Second messengers and divergent HD‐GYP phosphodiesterases regulate 3′,3′‐cGAMP signaling

Wright, Todd A.; Jiang, Lucy; Park, Namje; Anderson, Wyatt A.; Chen, Ge; Hallberg, Zachary F.; Nan, Beiyan; Hammond, Ming C.

doi:10.1111/mmi.14412

Cited by 25 publications

(35 citation statements)

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“…We found at least six distinct families of phosphodiesterases (PDease) that we predict to be the mainstay of counter-nucleotide defenses in jumbo phages, which are likely directed at different types of nucleotides ( Figure 5 c). Across the three jumbo phage groups, there are HD-GYP enzymes (e.g., QDB70412.1) of the HD superfamily of phosphoesterases that target cyclic di- and oligo-nucleotides [ 155 , 156 , 157 , 158 ] and are likely to serve as a defense against the SMODS-based and type I/III CRISPR systems that use such nucleotides as signals. Another member of the HD superfamily, HD-alarmone PDease from group 2 and 3 jumbo phages (e.g., BBI90576.1), likely targets the alarmone [ 159 ], a nucleotide used as the signal by the stringent response system and the recently described related host immune systems [ 131 , 160 ].…”

Section: Resultsmentioning

confidence: 99%

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

Iyer

Anantharaman

Krishnan

et al. 2021

Viruses

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Jumbo phages have attracted much attention by virtue of their extraordinary genome size and unusual aspects of biology. By performing a comparative genomics analysis of 224 jumbo phages, we suggest an objective inclusion criterion based on genome size distributions and present a synthetic overview of their manifold adaptations across major biological systems. By means of clustering and principal component analysis of the phyletic patterns of conserved genes, all known jumbo phages can be classified into three higher-order groups, which include both myoviral and siphoviral morphologies indicating multiple independent origins from smaller predecessors. Our study uncovers several under-appreciated or unreported aspects of the DNA replication, recombination, transcription and virion maturation systems. Leveraging sensitive sequence analysis methods, we identify novel protein-modifying enzymes that might help hijack the host-machinery. Focusing on host–virus conflicts, we detect strategies used to counter different wings of the bacterial immune system, such as cyclic nucleotide- and NAD+-dependent effector-activation, and prevention of superinfection during pseudolysogeny. We reconstruct the RNA-repair systems of jumbo phages that counter the consequences of RNA-targeting host effectors. These findings also suggest that several jumbo phage proteins provide a snapshot of the systems found in ancient replicons preceding the last universal ancestor of cellular life.

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Section: Resultsmentioning

confidence: 99%

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

Iyer

Anantharaman

Krishnan

et al. 2021

Viruses

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“…HD-GYPs are a special subclass of the PDE subfamily and are functionally homologous to EAL proteins (typified by the glutamate-alanine-leucine residue triad) [1,58]. They can be single domain proteins or fusions to extra regulatory, sensory, or catalytic protein domains [8,59,60].…”

Section: Hd-domain Pdes Acting On C-di-gmp and C-gamp; The Hd-gyp Subclassmentioning

confidence: 99%

“…Out of the nine HD-GYPs encoded in Vibrio cholerae, VCA0681, VCA0931, and VCA0210 are the only HD-GYPs to hydrolyze both c-di-GMP and 3 3 c-GAMP. More recently, PmxA from Myxococcus xanthus was identified as a 3 3 c-GAMP specific PDE that is hardly active toward c-di-GMP or c-di-AMP [60]. Selectivity for 3 3 c-GAMP is attributed to a glutamine near the active site, although this residue is not conserved in VCA0681, VCA0931, and VCA0210, suggesting that the molecular origins for 3 3 cGAMP specificity may vary among HD-GYPs.…”

