RpS12-mediated induction of the Xrp1short 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 Xrp1short isoform, which defines the Rp+/- loser identity. RpS12 overexpression is sufficient to induce Xrp1short and confer loser status. Expression of either Xrp1short or Xrp1long 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 Xrp1short-dependent competition. Therefore, RpS12-dependent Xrp1short expression emerges as the primary Rp+/- signal initiating cell competition.