FIGURE 13.

Model depicting the modulation of PlzA function by levels of c-di-GMP. Apo and holo-PlzA are hypothesized to have distinct functions in the vertebrate and tick hosts respectively. Recent studies identified PlzA RNA chaperone activity that is c-di-GMP independent (Van Gundy et al., 2023). In environments with no c-di-GMP, such as the vertebrate host, apo-PlzA engages in RNA chaperone activity to modulate gene expression required for survival in the vertebrate host. The phosphodiesterases PdeA and PdeB are likely to be highly active upon transmission and into vertebrate infection, lowering c-di-GMP levels and facilitating apo-PlzA functions (Sultan et al., 2010; Pitzer et al., 2011; Sultan et al., 2011; Novak et al., 2014; Groshong et al., 2021). Phosphodiesterase activity is likely to occur at all stages to regulate c-di-GMP levels and indirectly, PlzA function. When Hk1 is activated (signal unknown), Rrp1 is phosphorylated and produces c-di-GMP. Holo-PlzA can also engage in RNA chaperone activity by annealing RNAs, and potentially interact with RNAP (Grassmann et al., 2023; Van Gundy et al., 2023). We propose that levels of c-di-GMP impact the specific genes regulated by PlzA through altering nucleic acid binding affinity. At lower c-di-GMP levels, few holo-PlzA monomers exist resulting in weak PlzA binding affinity for certain target loci. As levels of c-di-GMP increase, more holo-PlzA molecules bind target genes with higher affinity, and PlzA could potentially multimerize on DNA.