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bioRxiv · 10.1101/2022.06.22.497213

COP9 signalosome component CSN-5 stabilizes PUF proteins FBF-1 and FBF-2 in C. elegans germline stem cells

Osterli, E.·Ellenbecker, M.·Wang, X.·Terzo, M.·Jacobson, K.·Voronina, E.
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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 SummaryGerm 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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Osterli, E., Ellenbecker, M., Wang, X., Terzo, M., Jacobson, K., Voronina, E.. 2022-06-26. COP9 signalosome component CSN-5 stabilizes PUF proteins FBF-1 and FBF-2 in C. elegans germline stem cells. https://doi.org/10.1101/2022.06.22.497213

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