RpS12-mediated induction of the Xrp1short isoform links ribosomal protein mutations to cell competition

<h2>Summary</h2> Cell competition, the context-dependent cell elimination phenomenon via short-range cell-cell interactions, was originally described in <i>Drosophila</i>, where heterozygous ribosomal protein (<i>Rp</i>^+/−) mutant cells are outcompeted by wild-type neighbors. The transcription factor Xrp1 mediates most <i>Rp</i>^+/− phenotypes, including reduced translation and competitiveness, yet how RpS12 induces Xrp1 was unclear. We show that RpS12 promotes a splice variant of <i>Xrp1</i> encoding the Xrp1^short isoform, which defines the <i>Rp</i>^+/− loser identity. RpS12 overexpression is sufficient to induce <i>Xrp1</i>^short and confer loser status. Expression of either Xrp1^short or Xrp1^long isoform can trigger competition, establishing <i>Xrp1</i> 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 <i>Rp</i>^+/− cells, as an <i>Xrp1</i> regulator whose depletion activates Xrp1^short-dependent competition. Therefore, RpS12-dependent <i>Xrp1</i>^short expression emerges as the primary <i>Rp</i>^+/− signal initiating cell competition.