RpS12-mediated induction of the Xrp1^short isoform links ribosomal protein mutations to cell competition

Cell competition, the context-dependent cell elimination phenomenon via short-range cell-cell interactions, was originally described in Drosophila, where heterozygous ribosomal protein (Rp^+/-) mutant cells are outcompeted by wild-type neighbors. The transcription factor Xrp1 mediates most Rp^+/- phenotypes, including reduced translation and competitiveness, yet how RpS12 induces Xrp1 was unclear. We show that RpS12 promotes a splice variant of Xrp1 encoding the Xrp1^short isoform, which defines the Rp^+/- loser identity. RpS12 overexpression is sufficient to induce Xrp1^short and confer loser status. Expression of either Xrp1^short or Xrp1^long isoform can trigger competition, establishing Xrp1 as the central driver of the loser fate. When the number of losers exceeds a critical threshold, a quorum-like response supports their survival by post-transcriptionally downregulating Xrp1. We identify the RNA-binding protein Syncrip, reduced in Rp^+/- cells, as an Xrp1 regulator whose depletion activates Xrp1^short-dependent competition. Therefore, RpS12-dependent Xrp1^short expression emerges as the primary Rp^+/- signal initiating cell competition.