Everything OLD is new again: How structural, functional, and bioinformatic advances have redefined a neglected nuclease family

Dot, Elena Wanvig; Thomason, Lynn C.; Chappie, Joshua S.

doi:10.1111/mmi.15074

Cited by 3 publications

(5 citation statements)

References 146 publications

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“…PARIS was recently assigned to a family of OLD-like defense systems that share an ABC ATPase and a TOPRIM nuclease 12 . This analysis identified four classes, where the single gene systems such as P2 Old are categorized as class 1, Gabija are class 2, reverse-transcriptase containing systems are class 3, and PARIS systems are class 4.…”

Section: Resultsmentioning

confidence: 99%

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Viral proteins activate PARIS-mediated tRNA degradation and viral tRNAs rescue infection

Burman,

Belukhina,

Depardieu

et al. 2024

Preprint

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Viruses compete with each other for limited cellular resources, and some viruses deliver defense mechanisms that protect the host from competing genetic parasites. PARIS is a defense system, often encoded in viral genomes, that is composed of a 53 kDa ABC ATPase (AriA) and a 35 kDa TOPRIM nuclease (AriB). Here we show that AriA and AriB assemble into a 425 kDa supramolecular immune complex. We use cryo-EM to determine the structure of this complex which explains how six molecules of AriA assemble into a propeller-shaped scaffold that coordinates three subunits of AriB. ATP-dependent detection of foreign proteins triggers the release of AriB, which assembles into a homodimeric nuclease that blocks infection by cleaving the host tRNALys. Phage T5 subverts PARIS immunity through expression of a tRNALysvariant that prevent PARIS-mediated cleavage, and thereby restores viral infection. Collectively, these data explain how AriA functions as an ATP-dependent sensor that detects viral proteins and activates the AriB toxin. PARIS is one of an emerging set of immune systems that form macromolecular complexes for the recognition of foreign proteins, rather than foreign nucleic acids.

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Section: Resultsmentioning

confidence: 99%

“…Association between ABC ATPase and TOPRIM domains is an emerging theme in recently discovered immune systems 12 . Examples include the Gabija system 13,14 , effector toxin proteins of retron immunity 15 , and bona fide toxin-antitoxin (TA) modules 16 .…”

Section: Introductionmentioning

confidence: 99%

Viral proteins activate PARIS-mediated tRNA degradation and viral tRNAs rescue infection

Burman,

Belukhina,

Depardieu

et al. 2024

Preprint

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“…Out of 4,802 genomes analyzed, the retron effector protein was an OLD nuclease 4% of the time ( Millman et al, 2020 ). OLD nucleases found as effector proteins in retron defense systems have been classified as Class 3 OLD enzymes, with further subdivision depending on whether the old gene lies upstream (Class 3A) or downstream (Class 3B) of the reverse transcriptase ( Dot et al, 2023 ). Within the retron naming system, these genomic organizations have been described as type I-B2 or type I-B1, respectively ( Mestre et al, 2020 ).…”

Section: Class 3 Old Proteins: Retron-driven Anti-phage Defensementioning

confidence: 99%

“…How many classes of OLD proteins exist, and in how many different systems? Class 4 OLD proteins have been proposed to contribute to the function of the PARIS system ( Rousset et al, 2022 ; Dot et al, 2023 ). Unlike the other three classes, in the PARIS system the ATPase and Toprim domains are encoded on separate genes (designated ariA and ariB, respectively; Rousset et al, 2022 ).…”

Section: Future Considerationsmentioning

confidence: 99%

“…A close look at several systems, including the Gabija system ( Doron et al, 2018 ; Cheng et al, 2021 ) and retrons ( Millman et al, 2020 ), illuminate a recurring appearance of overcoming lysogenization defect (OLD) family nucleases. A classification scheme has been proposed in which OLD proteins can be assigned to different classes depending on their surrounding genetic context ( Dot et al, 2023 ). In this review we will focus on the composition, structure, and function of Class 1, Class 2, and Class 3 OLD nucleases across diverse anti-phage defense systems.…”

Section: Introductionmentioning

confidence: 99%

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OLD family nuclease function across diverse anti-phage defense systems

Akritidou,

Thurtle-Schmidt

2023

Front. Microbiol.

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Bacteriophages constitute a ubiquitous threat to bacteria, and bacteria have evolved numerous anti-phage defense systems to protect themselves. These systems include well-studied phenomena such as restriction endonucleases and CRISPR, while emerging studies have identified many new anti-phage defense systems whose mechanisms are unknown or poorly understood. Some of these systems involve overcoming lysogenization defect (OLD) nucleases, a family of proteins comprising an ABC ATPase domain linked to a Toprim nuclease domain. Despite being discovered over 50 years ago, OLD nuclease function remained mysterious until recent biochemical, structural, and bioinformatic studies revealed that OLD nucleases protect bacteria by functioning in diverse anti-phage defense systems including the Gabija system and retrons. In this review we will highlight recent discoveries in OLD protein function and their involvement in multiple discrete anti-phage defense systems.

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Functionally comparable but evolutionarily distinct nucleotide-targeting effectors help identify conserved paradigms across diverse immune systems

Nicastro,

Burroughs,

Iyer

et al. 2023

Nucleic Acids Research

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While nucleic acid-targeting effectors are known to be central to biological conflicts and anti-selfish element immunity, recent findings have revealed immune effectors that target their building blocks and the cellular energy currency—free nucleotides. Through comparative genomics and sequence-structure analysis, we identified several distinct effector domains, which we named Calcineurin-CE, HD-CE, and PRTase-CE. These domains, along with specific versions of the ParB and MazG domains, are widely present in diverse prokaryotic immune systems and are predicted to degrade nucleotides by targeting phosphate or glycosidic linkages. Our findings unveil multiple potential immune systems associated with at least 17 different functional themes featuring these effectors. Some of these systems sense modified DNA/nucleotides from phages or operate downstream of novel enzymes generating signaling nucleotides. We also uncovered a class of systems utilizing HSP90- and HSP70-related modules as analogs of STAND and GTPase domains that are coupled to these nucleotide-targeting- or proteolysis-induced complex-forming effectors. While widespread in bacteria, only a limited subset of nucleotide-targeting effectors was integrated into eukaryotic immune systems, suggesting barriers to interoperability across subcellular contexts. This work establishes nucleotide-degrading effectors as an emerging immune paradigm and traces their origins back to homologous domains in housekeeping systems.

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Everything OLD is new again: How structural, functional, and bioinformatic advances have redefined a neglected nuclease family

Cited by 3 publications

References 146 publications

Viral proteins activate PARIS-mediated tRNA degradation and viral tRNAs rescue infection

Viral proteins activate PARIS-mediated tRNA degradation and viral tRNAs rescue infection

OLD family nuclease function across diverse anti-phage defense systems

Functionally comparable but evolutionarily distinct nucleotide-targeting effectors help identify conserved paradigms across diverse immune systems

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