Active JNK-dependent secretion of Drosophila Tyrosyl-tRNA synthetase by loser cells recruits haemocytes during cell competition

Abstract

Cell competition is a process by which the slow dividing cells (losers) are recognized and eliminated from growing tissues. Loser cells are extruded from the epithelium and engulfed by the haemocytes, the Drosophila macrophages. However, how macrophages identify the dying loser cells is unclear. Here we show that apoptotic loser cells secrete Tyrosyl-tRNA synthetase (TyrRS), which is best known as a core component of the translational machinery. Secreted TyrRS is cleaved by matrix metalloproteinases generating MiniTyr and EMAP fragments. EMAP acts as a guiding cue for macrophage migration in the Drosophila larvae, as it attracts the haemocytes to the apoptotic loser cells. JNK signalling and Kish, a component of the secretory pathway, are autonomously required for the active secretion of TyrRS by the loser cells. Altogether, this mechanism guarantees effective removal of unfit cells from the growing tissue.

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

“…Chemoattraction of hemocytes toward dying loser cells is controlled by the secretion of the tyrosyl-tRNA synthetase (TyrRS), driven by JNK activation in loser cells [54].…”

MYC, Cell Competition, and Cell Death in Cancer: The Inseparable Triad

“…Since then, the scientific community has been working to decipher the intricate relationships intervening between winner and loser cells, leading to the identification of a number of traits, central to CC (Figure 1), summarised in the following in-progress list: competitive interactions are established when mutational events occur in a cell that reduce or increase its fitness in the context [8,54];loser cells suffer from shortage of survival/growth factors such as the Drosophila TGFβ orthologue Decapentaplegic (Dpp) [52];cells engaged in the competitive event release soluble factors [55] and express specific genetic fingerprints that confer them a loser or winner state [56,57,58];loser cells undergo JNK-dependent apoptosis due to the low levels of survival signals and to the expression of the pro-apoptotic gene hid [40,52];the high contact tension at the interface of winner and loser cell leads to the elimination of loser cells through cell-cell intercalation [59];local tissue crowding can induce mechanical competition, independent of known markers of cell fitness [60];winner cells can acquire the ability to engulf adjacent losers [61];the most part of the loser cells is extruded from the tissue and recruits professional haemocytes, responsible for the elimination of cell debris [62,63];elimination of the loser cells leads to overproliferation of the winners [54]. …”

“…the most part of the loser cells is extruded from the tissue and recruits professional haemocytes, responsible for the elimination of cell debris [62,63];…”

Both Drosophila matrix metalloproteinases have released and membrane-tethered forms but have different substrates

“…2A,B). Previous genetic studies have utilized catalytically inactive Drosophila MMP mutants Mmp1 E225A and Mmp2 E258A 222527282930. We expressed these inactive mutants in S2 cells, and they were reproducibly expressed at elevated levels compared to the wild-type proteases.…”