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• W4310522711 abstract "Second-messenger-mediated signaling by cyclic oligonucleotides (cOs) composed of distinct base, ring size, and 3′-5′/2′-5′ linkage combinations constitutes the initial trigger resulting in activation of signaling pathways that have an impact on immune-mediated antiviral defense against invading viruses and phages. Bacteria and archaea have evolved CRISPR, CBASS, Pycsar, and Thoeris surveillance complexes that involve cO-mediated activation of effectors resulting in antiviral defense through either targeted nuclease activity, effector oligomerization-mediated depletion of essential cellular metabolites or disruption of host cell membrane functions. Notably, antiviral defense capitalizes on an abortive infection mechanism, whereby infected cells die prior to completion of the phage replication cycle. In turn, phages have evolved small proteins that target and degrade/sequester cOs, thereby suppressing host immunity. This review presents a structure-based mechanistic perspective of recent advances in the field of cO-mediated antiviral defense, in particular highlighting the ancient evolutionary adaptation by metazoans of bacterial cell-autonomous innate immune mechanisms. Second-messenger-mediated signaling by cyclic oligonucleotides (cOs) composed of distinct base, ring size, and 3′-5′/2′-5′ linkage combinations constitutes the initial trigger resulting in activation of signaling pathways that have an impact on immune-mediated antiviral defense against invading viruses and phages. Bacteria and archaea have evolved CRISPR, CBASS, Pycsar, and Thoeris surveillance complexes that involve cO-mediated activation of effectors resulting in antiviral defense through either targeted nuclease activity, effector oligomerization-mediated depletion of essential cellular metabolites or disruption of host cell membrane functions. Notably, antiviral defense capitalizes on an abortive infection mechanism, whereby infected cells die prior to completion of the phage replication cycle. In turn, phages have evolved small proteins that target and degrade/sequester cOs, thereby suppressing host immunity. This review presents a structure-based mechanistic perspective of recent advances in the field of cO-mediated antiviral defense, in particular highlighting the ancient evolutionary adaptation by metazoans of bacterial cell-autonomous innate immune mechanisms. A range of antiphage defense systems have been identified in the microbial pangenome based on their enrichment within defense islands.1Doron S. Melamed S. Ofir G. Leavitt A. Lopatina A. Keren M. Amitai G. Sorek R. Systematic discovery of antiphage defense systems in the microbial pangenome.Science. 2018; 359 (eaar4120)Crossref Scopus (433) Google Scholar This review focuses on recent advances from a structural and mechanistic perspective of cO (cyclic oligonucletide)-mediated activation of CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated genes), CBASS (cyclic-oligonucleotide-based antiphage signaling system), Pycsar (pyrimidine cyclase system for antiphage resistance), and Thoeris (Egyptian protective deity of childbirth and fertility) defense pathways that trigger an antiviral defense response. The emphasis of this review is on the recent publications, together with mentioning of the earlier literature to place the more recent contributions in context. To this end, research on CRISPR-Cas has addressed the role of cO-mediated activation and regulation of CARF (CRISPR-associated Rossman fold)-domain-containing accessory RNA and/or DNA nucleases. The CBASS pathway is extremely diverse in that the antiviral response initiated by cO-mediated activation of CD-NTases (cGAS [cyclic GAMP-AMP synthase]/DncV-like nucleotidyltransferases), in turn, triggers the oligomerization-mediated activities of Cap (CD-NTase-associated protein) effector modules ranging from nuclease activation to depletion of essential cellular metabolites and disruption of host cell membrane function. The transmembrane (TM)-containing