Gene-in-gene coding generates a dual-isoform condensate that promotes the ecological resilience of Vibrio cholerae
Abstract
While eukaryotes employ alternative splicing to diversify protein functions, analogous strategies in bacteria remain underexplored. Here we identify a conserved intragenic coding mechanism in Vibrio cholerae that generates two isoforms of the essential scaffold Fha and show that these isoforms cooperate through liquid–liquid phase separation to regulate the type VI secretion system (T6SS). The full-length isoform, FhaL, seeds assembly by engaging the membrane complex, whereas an internally translated isoform, FhaS, enhances secretion efficiency by strengthening specific interactions with baseplate components. This isoform partitioning is ecologically critical; a mutant producing only FhaL is impaired in bacterial competition, susceptible to eukaryotic predation, and defective in host colonization. Both isoforms form condensates, and a single residue change within a C-terminal helix abolishes condensate formation and significantly reduces T6SS activities. The internal translation and condensate-forming residues are strictly conserved across >10,000 V. cholerae isolates and active in diverse Vibrio species. These findings define a translational–biophysical mechanism that tunes a widespread contractile protein nanomachine for ecological success.
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