Defining the Role of ER-Localized TRIM5α in Orthoflavivirus Restriction Using Advanced Imaging
Bibliographic record
Abstract
Tick-borne encephalitis virus (TBEV) is an important human pathogen present in Europe, Russia, China, and Japan, causing several thousand human cases associated with febrile illness and neurologic complications including encephalitis [1,2]. Furthermore, viruses belonging to the TBEV serogroup including Powassan virus, Kyasanur Forest disease virus and Omsk hemorrhagic fever virus are considered emerging public health threats [3]. Tripartite motif-containing protein 5 alpha (TRIM5α) is a host cellular restriction factor and innate immune sensor with antiviral function against tick-borne orthoflaviviruses thought to function by degrading the viral protease and RNA helicase encoded by nonstructural protein NS3 together with the cofactor NS2B3. However, orthoflavivirus replication occurs on modified ER membranes that shield the replication complex from recognition by host innate immune sensors. Therefore, whether and how TRIM5α can access NS2B/3 inside replication organelles is unknown. Here, we use a combination of biochemical studies and super-resolution microscopy to investigate TRIM5α association with sites of tick-borne orthoflavivirus replication. Additionally, we utilize a correlative approach to cryo-electron tomography to localize TRIM5α on-lamella and demonstrate TRIM5α can be found at replication organelles. Although the majority of TRIM5α in cells fractionates in soluble fractions, we reveal that TRIM5α can localize to purified ER membranes in the presence of viral infection and is further recruited to the ER via ATG8 proteins, which is required to access the viral target, NS3, and restrict virus replication. Thus, we propose that a distinct population of TRIM5α functions in surveillance of the ER to protect against viruses that utilize the ER as a source of membranes for replication. This continued work also aims to further reveal if TRIM5α possesses unknown functional plasticity in recognition of viral molecular patterns as it pertains to recognition of NS2B/3 [4].
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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 | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 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".