Control of bacterial immune signaling by a WYL domain transcription factor.

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Bacteria use diverse immune systems to defend themselves from ubiquitous viruses termed bacteriophages (phages). While the molecular mechanisms of many such systems have been detailed in recent years, how these systems are controlled and the signals that activate them remain mostly unknown. Here, we identify a transcription factor associated with a fraction of CBASS immune systems that we term CapW. CapW is similar to the recently-discovered BrxR transcription factor found in some BREX immune systems, and homologs of CapW/BrxR are associated with a variety of bacterial immune systems. Combining X-ray crystallography and biochemical analysis, we show that CapW forms a homodimer and binds a palindromic DNA sequence in the CBASS promoter region. Two crystal structures of CapW suggest that the protein switches from an unliganded, DNA binding-competent state to a ligand-bound state unable to bind DNA. Using a reporter assay, we show that CapW strongly represses CBASS gene expression in uninfected cells and that CBASS expression is increased either upon phage infection or the addition of DNA damaging drugs. These results suggest that CapW enables its associated CBASS system to respond not only to phage infection but also to DNA damage, a universal signal of cell stress. We propose two hypotheses for the role of CapW and the functionally-related CapH+CapP system: first, these regulators may enable multiple bacterial immune systems to coordinate their functions in an infected cell, to mount a multi-pronged defensive response. Alternatively, CapW and CapH+CapP may enable bacteria to combat the conversion of phages from lysogenic to lytic lifestyles, by responding to the same stress signal(s) that induce prophage mobilization.