COP9 signalosome component CSN-5 stabilizes PUF proteins FBF-1 and FBF-2 in <i>Caenorhabditis elegans</i> germline stem cells
Bibliographic record
Abstract
Abstract RNA-binding proteins FBF-1 and FBF-2 (FBFs) are required for germline stem cell maintenance and the sperm/oocyte switch in Caenorhabditis elegans , though the mechanisms controlling FBF protein levels remain unknown. We identified an interaction between both FBFs and CSN-5, a component of the COP9 (constitutive photomorphogenesis 9) signalosome. Here, we find that the MPN (Mpr1/Pad1 N terminal) metalloprotease domain of CSN-5 interacts with the PUF (Pumilio and FBF) RNA-binding domain of FBFs and the interaction is conserved for human homologs PUM1 and CSN5. The interaction between FBF-2 and CSN-5 can be detected in vivo by proximity ligation. csn-5 mutation results in destabilization of FBF proteins, a decrease in the numbers of germline stem cells, and disruption of the switch from spermatogenesis to oogenesis. The loss of csn-5 does not decrease the levels of a related PUF protein PUF-3 and csn-5(lf ) phenotype is not enhanced by fbf-1/2 depletion, suggesting that the effect is specific to FBFs. The effect of csn-5 on germline sex determination is largely independent of the COP9 signalosome and is cell autonomous. Surprisingly, regulation of FBF protein levels involves a combination of COP9-dependent and –independent mechanisms differentially affecting FBF-1 and FBF-2. This work supports a previously unappreciated role for CSN-5 in stabilization of germline stem cell regulatory proteins FBF-1 and FBF-2. Author Summary Germ cell development and reproductive success in the nematode C. elegans rely on the function of germline stem cells. Continued maintenance of these cells is supported by the activity of conserved RNA-binding proteins FBF-1 and FBF-2 (FBFs). However, it is unknown how FBF protein levels are regulated. Here, we identify a direct interaction between FBFs and CSN-5, a component of the COP9 signalosome best known for its role in regulating protein degradation. We find that CSN-5 promotes FBF stability and allows for accumulation of steady-state protein levels, thereby promoting FBF function. In csn-5 mutants, we find a significant reduction of FBF proteins, decrease of stem cells, and failure to promote oogenesis consistent with compromised FBF function. Furthermore, CSN-5 contributes to FBF protein stability through two mechanisms. This work demonstrates a previously unappreciated role for CSN-5 in stabilization of FBF proteins. Based on our finding that the FBF/CSN-5 interaction is conserved and detectable between homologous human proteins, we speculate this relationship might be relevant for understanding stem cell maintenance in a range of species, from nematodes to humans.
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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".