Highly regulated, diversifying NTP-dependent biological conflict systems with implications for the emergence of multicellularity

Kaur, Gurmeet; Burroughs, A. Maxwell; Iyer, Lakshminarayan M.; Aravind, L.

doi:10.7554/elife.52696

Cited by 43 publications

(121 citation statements)

References 233 publications

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“…These include disparate mechanisms such as the modification of cell-surface molecules to prevent attachment of the virus, targeting of viral nucleic acids by restriction and CRISPR/Cas systems, limiting essential metabolites such as NAD + by targeted degradation, apoptotic or self-targeting mechanisms that limit viral replication and spread by targeting the ribosome or inducing cell-suicide [ 130 ]. These processes, especially those involving self-targeting or suicide, are often under tight-regulatory control by threshold-setting signals in the form of diverse nucleotides and NAD + derivatives [ 24 , 131 , 132 ]. On the phage side, the counter-mechanisms against host defense and competing viruses are less understood.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the differences in cellular genome sizes can be seen as occupying a spectrum similar to what in ecology has been described as the r-K selection spectrum—those with smaller genomes are selected by higher replication rates (r), whereas those with larger genomes replicate more slowly but have an entire array of features that make them stronger competitors [ 132 , 233 ]. Similarly, the caudoviral genomes may be seen as being selected along a similar spectrum with fast replication on one end and a stronger capacity to weather host immune attacks and metabolic restrictions on the other.…”

Section: Resultsmentioning

confidence: 99%

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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%

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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“…1B) (see Materials and Methods). We then extracted conserved gene neighborhood information for all newly identified candidate proteins and screened them for features characteristic of the mobility and variability of biological conflict systems: (i) high variability in domain architecture while retaining the same overall architectural "grammar" (7,18,32), (ii) rapid sequence divergence within predicted effector domains (this is one of the strongest indicators as it can be objectively measured using statistically significant differences in the mean column-wise Shannon entropy values for alignments of domains from conflict systems compared to their counterparts from nonconflict systems [see Materials and Methods and the supplemental material]), and (iii) extensive lateral transfer and dramatic differences in presence/absence between closely related organisms (13,18,33,34) (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Identification of Uncharacterized Components of Prokaryotic Immune Systems and Their Diverse Eukaryotic Reformulations

Burroughs

Aravind

2020

J Bacteriol

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Nucleotide-activated effector deployment, prototyped by interferon-dependent immunity, is a common mechanistic theme shared by immune systems of several animals and prokaryotes. Prokaryotic versions include CRISPR/Cas with the CRISPR polymerase domain, their minimal variants, and systems with Second Messenger Oligonucleotide or Dinucleotide Synthetase (SMODS). Cyclic or linear oligonucleotide signals in these systems help set a threshold for the activation of potentially deleterious downstream effectors in response to invader-detection. We establish such a regulatory mechanism to be a more general principle of immune systems, which can also operate independently of such messengers. Using sensitive sequence analysis and comparative genomics we identify 12 new prokaryotic immune systems, which we unify by this principle of threshold-dependent effector activation. These display regulatory mechanisms paralleling physiological signaling based on 3′-5′ cyclic mononucleotides, NAD+-derived messengers, two- and one-component signaling that include histidine kinase-based signaling, and proteolytic activation. Further, these systems allowed identification of multiple new sensory signal sensory components, such as a tetratricopeptide-repeat-scaffold predicted to recognize NAD+-derived signals, unreported versions of the STING domain, prokaryotic YEATS domains, and a predicted nucleotide-sensor related to receiver domains. We also identify previously unrecognized invader-detection components and effector components, such as prokaryotic versions of the Wnt domain. Finally, we show that there have been multiple acquisitions of unidentified STING domains in eukaryotes, while the TPR scaffold was incorporated into the animal immunity/apoptosis ASK signalosome. IMPORTANCE Both prokaryotic and eukaryotic immune systems face the danger of premature activation of effectors and degradation of self-molecules in the absence of an invader. To mitigate this, they have evolved threshold-setting regulatory mechanisms for the triggering of effectors only upon detection of a sufficiently strong invader-signal. This work defines general templates for such regulation in effector-based immune systems. Using this, we identify several previously uncharacterized prokaryotic immune mechanisms that accomplish regulation of downstream effector deployment by using nucleotide, NAD+-derived, two-component and one-component signals paralleling physiological homeostasis. This study has also helped identify several previously unknown sensor and effector modules in these systems. Our findings also augment the growing evidence for the emergence of key animal immunity and chromatin regulatory components from prokaryotic progenitors.