Pycsar signaling pathway depends on cyclic pyrimidine monophosphates as second messengers with abortive infection resulting from either disruption of membrane integrity or depletion of cellular metabolite levels. More recently, it has been shown that the newly characterized Thoeris antiviral defense pathway is triggered by an unusual cyclic nucleotide gcADPR (1′′-2′ and 1′-3′′ cyclic ADPR ribose), leading to depletion of cellular NAD+ (nicotinamide adenine dinucleotide) levels. These CRISPR, CBASS, Pycsar, and Thoeris surveillance pathways are in turn compromised by virus-encoded nucleases that target and degrade/sequester cOs involved in activation of host immunity. The review outlines the distinct features of individual systems and concludes with an emphasis on common elements connecting these bacterial defense pathways, which following comparison with the metazoan cGAS-stimulator of interferon genes (STING) pathway, highlights the ancient evolutionary adaptation by metazoans of bacterial cell-autonomous innate immune mechanisms. In general, bacterial CRISPR-Cas systems utilize effector nucleases loaded with guide sequences to specifically target and degrade foreign nucleic acids.2Wang J.Y. Pausch P. Doudna J.A. Structural biology of CRISPR-Cas immunity and genome editing enzymes.Nat. Rev. Microbiol. 2022; 20: 641-656Crossref PubMed Scopus (26) Google Scholar,3Mohanraju P. Saha C. van Baarlen P. Louwen R. Staals R.H.J. van der Oost J. Alternative functions of CRISPR-Cas systems in the evolutionary arms race.Nat. Rev. Microbiol. 2022; 20: 351-364Crossref PubMed Scopus (18) Google Scholar,4Koonin E.V. Makarova K.S. Evolutionary plasticity and functional versatility of CRISPR systems.PLoS Biol. 2022; 20 (e3001481)Crossref PubMed Scopus (20) Google Scholar Among the single subunit class 2 Cas (types II, V, and VI) and multi-subunit class 1 (types I, II, and IV) CRISPR-Cas surveillance complexes, the diverse and polymorphic type III system is the most interesting and challenging, given that it exhibits multiple nuclease cleavage activities. Unlike most CRISPR systems, the crRNA pairs with transcribed target ssRNA rather than dsDNA in the type III system.5Hale C.R. Zhao P. Olson S. Duff M.O. Graveley B.R. Wells L. Terns R.M. Terns M.P. RNA-guided RNA cleavage by a CRISPR RNA-Cas protein complex.Cell. 2009; 139: 945-956Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar,6Tamulaitis G. Kazlauskiene M. Manakova E. Venclovas Č. Nwokeoji A.O. Dickman M.J. Horvath P. Siksnys V. Programmable RNA shredding by the type III-A CRISPR-Cas system of Streptococcus thermophilus.Mol. Cell. 2014; 56: 506-517Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar,7Pyenson N.C. Marraffini L.A. Type III CRISPR-Cas systems: when DNA cleavage just isn't enough.Curr. Opin. Microbiol. 2017; 37: 150-154Crossref PubMed Scopus (39) Google Scholar,8Tamulaitis G. Venclovas Č. Siksnys V. Type III CRISPR-Cas immunity: major differences brushed aside.Trends Microbiol. 2017; 25: 49-61Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar In turn, binding of ATPs to the signature Cas10 subunit generates cOs that target the CARF domains of dimeric accessory nucleases, thereby allosterically activating their linked nuclease domains to non-specifically degrade both host and viral nucleic acids, resulting in the growth arrest of the infected cell (shown schematically in Figure 1A for the type III-A Csm system).9Athukoralage J.S. White M.F. Cyclic oligoadenylate signaling and regulation by ring nucleases during type III CRISPR defense.RNA. 2021; 27: 855-867Crossref PubMed Scopus (18) Google Scholar,10Das A. Goswami H.N. Whyms C.T. Sridhara S. Li H. Structural principles of CRISPR-Cas enzymes used in nucleic acid detection.J. Struct. Biol. 2022; 214: 107838Crossref PubMed Scopus (3) Google Scholar Importantly, target RNA-activated cO formation is tightly regulated, with accessory nuclease activity requiring intact crRNA:target RNA pairing. Notably, trans-acting ring nucleases that target and cleave cO second messengers regulate the activity of the accessory nucleases.11Athukoralage J.S. White M.F. Cyclic nucleotide signaling in phage defense and counter-defense.Annu. Rev. Virol. 