Trigger phosphodiesterases as a novel class of c-di-GMP effector proteins

Abstract

The bacterial second messenger c-di-GMP controls bacterial biofilm formation, motility, cell cycle progression, development and virulence. It is synthesized by diguanylate cyclases (with GGDEF domains), degraded by specific phosphodiesterases (PDEs, with EAL of HD-GYP domains) and sensed by a wide variety of c-di-GMP-binding effectors that control diverse targets. c-di-GMP-binding effectors can be riboswitches as well as proteins with highly diverse structures and functions. The latter include ‘degenerate’ GGDEF/EAL domain proteins that are enzymatically inactive but still able to bind c-di-GMP. Surprisingly, two enzymatically active ‘trigger PDEs’, the Escherichia coli proteins PdeR and PdeL, have recently been added to this list of c-di-GMP-sensing effectors. Mechanistically, trigger PDEs are multifunctional. They directly and specifically interact with a macromolecular target (e.g. with a transcription factor or directly with a promoter region), whose activity they control by their binding and degradation of c-di-GMP—their PDE activity thus represents the c-di-GMP sensor or effector function. In this process, c-di-GMP serves as a regulatory ligand, but in contrast to classical allosteric control, this ligand is also degraded. The resulting kinetics and circuitry of control are ideally suited for trigger PDEs to serve as key components in regulatory switches.This article is part of the themed issue ‘The new bacteriology’.

Alterations of c‐di‐GMP turnover proteins modulate semi‐constitutive rdar biofilm formation in commensal and uropathogenic Escherichia coli

“…In summary, consistent with the proposed functionality of YciR as a trigger enzyme that regulates csgD expression through protein–protein interactions (Hengge, ; Lindenberg et al., ), aa outside of the catalytic motifs contribute to the activity of YciR and are critical for regulation of rdar biofilm formation. Whereas all besides four introduced aa substitutions hampered the ability of YciR Fec10 to downregulate the rdar morphotype at 37°C, only two substitutions proved to be highly relevant at 28°C.…”

“…For example, the DGC YliF presented a nonsense mutation in strain B‐11870. As reflected by our data, though, the DGCs YcdT and YddV (DosC) were frequently absent independently of strain origin (Povolotsky & Hengge, ). Strains lacking DosC and/or DosP might not fully respond to oxygen to regulate biofilm formation, as the DosC/P system was shown to regulate curli and PNAG expression in response to oxygen levels (Jonas et al., ; Tagliabue, Maciag, Antoniani, & Landini, ; Tagliabue, Antoniani, Maciag, Bocci, et al.…”

“…YciR is hypothesized to affect csgD expression through the interaction with the DGC YdaM and the transcriptional regulator MlrA in response to c‐di‐GMP signaling (Hengge, ; Lindenberg et al., ). We tested the effect of mutations in the consensus catalytic motifs in YciR Fec101 and YciR Tob1 , being the two extremes in effectiveness on rdar morphotype formation at 28°C and 37°C (Figure a).…”

“…In E. coli , YciR is proposed to inhibit the DGC YdaM and MlrA through protein–protein interactions in a c‐di‐GMP‐dependent manner, to downregulate csgD expression. YdaM and MlrA are then released upon rising c‐di‐GMP levels (Hengge, ; Lindenberg et al., ). A more pronounced effect of EAL domain mutants in downregulation of the rdar morphotype (Figure ) apparently confirms the previously described unresponsiveness to c‐di‐GMP levels with tighter binding of YdaM and MlrA.…”

The new bacteriology

“…In the second session, Hengge [4] (Humboldt Universitat Zu Berlin, Germany) gave an overview on biofilm formation and the role of cyclic diGMP (c-di-GMP). This molecule appears to be critical in biofilm formation and in cell cycle progression, development and virulence.…”