A pseudokinase couples signaling pathways to enable asymmetric cell division in a bacterium

Bacteria face complex decisions when initiating developmental events such as sporulation, nodulation, virulence, and asymmetric cell division. These developmental decisions require global changes in genomic readout, and bacteria typically employ intricate (yet poorly understood) signaling networks that enable changes in cell function. The bacterium Caulobacter crescentus divides asymmetrically to yield two functionally distinct cells: a motile, chemotactic swarmer cell, and a sessile stalked cell with replication and division capabilities. Work from several Caulobacter labs has revealed that differentiation requires concerted regulation by several two-component system (TCS) signaling pathways that are differentially positioned at the poles of the predivisional cell (Figure 1). The strict unidirectional flow from histidine kinase (HK) to the response regulator (RR), observed in most studied TCS, is difficult to reconcile with the notion that information can be transmitted between two or more TCS signaling pathways. In this study, we uncovered a mechanism by which daughter cell fate, which is specified by the DivJ-DivK-PleC system and effectively encoded in the phosphorylation state of the single-domain RR DivK, is communicated to the CckA-ChpT-CtrA signaling pathway that regulates more than 100 genes for polar differentiation, replication initiation and cell division. Using structural biology and biochemical findings we proposed a mechanistic basis for TCS pathway coupling in which the DivL pseudokinase is repurposed as a sensor rather than participant in phosphotransduction.