Cellular fitness is determined by ribosomal protein S12-mediated release of a truncated Xrp1

Multicellular tissues require continuous optimization to maintain their integrity by eliminating viable but unfit cells through cell competition. During this process, unfit "loser" cells upregulate the C/EBP-family transcription factor Xrp1, which drives their elimination and thus determines cellular fitness. However, the mechanism underlying Xrp1 upregulation remains unclear. Here, we show that Xrp1 is upregulated through a post-transcriptional mechanism mediated by ribosomal protein S12 (RpS12). Although Xrp1 mRNA is abundantly expressed in wild-type cells, its translation is repressed by an upstream open reading frame (uORF) in the 5' UTR. In unfit cells, RpS12 promotes splicing-mediated skipping of the uORF-containing exon, enabling the use of an alternate start codon that produces a short Xrp1 isoform triggering cell death. Structural analysis reveals strong similarity between RpS12 and the spliceosomal component SNU13, suggesting a direct role for RpS12 in alternative splicing. Our findings provide mechanistic insight into how cellular fitness is determined.