The SOS response-induced cell division inhibitor YneA interacts with FtsW to block septal peptidoglycan synthesis in Bacillus subtilis.

Maintenance of genome integrity is critical for the survival and proliferation of bacteria. Following DNA damage, many bacteria launch the SOS response, which up-regulates many enzymes involved in DNA damage repair, as well as cell division inhibitors which coordinate DNA repair and cell division. YneA is a potent SOS response-inducible cell division inhibitor in Bacillus subtilis. It consists of a single transmembrane (TM) domain linked to an extracellular LysM domain. Previous studies suggest that YneA interferes with divisome assembly and septal peptidoglycan (sPG) synthesis, however, the underlying mechanism remains unclear. In this study, we show that overexpression of YneA does not disrupt divisome assembly but blocks sPG synthesis. It localizes to the division site through an interaction between its TM domain and TM7 of FtsW, which is a SEDS-family peptidoglycan polymerase that partners with PBP2B (FtsI) to synthesize sPG. Mutations in the TM domain of YneA and the TM7 of FtsW eliminate YneA localization to midcell and its toxicity. Moreover, its ability to bind PG through its LysM domain is essential for inhibition of sPG synthesis. Taken together, these results indicate that YneA inhibits cell division by targeting FtsW and blocking its PG synthetic activity. Intriguingly, AlphaFold 3 structure predictions suggest that several SOS response-inducible cell division inhibitors also target FtsW, implying that inhibition of FtsW function is a common way to block cell division during SOS response.