2022; 9: 451-468Crossref PubMed Scopus (10) Google Scholar Such regulation has also been demonstrated by type III CRISPR accessory nucleases, such as Csm6, whose CARF domain unexpectedly functions as a cis-acting ring nuclease, thereby self-limiting the duration of the activating signal.12Jia N. Jones R. Yang G.L. Ouerfelli O. Patel D.J. CRISPR-Cas III-A Csm6 CARF domain is a ring nuclease triggering stepwise cA(4) cleavage with ApA>p formation terminating RNase activity.Mol. Cell. 2019; 75 (944–956.e6)Abstract Full Text Full Text PDF Scopus (58) Google Scholar Notably, two groups independently demonstrated that binding of ATPs within the composite Palm domains of Cas10, the largest subunit within the type III CRISPR complex, generate cOs that target the CARF domains of dimeric accessory nucleases (Csm6 and Csx1) to allosterically activate linked nuclease domains.13Kazlauskiene M. Kostiuk G. Venclovas Č. Tamulaitis G. Siksnys V. A cyclic oligonucleotide signaling pathway in type III CRISPR-Cas systems.Science. 2017; 357: 605-609Crossref PubMed Scopus (259) Google Scholar,14Niewoehner O. Garcia-Doval C. Rostøl J.T. Berk C. Schwede F. Bigler L. Hall J. Marraffini L.A. Jinek M. Type III CRISPR-Cas systems produce cyclic oligoadenylate second messengers.Nature. 2017; 548: 543-548Crossref PubMed Scopus (257) Google Scholar This unanticipated cO signaling pathway coordinating type III CRISPR systems with accessory nucleases plays a critical role in cell growth arrest during antiviral defense by preventing phage infection and propagation.15Rostøl J.T. Marraffini L.A. Non-specific degradation of transcripts promotes plasmid clearance during type III-A CRISPR-Cas immunity.Nat. Microbiol. 2019; 4: 656-662Crossref PubMed Scopus (83) Google Scholar Structural studies on type III CRISPR systems have been undertaken on subtype III-A16You L.L. Ma J. Wang J.Y. Artamonova D. Wang M. Liu L. et al.Structure studies of the CRISPR-Csm complex reveal mechanism of co-transcriptional interference.Cell. 2019; 176 (239–253.)Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar,17Jia N. Mo C.Y. Wang C.Y. Eng E.T. Marraffini L.A. Patel D.J. Type III-A CRISPR-Cas Csm complexes: assembly, periodic RNA cleavage, DNase activity regulation, and autoimmunity.Mol. Cell. 2019; 73 (264–277.)Abstract Full Text Full Text PDF Scopus (58) Google Scholar and subtype III-B18Osawa T. Inanaga H. Sato C. Numata T. Crystal structure of the CRISPR-Cas RNA silencing Cmr complex bound to a target analog.Mol. Cell. 2015; 58: 418-430Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,19Taylor D.W. Zhu Y.F. Staals R.H.J. Kornfeld J.E. Shinkai A. van der Oost J. Nogales E. Doudna J.A. Structural biology. Structures of the CRISPR-Cmr complex reveal mode of RNA target positioning.Science. 2015; 348: 581-585Crossref PubMed Scopus (101) Google Scholar,20Sofos N. Feng M.X. Stella S. Pape T. Fuglsang A. Lin J.Z. et al.Structures of the Cmr-beta complex reveal the regulation of the immunity mechanism of type III-B CRISPR-Cas.Mol. Cell. 2020; 79 (741–757.)Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar systems toward an understanding of the allosteric transitions triggering transcriptionally active ssDNA cleavage and also cO formation. Structural aspects of the Thermococcus onnurineus type III-A Csm system composed of multiple subunits, crRNA, and target RNA has been systematically investigated in detail by cryo-EM studies to elucidate complex assembly, periodic target RNA cleavage, DNase activity regulation, and self/non-self-discrimination resulting in autoimmunity.16You L.L. Ma J. Wang J.Y. Artamonova D. Wang M. Liu L. et al.Structure studies of the CRISPR-Csm complex reveal mechanism of co-transcriptional interference.Cell. 2019; 176 (239–253.)Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar,17Jia N. Mo C.Y. Wang C.Y. Eng E.T. Marraffini L.A. Patel D.J. Type III-A CRISPR-Cas Csm complexes: assembly, periodic RNA cleavage, DNase activity regulation, and autoimmunity.Mol. Cell. 2019; 73 (264–277.)Abstract Full Text Full Text PDF Scopus (58) Google Scholar In addition, molecular details regarding conversion of bound ATPs within the composite Palm domain to pppAp(A)n,16You L.L. Ma J. Wang J.Y. Artamonova D. Wang M. Liu L. et al.Structure studies of the CRISPR-Csm complex reveal mechanism of co-transcriptional interference.Cell. 2019; 176 (239–253.)Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar,21Jia N. Jones R. Sukenick G. Patel D.J. Second messenger cA(4) formation within the composite Csm1 palm pocket of Type III-A CRISPR-Cas Csm complex and its release path.Mol. Cell. 2019; 75 (933–943.)Abstract Full Text Full Text PDF Scopus (23) Google Scholar and in turn to cOs (Figure 1B)21Jia N. Jones R. Sukenick G. Patel D.J. Second messenger cA(4) formation within the composite Csm1 palm pocket of Type III-A CRISPR-Cas Csm complex and its release path.Mol. Cell. 2019; 75 (933–943.)Abstract Full Text Full Text PDF Scopus (23) Google Scholar have emerged from X-ray and cryo-EM studies of type III-A Csm quaternary complexes (see schematic outlining crRNA and target RNA alignment, Figure 1C). These studies identified a network of intermolecular hydrogen bond alignments involving bound ATPs within the composite Palm pocket (contains a pair of Palm domains and a single conserved GGDD active site motif) of Csm1 (Cas10 equivalent in type III-A CRISPR) that account for the adenosine specificity. These include precise positioning of ATPs dictating formation of linear pppAp(A)n intermediates (Figure 1D) and positioning of linear intermediates dictating formation of cyclic cA4 product (Figure 1E). These studies also elucidated the inter-subunit pathway for cAn product release from the composite Palm domain.21Jia N. Jones R. Sukenick G. Patel D.J. Second messenger cA(4) formation within the composite Csm1 palm pocket of Type III-A CRISPR-Cas Csm complex and its release path.Mol. Cell. 2019; 75 (933–943.)Abstract Full Text Full Text PDF Scopus (23) Google Scholar The canonical dimeric Csm6 and Csx1 accessory nucleases are composed of cO-binding CARF domains linked to ssRNA-cleaving HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domains.22Makarova K.S. Timinskas A. Wolf Y.I. Gussow A.B. Siksnys V. Venclovas Č. Koonin E.V. Evolutionary and functional classification of the CARF domain superfamily, key sensors in prokaryotic antivirus defense.Nucleic Acids Res. 2020; 48: 8828-8847Crossref PubMed Scopus (40) Google Scholar Structural studies have addressed mechanistic issues related to cO-mediated targeting and activation of accessory nucleases through studies on Thermus thermophilus Csm623Niewoehner O. Jinek M. Structural basis for the endoribonuclease activity of the type III-A CRISPR-associated protein Csm6.Rna. 2016; 22: 318-329Crossref PubMed Scopus (89) Google Scholar and HB8 uncharacterized protein TTHB14424Athukoralage J.S. Graham S. Grüschow S. Rouillon C. White M.F. A Type III CRISPR ancillary ribonuclease degrades its cyclic oligoadenylate activator.J. Mol. Biol. 2019; 431: 2894-2899Crossref PubMed Scopus (43) Google Scholar in the apo state, T. onnurineus Csm6 in apo- and cA4-bound states,12Jia N. Jones R. Yang G.L. Ouerfelli O. Patel D.J. CRISPR-Cas III-A Csm6 CARF domain is a ring nuclease triggering stepwise cA(4) cleavage with ApA>p formation terminating RNase activity.Mol. Cell. 2019; 75 (944–956.e6)Abstract Full Text Full Text PDF Scopus (58) Google Scholar Sulfolobus islandicus Csx1 bound to cA4,25Molina R. Stella S. Feng M.X. Sofos N. Jauniskis V. Pozdnyakova I. et al.Structure of Csx1-cOA(4) complex reveals the basis of RNA decay in type III-B CRISPR-Cas.Nat. Commun. 2019; 10: 4302Crossref PubMed Scopus (44) Google Scholar,26Molina R. Jensen A.L.G. Marchena-Hurtado J. López-Méndez B. Stella S. Montoya G. Structural basis of cyclic oligoadenylate degradation by ancillary type III CRISPR-Cas ring nucleases.Nucleic Acids Res. 2021; 49: 12577-12590Crossref PubMed Scopus (5) Google Scholar Enteroccocus italicus Csm6 bound to cA6,27Garcia-Doval C. Schwede F. Berk C. Rostøl J.T. Niewoehner O. Tejero O. Hall J. Marraffini L.A. Jinek M. Activation and self-inactivation mechanisms of the cyclic oligoadenylate-dependent CRISPR ribonuclease Csm6.Nat. Commun. 