A translation-independent function of PheRS activates growth and proliferation in Drosophila

Abstract

ABSTRACT Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNAs, but many of them also perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl tRNA synthetase (PheRS/FARS) levels are elevated in multiple cancers compared to their normal cell counterparts. Our results show that downregulation of PheRS, or only its α-PheRS subunit, reduces organ size, whereas elevated expression of the α-PheRS subunit stimulates cell growth and proliferation. In the wing disc system, this can lead to a 67% increase in cells that stain for a mitotic marker. Clonal analysis of twin spots in the follicle cells of the ovary revealed that elevated expression of the α-PheRS subunit causes cells to grow and proliferate ∼25% faster than their normal twin cells. This faster growth and proliferation did not affect the size distribution of the proliferating cells. Importantly, this stimulation proliferation turned out to be independent of the β-PheRS subunit and the aminoacylation activity, and it did not visibly stimulate translation. This article has an associated First Person interview with the joint first authors of the paper. Summary: A moonlighting activity of the α-subunit of the Phenylalanyl tRNA synthetase in Drosophila promotes growth and proliferation through a novel mechanism that neither involves aminoacylation nor translation.