Production of β-PheRS fragments correlates with food avoidance and slow growth, and is suppressed by the appetite-inducing hormone CCHa2

The housekeeping tRNA synthetases play many non-canonical roles with diverse functions. The phenylalanyl-tRNA synthetase (PheRS/FARS) is an α 2 β 2 tetramere. Recently, human patients with mutations in FARSB , the homolog of β-PheRS in Drosophila, have been reported to display problems gaining weight. Here, we show in Drosophila that overexpressing the β subunit in the context of the complete PheRS leads to larval roaming, food avoidance, slow growth, and a developmental delay that can last several days and even prevents pupation. Narrowing down the tissue involved in this behavioral and developmental effect revealed that expression in CCHa2 + and Pros + cells induced this phenotype. Simultaneous expression of β-PheRS, α-PheRS, and the appetite-inducing CCHa2 peptide rescued these phenotypes, linking this β-PheRS activity to the appetite-controlling pathway. The fragmentation dynamics of the excessive β-PheRS points to a β-PheRS fragment as a likely candidate inducer of these phenotypes. Fragmentation of PheRS (FARS) has also been observed in humans and mutations in human β-PheRS (FARSB) can lead to problems in gaining weight. This study, therefore, points to a potential mechanism for the human phenotype and to possible novel approaches to research ways to correct the balance between hunger and satiety signals in the context of obesity.