Summary / Abstract
Aminoacyl tRNA synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNA, many of them perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl tRNA synthetase (PheRS/FARS) levels are elevated in multiple cancers and, interestingly, also in normal stem cells. Our results show that elevated expression of the α-PheRS subunit stimulates cell proliferation in different tissues, while downregulation of α-PheRS reduces organ size. The stimulation of proliferation is independent of the β-PheRS subunit and the aminoacylation activity, and it does not visibly stimulate translation. Furthermore, stem cell-specific overexpression of α-PheRS caused a tumor phenotype in the intestine, a phenotype indistinguishable from the Notch RNAi phenotype in the same cells. Genetic interactions between α-PheRS and Notch suggest that their activities neutralize each other and that elevated α-PheRS levels attenuate Notch signaling whether Notch induces differentiation into enterocytes or neuroblast stem cell proliferation. Indeed, in the wing discs system, elevated α-PheRS levels suppress Notch transcriptional activity. α-PheRS therefore seems to act as a general regulator of Notch signaling, and its own levels are in turn controlled by Stat92E, the transcription factor of the JAK/STAT signaling pathway that is needed for the differentiation of intestinal stem cells during tissue homeostasis under normal conditions. From this we conclude that the α-PheRS subunit can transmit the activity status of the JAK/STAT pathway to the Notch pathway as a mechanism to coordinate stem cell proliferation with differentiation. In this process, α-PheRS levels balance between tissue development and tissue growth to regulate tissue homeostasis.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
We added data obtained from adult guts and more results requested by reviewers. We also made a number of other changes based on their feedback.