SLIMP: a mitochondrial protein involved in cell cycle regulation
[eng] SLIMP (Seryl-tRNA Synthetase-Like Insect Mitochondrial Protein) was identified during the generation of a mitochondrial human disease fly model. SLIMP was described as a previously uncharacterized paralog of the Drosophila mitochondrial seryl-tRNA synthetase (SerRS2), which became an essential...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2021 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/186171 |
| Acesso em linha: | https://hdl.handle.net/2445/186171 http://hdl.handle.net/10803/674376 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Citologia Cicle cel·lular Mitocondris Proteïnes Cytology Cell cycle Mitochondria Proteins |
| Resumo: | [eng] SLIMP (Seryl-tRNA Synthetase-Like Insect Mitochondrial Protein) was identified during the generation of a mitochondrial human disease fly model. SLIMP was described as a previously uncharacterized paralog of the Drosophila mitochondrial seryl-tRNA synthetase (SerRS2), which became an essential protein, universally distributed in insects, echinoderms, and molluscs. Notably, SLIMP constitutes an aaRS-like protein that can bind to tRNAs, but it has lost the aminoacylation activity (Guitart, Bernardo, Sagalés, et al., 2010). Interestingly, we recently reported that SLIMP plays an essential role in the mitochondria by simultaneously regulating the mitochondrial protein synthesis and mtDNA copy number through interacting with SerRS2 and LON, respectively (Picchioni, Antolin-Fontes, et al., 2019). On the other hand, two reported studies pointed to SLIMP as an essential cell cycle regulator (Ambrus et al., 2009; Liang et al., 2014). Previous experiments in our group showed a G2 accumulation phenotype in SLIMP-KD cells, which can be rescued by overexpressing SLIMP without the mitochondria-targeting signal. Additionally, transcriptional upregulation of a core set of E2F1-target genes was detected upon SLIMP depletion. All these data point to a cell cycle-related role of SLIMP, potentially carried out from outside the organelle. Interestingly, here we first experimentally characterized the SLIMP MSP and proved that it is essential for driving the protein into the organelle. Moreover, we discovered an extra-mitochondrial population of SLIMP potentially shuttling between the cytosol and the nucleus, presumably in charge of the cell cycle role of SLIMP. Furthermore, our results suggest a role of SLIMP repressing the transition from the G1 to S phase during the cell cycle progression in an E2F1-independent pathway. Finally, interestingly, we demonstrate that the CDK1-P levels are increased upon SLIMP depletion, suggesting an activation of the G2/M checkpoint. In balance, the data presented in this thesis reinforces the idea of SLIMP playing a non-canonical function outside the mitochondria regulating the cell cycle progression near the R point. Thus, SLIMP would represent a single molecule at the crossroad between the mitochondrial homeostasis and cell cycle regulation. |
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