Functional Evidence for the Involvement of Microtubules and Dynein Motor Complexes in TRIM5α-Mediated Restriction of Retroviruses
Bibliographic record
Abstract
UNLABELLED: The tripartite motif (TRIM) family of proteins includes the TRIM5α antiretroviral restriction factor. TRIM5α from many Old World and some New World monkeys can restrict the human immunodeficiency virus type 1 (HIV-1), while human TRIM5α restricts N-tropic murine leukemia virus (N-MLV). TRIM5α forms highly dynamic cytoplasmic bodies (CBs) that associate with and translocate on microtubules. However, the functional involvement of microtubules or other cytoskeleton-associated factors in the viral restriction process had not been shown. Here, we demonstrate the dependency of TRIM5α-mediated restriction on microtubule-mediated transport. Pharmacological disruption of the microtubule network using nocodazole or disabling it using paclitaxel (originally named taxol) decreased the restriction of N-MLV and HIV-1 by human or simian alleles of TRIM5α, respectively. In addition, pharmacological inhibition of dynein motor complexes using erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and small interfering RNA-mediated depletion of the dynein heavy chain (DHC) similarly decreased TRIM5α-mediated restriction. The loss in restriction resulting from either the disassembly of microtubules or the disruption of dynein motor activity was seen for both endogenous and overexpressed TRIM5α and was not due to differences in protein stability or cell viability. Both nocodazole treatment and DHC depletion interfered with the dynamics of TRIM5α CBs, increasing their size and altering their intracellular localization. In addition, nocodazole, paclitaxel, and DHC depletion were all found to increase the stability of HIV-1 cores in infected cells, providing an alternative explanation for the decreased restriction. In conclusion, association with microtubules and the translocation activity of dynein motor complexes are required to achieve efficient restriction by TRIM5α. IMPORTANCE: The primate innate cellular defenses against infection by retroviruses include a protein named TRIM5α, belonging to the family of restriction factors. TRIM5α is present in the cytoplasm, where it can intercept incoming retroviruses shortly after their entry. How TRIM5α manages to be present at the appropriate subcytoplasmic location to interact with its target is unknown. We hypothesized that TRIM5α, either as a soluble protein or a high-molecular-weight complex (the cytoplasmic body), is transported within the cytoplasm by a molecular motor called the dynein complex, which is known to interact with and move along microtubules. Our results show that destructuring microtubules or crippling their function decreased the capacity of human or simian TRIM5α to restrict their retroviral targets. Inhibiting dynein motor activity, or reducing the expression of a key component of this complex, similarly affected TRIM5α-mediated restriction. Thus, we have identified specific cytoskeleton structures involved in innate antiretroviral defenses.
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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) | 0.002 | 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".