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“…The commonalities aside, the Quimbyvirus DGR RT is encoded by three overlapping reading frames and targets two proteins, one in the structural module and one in a defense-related island. DGRs have been associated with putative defense and signaling systems in cyanobacterial and gammaproteobacterial genomes [118,119], but beyond the presence of the C-type lectin fold, the hypervariable proteins possess few other recognizable domains that obfuscate their precise roles.…”

Section: Discussionmentioning

confidence: 99%

Thousands of previously unknown phages discovered in whole-community human gut metagenomes

Benler

Yutin

Antipov

et al. 2021

Preprint

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Background: Double-stranded DNA bacteriophages (dsDNA phages) play pivotal roles in structuring human gut microbiomes; yet, the gut virome is far from being fully characterized, and additional groups of phages, including highly abundant ones, continue to be discovered by metagenome mining. A multilevel framework for taxonomic classification of viruses was recently adopted, facilitating the classification of phages into evolutionary informative taxonomic units based on hallmark genes. Together with advanced approaches for sequence assembly and powerful methods of sequence analysis, this revised framework offers the opportunity to discover and classify unknown phage taxa in the human gut.Results: A search of human gut metagenomes for circular contigs encoding phage hallmark genes resulted in the identification of 3,738 apparently complete phage genomes that represent 451 putative genera. Several of these phage genera are only distantly related to previously identified phages and are likely to found new families. Two of the candidate families, “Flandersviridae” and “Quimbyviridae”, include some of the most common and abundant members of the human gut virome that infect Bacteroides, Parabacteroides and Prevotella. The third proposed family, “Gratiaviridae”, consists of less abundant phages that are distantly related to the families Autographiviridae, Drexlerviridae and Chaseviridae. Analysis of CRISPR spacers indicates that phages of all three putative families infect bacteria of the phylum Bacteroidetes. Comparative genomic analysis of the three candidate phage families revealed features without precedent in phage genomes. Some “Quimbyviridae” phages possess Diversity-Generating Retroelements (DGRs) that generate hypervariable target genes nested within defense-related genes, whereas the previously known targets of phage-encoded DGRs are structural genes. Several “Flandersviridae” phages encode enzymes of the isoprenoid pathway, a lipid biosynthesis pathway that so far has not been known to be manipulated by phages. The “Gratiaviridae” phages encode a HipA-family protein kinase and glycosyltransferase, suggesting these phages modify the host cell wall, preventing superinfection by other phages. Hundreds of phages in these three and other families are shown to encode catalases and iron-sequestering enzymes that can be predicted to enhance cellular tolerance to reactive oxygen species.Conclusions: Analysis of phage genomes identified in whole-community human gut metagenomes resulted in the delineation of at least three new candidate families of Caudovirales and revealed diverse putative mechanisms underlying phage-host interactions in the human gut. Addition of these phylogenetically classified, diverse and distinct phages to public databases will facilitate taxonomic decomposition and functional characterization of human gut viromes.

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Highly regulated, diversifying NTP-dependent biological conflict systems with implications for the emergence of multicellularity

Cited by 43 publications

References 233 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

Identification of Uncharacterized Components of Prokaryotic Immune Systems and Their Diverse Eukaryotic Reformulations

Thousands of previously unknown phages discovered in whole-community human gut metagenomes

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