capsids assemble in the cell nucleus but are too large to exit via nuclear pores. Instead, they bud into the inner nuclear membrane to acquire a provisional lipid envelope that is shed through fusion with the outer nuclear membrane, delivering the capsid to the cytoplasm for subsequent steps in assembly and egress. These nuclear membranes are dynamic, with the ability to fold into invaginations that access the nuclear interior. Here, we demonstrate that during Kaposi's sarcoma-associated herpesvirus (KSHV) replication, nuclear membrane infolding increases, coinciding with recruitment of a host enzyme required for PtdCho synthesis at these sites. We observed accumulation of KSHV capsids at infoldings of the inner nuclear membrane and tracked the association and trafficking of fluorescent viral particles through these structures by live cell microscopy. This complements a more well-established mechanism of KSHV egress at the nuclear periphery and suggests versatility in nuclear egress mechanisms.
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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 | 0.000 |
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".