Section: Hd-domain Pdes Acting On C-di-gmp and C-gamp; The Hd-gyp Subclassmentioning

confidence: 99%

The HD-Domain Metalloprotein Superfamily: An Apparent Common Protein Scaffold with Diverse Chemistries

et al. 2020

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The histidine–aspartate (HD)-domain protein superfamily contains metalloproteins that share common structural features but catalyze vastly different reactions ranging from oxygenation to hydrolysis. This chemical diversion is afforded by (i) their ability to coordinate most biologically relevant transition metals in mono-, di-, and trinuclear configurations, (ii) sequence insertions or the addition of supernumerary ligands to their active sites, (iii) auxiliary substrate specificity residues vicinal to the catalytic site, (iv) additional protein domains that allosterically regulate their activities or have catalytic and sensory roles, and (v) their ability to work with protein partners. More than 500 structures of HD-domain proteins are available to date that lay out unique structural features which may be indicative of function. In this respect, we describe the three known classes of HD-domain proteins (hydrolases, oxygenases, and lyases) and identify their apparent traits with the aim to portray differences in the molecular details responsible for their functional divergence and reconcile existing notions that will help assign functions to yet-to-be characterized proteins. The present review collects data that exemplify how nature tinkers with the HD-domain scaffold to afford different chemistries and provides insight into the factors that can selectively modulate catalysis.

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“…PmxA is a PDE with higher activity towards cGAMP than c-di-GMP (40,54). Accordingly, the cellular pool of c-di-GMP is unaltered in a ΔpmxA mutant compared to WT.…”

Section: Discussionmentioning

confidence: 99%

“…DmxB is the DGC responsible for the dramatic increase in the c-di-GMP level during development (40). PmxA degrades c-di-GMP as well as the di-nucleotide 3'-5', 3'-5' cyclic GMP-AMP (cGAMP) in vitro and with the highest activity towards cGAMP (40,54). Lack of PmxA does not lead to significant changes in the c-di-GMP level during development (40) while it remains unknown how lack of PmxA may affect cGAMP accumulation in vivo.…”

Section: Introductionmentioning

confidence: 99%

The CRP-like transcriptional regulator MrpC curbs c-di-GMP and 3’, 3’ cGAMP nucleotide levels during development in Myxococcus xanthus

Kuzmich

Blumenkamp

Meier

et al. 2021

Preprint

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Myxococcus xanthus has a nutrient-regulated biphasic lifecycle forming predatory swarms in the presence of nutrients and spore-filled fruiting bodies in the absence of nutrients. The second messenger c-di-GMP is essential during both stages of the lifecycle; however, different enzymes involved in c-di-GMP synthesis and degradation as well as several c-di-GMP receptors are important during distinct lifecycle stages. To address this stage specificity, we determined transcript levels using RNA-seq and transcription start sites using Cappable-seq during growth and development at a genome-wide scale. All 70 genes encoding c-di-GMP associated proteins were expressed, with 28 up-regulated and 10 down-regulated during development. In particular, the three genes encoding enzymatically active proteins with a stage-specific function were expressed stage-specifically. By combining operon mapping with published ChIP-seq data for MrpC (Robinson et al., 2014), the CRP-like master regulator of development, we identified nine developmentally regulated genes as regulated by MrpC. In particular, MrpC directly represses expression of dmxB, which encodes the diguanylate cyclase DmxB that is essential for development and responsible for the c-di-GMP increase during development. Moreover, MrpC directly activates transcription of pmxA, which encodes a bifunctional phosphodiesterase that degrades c-di-GMP and 3,3 cGAMP in vitro and is essential for development. Thereby, MrpC regulates and curbs the cellular pools of c-di-GMP and 3,3 cGAMP during development. We conclude that temporal regulation of the synthesis of proteins involved in c-di-GMP metabolism contributes to c-di-GMP signaling specificity. MrpC is important for this regulation, thereby being a key regulator of developmental cyclic di-nucleotide metabolism in M. xanthus.

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Second messengers and divergent HD‐GYP phosphodiesterases regulate 3′,3′‐cGAMP signaling

Cited by 25 publications

References 50 publications

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

The HD-Domain Metalloprotein Superfamily: An Apparent Common Protein Scaffold with Diverse Chemistries

The CRP-like transcriptional regulator MrpC curbs c-di-GMP and 3’, 3’ cGAMP nucleotide levels during development in Myxococcus xanthus

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