The RaxH-RaxR Two-Component Regulatory System Is Orthologous to the Zinc-Responsive ColS-ColR System

Genome sequence comparisons to infer likely gene functions require accurate ortholog assignments. In spp., the sensor-regulator ColS-ColR two-component regulatory system responds to zinc and other metals to control certain membrane-related functions, including lipid A remodeling. In spp., three different two-component regulatory systems, RaxH-RaxR, VgrS-VgrR, and DetS-DetR, have been denoted as ColS-ColR in several different genome annotations and publications. To clarify these assignments, we compared the sensor periplasmic domain sequences and found that those from ColS and RaxH share a similar size as well as the location of a Glu-X-X-Glu metal ion-binding motif. Furthermore, we determined that three genes adjacent to are predicted to encode enzymes that remodel the lipid A component of lipopolysaccharide. The modifications catalyzed by lipid A phosphoethanolamine transferase (EptA) and lipid A 1-phosphatase (LpxE) previously were detected in lipid A from multiple spp. The third gene encodes a predicted lipid A glycosyl transferase (ArnT). Together, these results indicate that the RaxH-RaxR system is orthologous to the ColS-ColR system that regulates lipid A remodeling. To avoid future confusion, we recommend that the terms ColS and ColR no longer be applied to spp., and that the Vgr, Rax, and Det designations be used instead.