Unconventional receptor functions and location-biased signaling of the lactate GPCR in the nucleus
Bibliographic record
Abstract
G-protein-coupled receptors (GPCRs) are virtually involved in every physiological process. However, mechanisms for their ability to regulate a vast array of different processes remain elusive. An unconventional functional modality could at least in part account for such diverse involvements but has yet to be explored. We found HCAR1, a multifunctional lactate GPCR, to localize at the nucleus and therein capable of initiating location-biased signaling notably nuclear-ERK and AKT. We discovered that nuclear HCAR1 (N-HCAR1) is directly involved in regulating diverse processes. Specifically, N-HCAR1 binds to protein complexes that are involved in promoting protein translation, ribosomal biogenesis, and DNA-damage repair. N-HCAR1 also interacts with chromatin remodelers to directly regulate gene expression. We show that N-HCAR1 displays a broader transcriptomic signature than its plasma membrane counterpart. Interestingly, exclusion of HCAR1 from the nucleus has the same effect as its complete cellular depletion on tumor growth and metastasis in vivo. These results reveal noncanonical functions for a cell nucleus-localized GPCR that are distinct from traditional receptor modalities and through which HCAR1 can participate in regulating various cellular processes.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".