The signal sequence of yeast killer toxin K2 confers producer self-protection and allows conversion into a modular toxin-antitoxin system

Some antimicrobial proteins secreted by yeast, known as yeast killer toxins, also target the producer species itself, necessitating a means of self-protection. Intriguingly, the M2 dsRNA killer virus in Saccharomyces cerevisiae contains a single open reading frame (ORF) that encodes both the pore-forming killer toxin K2 as well as a cognate immunity factor. Here, a systematic deletion screen reveals that expression of a 49-amino acid N-terminal peptide from this ORF is both necessary and sufficient for immunity and that the K2 toxin and this 49-residue immunity peptide can be functionally split into a modular toxin-antitoxin system. Further, the immunity peptide exhibits characteristics of a signal peptide and we thus propose that the K2 signal peptide serves a dual function: 1) Toxin targeting into the secretory pathway, and 2) establishing self-protective immunity. This case further implies that (signal) peptides form a potential source for antimicrobial resistance.