An aminoacylation independent activity of PheRS/FARS promotes growth and proliferation

Abstract

Aminoacyl-tRNA synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNA, but many of them perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl-tRNA synthetase (PheRS/FARS) levels are elevated in various cancer cells compared to their normal cell counterparts. However, whether and how these levels might contribute to tumor formation was not clear. Here, we show that PheRS is required for cell growth and proliferation. Interestingly, elevated expression of the α-PheRS subunit alone stimulates cell growth and proliferation. In the wing discs system, this leads to a strong increase of mitotic cells. Clonal analysis of twin spots in dividing follicle cells revealed that elevated expression of the α-PheRS subunit causes cells to grow and proliferate about 25% faster than their normal twin cells. Importantly, this stimulation of growth and proliferation neither required the β-PheRS subunit nor the aminoacylation activity, and it did not visibly stimulate translation. These results, therefore, revealed a non-canonical function of an ancient housekeeping enzyme, providing novel insight into its roles in health and diseases.

α-Phenylalanyl tRNA synthetase competes with Notch signaling through its N-terminal domain

“…Reminiscent of its function in neuroblasts, Notch signaling at the D/V boundary region of the wing disc promotes proliferation (de Celis et al, 1996). Upon additional expression of α-PheRS in this region, not only Notch activity (Fig 5), but also PH3 + cells became absent from this region (Ho et al ., 2020). Interestingly, however, in regions of the posterior wing disc compartment where there is no Notch activity, elevated α-PheRS caused the appearance of additional pH3 + cells (Ho et al ., 2020).…”

“…PheRS promotes growth and proliferation in different tissues (Ho et al ., 2020). In the Drosophila midgut, intestinal stem cells (ISCs) display very high proliferation rates (Nagy et al, 2018) due to a high turnover of the cells with a nutrient absorption mission.…”

“…We previously constructed a mutant α- PheRS gene, that encodes an aminoacylation-dead subunit (α- PheRS Cys ) that still displays the non-canonical activity of promoting growth and proliferation (Ho et al ., 2020). This mutant allows us to specifically study the activities of α- PheRS that are not dependent on the aminoacyl tRNA synthetase activity of PheRS.…”

“…Such a correlation had been reported already two decades earlier and it was suggested that an alternative activity of PheRS might contribute to the tumorigenic events (Sen et al, 1997) (Rodova et al, 1999). A moonlighting function of the α subunit of Drosophila PheRS has recently been found to promote growth and proliferation in different tissues (Ho et al, 2020). Despite this, a possible mechanism explaining the connection between elevated PheRS levels and tumor formation had so far not been reported and, to our knowledge, also not been studied.…”

“…We set out to address the question of whether and how the elevated levels of α–PheRS that induce growth and proliferation (Ho et al ., 2020) might contribute to tumor formation. To test for this activity, we studied the role of α–PheRS levels in the Drosophila model system to dissect the molecular mechanism of such a moonlighting role of α– PheRS.…”