The architecture and conservation pattern of whole-cell control circuitry

Abstract

The control circuitry that directs and paces Caulobacter cell cycle progression involves the entire cell operating as an integrated system. This control circuitry monitors the environment and the internal state of the cell, including the cell topology, as it orchestrates orderly activation of cell cycle subsystems and Caulobacter's asymmetric cell division. The proteins of the Caulobacter cell cycle control system and its internal organization are co-conserved across many alphaproteobacteria species, but there are great differences in the regulatory apparatus' functionality and peripheral connectivity to other cellular subsystems from species to species. This pattern is similar to that observed for the "kernels" of the regulatory networks that regulate development of metazoan body plans. The Caulobacter cell cycle control system has been exquisitely optimized as a total system for robust operation in the face of internal stochastic noise and environmental uncertainty. When sufficient details accumulate, as for Caulobacter cell cycle regulation, the system design has been found to be eminently rational and indeed consistent with good design practices for human-designed asynchronous control systems.

Figure 1. Hierarchical organization of the cell

The cell's signaling and the control subsystem interface interfaces with the environment by means of sensory modules largely located on the cell surface. The genetic network logic responses to signals received from the environment and from internal cell status sensors to adapt the cell to current conditions. A major function of the top-level control is to assure that the operations involved in the cell cycle occur in the proper temporal order. In Caulobacter this involves a genetic regulatory circuit with five master regulators organized as a cyclical genetic circuit (Fig. 2B) and an associated phospho-signaling network (Fig. 3). The phospho-signaling network monitors the state of progression of the cell cycle and plays an essential role in accomplishment of asymmetric cell division. The cell cycle control system is tightly integrated with the mechanisms that implement the cell cycle. The control system manages the time and place of the initiation of chromosome replication and cytokinesis as well as the development of polar organelles appropriate to the cell type and stage in the cell cycle. Underlying all these operations are the mechanisms for production of protein and structural components and energy production. The metabolic and catabolic subsystems provide the energy and the molecular raw materials for protein synthesis cell wall construction and other operations of the cell.

Figure 2

(A) Caulobacter cell cycle. Shading shows temporal and spatial localization pattern of CtrA. Dynamic protein concentrations are indicated below for DnaA, GcrA, CtrA, SciP, and CcrM. Diagrams inside the cell show progression of chromosome replication. (B) Five genes organized in a cyclical genetic circuit provide the core engine that drives the Caulobacter cell cycle^; .

Figure 3

Polar localized phospho-signaling proteins central to asymmetric cell division are coupled to the core cell cycle engine. The primary function of the cyclical genetic circuit comprising the cell cycle engine is to activate the subsystems that implement the cell cycle in the proper order and to drive the cell cycle forward. The phosphosignaling circuitry senses the cell topology and is tightly coupled to the progression of the engine through control of the stability and phosphorylation state of CtrA. Localization of DivL and CckA leads to phosphorylation of the phospho-signaling protein, ChpT, that phosphorylates CtrA and prevents CtrA proteolysis by simultaneously phosphorylating CpdR. Subsequent interruption of this cascade at the instant of the cell compartmentalization leads to rapid dephosphorylation and proteolysis of CtrA to enable initiation of chromosome replication.