Sensory Perception in Bacterial Cyclic Diguanylate Signal Transduction

Abstract

Cyclic diguanylate (c-di-GMP) signal transduction systems provide bacteria with the ability to sense changing cell status or environmental conditions and then execute suitable physiological and social behaviors in response. In this review, we provide a comprehensive census of the stimuli and receptors that are linked to the modulation of intracellular c-di-GMP. Emerging evidence indicates that c-di-GMP networks sense light, surfaces, energy, redox potential, respiratory electron acceptors, temperature, and structurally diverse biotic and abiotic chemicals. Bioinformatic analysis of sensory domains in diguanylate cyclases and c-di-GMP-specific phosphodiesterases as well as the receptor complexes associated with them reveals that these functions are linked to a diverse repertoire of protein domain families. We describe the principles of stimulus perception learned from studying these modular sensory devices, illustrate how they are assembled in varied combinations with output domains, and summarize a system for classifying these sensor proteins based on their complexity. Biological information processing via c-di-GMP signal transduction not only is fundamental to bacterial survival in dynamic environments but also is being used to engineer gene expression circuitry and synthetic proteins with à la carte biochemical functionalities.

Keywords: biofilms; cyclic diguanylate; diguanylate cyclase; phosphodiesterase; sensor domain; signal transduction; stimulus perception.

FIG 1

An overview of sensory domains found in c-di-GMP signaling proteins and their functions that have been substantiated in vitro and in vivo. Based on an analysis of 50 unique proteins from diverse bacterial species, integers in parentheses denote the number of unique proteins containing the sensory domain with the indicated function. All examples of sensor domains found in diguanylate cyclases or phosphodiesterases as well as their oligomeric receptor complexes are described in the text. Sensor domains have been categorized according to the complexity of the system in which they are found, namely, one-component system (OCS), two-component system (TCS), chemosensory system, or others.

FIG 2

The complexity scheme provides a basis for classifying signal transduction proteins. One-component systems are comprised of 1 protein that codes for both input and output functions. Two-component systems are minimally comprised of 2 proteins, of which 1 includes a histidine kinase (HATPase) domain and 1 includes a phosphoreceiver (REC) domain that is phosphorylated by the kinase. Chemosensory systems are minimally comprised of 6 proteins with homology to the archetypal E. coli chemosensory complex, which also includes a histidine kinase and partner phosphoreceiver protein.

FIG 3

The complexity scheme classification illustrates the systematic but varied integration of sensory input domains in c-di-GMP signaling proteins and their receptor complexes. All examples of c-di-GMP signaling proteins are discussed in the main text. DGC and PDE proteins often function as higher order oligomers; however, for simplicity, protein oligomeric states are not illustrated here. Protein lengths are not drawn to scale. Transmembrane regions of proteins are not illustrated.

FIG 4

Identity, abundance, and diversity of putative sensory and receiver domains found in the conserved domain architectures of c-di-GMP signaling proteins. Counts represent the number of unique protein domain architectures that contain 1 or more of the indicated putative sensory or receiver domains and a putative GGDEF, EAL, and/or HD_5 domain. Pfam clans contain >1 domain family, and architectures were counted more than once in the clan categories if they contain >1 identifiable domain family from that clan. The Pfam HD_5 domain encompasses many but not all the architectures containing the CDD HD-GYP domain. Putative sensory domains are ordered by their overall abundance in DGCs and PDEs; the 2 representative receiver domains (RRRD and PTS_EIIC) are positioned on the right side of the x axis. Domain architectures were retrieved from the Pfam database v34.0 on 24 July 2021. This list is nonexhaustive and highlights domains discussed in the text. See Table S1 for additional data and accession numbers.

FIG 5

The thermosensory diguanylate cyclase fine tunes Pseudomonas aeruginosa biofilm formation and c-di-GMP levels in response to temperature. (A) Colony morphology of P. aeruginosa CF39S (tdcA⁺) at 30, 32, 34, and 37°C (from left to right). (B) Temperature-dependent biofilm formation by P. aeruginosa CF39 (tdcA⁻) and CF39S (tdcA⁺). (C) Temperature-dependent increases in intracellular c-di-GMP from P. aeruginosa CF39 (tdcA⁻) and CF39S (tdcA⁺). Data were taken from reference .