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Ménage à trois to control cell development


Our results show the existence of a tripartite protein complex which allows the regulation of the MYC protein (product of the c-Myc oncogene over-expressed in more than 70% of human cancers) in the nucleus through the control of its ubiquitination level. This mechanism, conserved during evolution, participates directly in the processes of cell growth and proliferation involved during development or in cancer.

Published on 8 September 2020
The c-Myc oncogene encodes a transcription factor that controls the expression of a large number of genes involved in cell growth and proliferation. It is over-expressed in more than 70% of human cancers, which shows the importance of controlling the amount of MYC protein present in the cells. In humans, and in model organisms such as Drosophila melanogaster, this control is ensured by the protein degradation pathway mediated by the ubiquitin-proteasome system. This protein degradation pathway is characterised by two sequential events: the first is the labelling of substrates intended to be degraded by a polymer of ubiquitin molecules via a ubiquitin ligase; the second is the recognition and then degradation of these poly-ubiquitinated substrates by a multi-protein enzymatic complex, the proteasome. Deubiquitinases that catalyze the removal of ubiquitin polymers can counteract this degradation and stabilize the targeted protein. While the ubiquitin ligases involved in the regulation of MYC by the ubiquitin-proteasome system are well known, the deubiquitinases are much less documented.

We show that the Drosophila homologue of human deubiquitinase USP36 has different isoforms, each with specific subcellular locations. Using CRISPR-Cas9 mutagenesis to introduce mutations in the gene coding for USP36, we identify one of the isoforms as being specifically required for the development of larval stages and cell growth within the whole organism (Figure).


Above and left is a normal Drosophila larva and below is a confocal microscopic image of the larval fat body cells (the cell contours are stained in green and the nuclei in blue). Above and to the right is a larva of the same age in which one of the isoforms of USP36 has been inactivated. Growth defects in the whole organism and in fat body cells indicate that this isoform plays a role in these processes.

We show that this isoform of USP36 forms a protein complex comprising not only the MYC protein but also the ubiquitin ligase AGO. In a cultured Drosophila cell system, we then demonstrated that the AGO ligase controls the ubiquitination and degradation of MYC while the deubiquitinase USP36 induces the opposite effect. Experiments of genetic interaction conducted in vivo then confirmed the antagonistic roles of these two proteins on cell growth.

These results therefore highlight the existence of a functional tripartite protein complex, composed of MYC, AGO and USP36, which allows a fine and dynamic regulation of the quantity of MYC protein in the nucleus through the control of its ubiquitination level. This regulatory mechanism is conserved during evolution and participates directly in the processes of cell growth and proliferation that are involved during development or in cancer.

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