2020; 11: 1596Crossref PubMed Scopus (45) Google Scholar Pyroccocus furiosus Csx1 bound to cA428Foster K. Grüschow S. Bailey S. White M.F. Terns M.P. Regulation of the RNA and DNA nuclease activities required for Pyrococcus furiosus type III-B CRISPR-Cas immunity.Nucleic Acids Res. 2020; 48: 4418-4434Crossref PubMed Scopus (7) Google Scholar and Streptococcous theremophilus Csm6 bound to cA6.29Smalakyte D. Kazlauskiene M. F Havelund J. Rukšėnaitė A. Rimaite A. Tamulaitiene G. Færgeman N.J. Tamulaitis G. Siksnys V. Type III-A CRISPR-associated protein Csm6 degrades cyclic hexa-adenylate activator using both CARF and HEPN domains.Nucleic Acids Res. 2020; 48: 9204-9217Crossref PubMed Scopus (16) Google Scholar Despite these efforts, it remains unclear how binding of cO to the CARF domain allosterically activates the RNase activity of the HEPN domain, given the absence of pronounced ligand-mediated conformational changes in these systems. Key mechanistic insights have emerged from structural studies undertaken on T. onnurineus (To) Csm6 and S. islandicus (Si) Csx1 in the apo- and cA4-bound states. We first outline the results on SiCsx1 follows by results on ToCsm6. Dimeric SisCsx1 is composed of CARF and HEPN domains bridged by a HTH (helix-turn-helix) domain (Figure 2A). SiCsx1 adopts a hexameric fold composed of a trimer of dimers in both the apo- and cA4-bound states (Figure 2B).25Molina R. Stella S. Feng M.X. Sofos N. Jauniskis V. Pozdnyakova I. et al.Structure of Csx1-cOA(4) complex reveals the basis of RNA decay in type III-B CRISPR-Cas.Nat. Commun. 2019; 10: 4302Crossref PubMed Scopus (44) Google Scholar The cA4 binds to the CARF domain (Figure 2C and insert) of each dimer in the hexamer by adopting a range of conformations and triggers subtle allosteric conformational changes that are propagated via the HTH domain to the HEPN domain. The CARF domain of dimeric ToCsm6 composed of CARF and HEPN domains (Figure 2D) binds preferentially to cA4, with crystal structures determined in the apo- and cA4-bound states.12Jia N. Jones R. Yang G.L. Ouerfelli O. Patel D.J. CRISPR-Cas III-A Csm6 CARF domain is a ring nuclease triggering stepwise cA(4) cleavage with ApA>p formation terminating RNase activity.Mol. Cell. 2019; 75 (944–956.e6)Abstract Full Text Full Text PDF Scopus (58) Google Scholar ToCsm6 adopts a dimeric topology with cA4 bound within both the CARF and HEPN pockets under conditions where cA4 was diffused into crystals of apo-ToCsm6 (Figure 2E). The density is weak or missing at opposing phosphodiester linkages connecting A2-A3 and A4-A1 steps of cA4 bound within the CARF domain (insert, Figure 2E), indicative of intrinsic nuclease activity in the CARF pocket. Notably, no allosteric conformational change was detected in the HEPN domain fold on comparison of the apo- and cA4-bound structures of ToCsm6. By contrast, when cA4 was co-crystallized with ToCsm6, ApA>p was found to be bound in the CARF pocket, while AMP was bound in the HEPN pocket (Figure 2F and insert). These structural studies supplemented by cleavage assays demonstrate the unanticipated observation that the CARF domain of ToCsm6 is a ring nuclease triggering stepwise cA4 cleavage to first form linear ApApApA>p resulting from a single nick and subsequently to form ApA>p resulting from a second symmetrical nick. Significantly, cleavage assays demonstrate that ApA>p formation terminates the RNase activity of the HEPN domain, thereby using a unique timer mechanism to regulate HEPN-mediated cleavage activity in cis, thereby mitigating collateral damage.12Jia N. Jones R. Yang G.L. Ouerfelli O. Patel D.J. CRISPR-Cas III-A Csm6 CARF domain is a ring nuclease triggering stepwise cA(4) cleavage with ApA>p formation terminating RNase activity.Mol. Cell. 2019; 75 (944–956.e6)Abstract Full Text Full Text PDF Scopus (58) Google Scholar The ring nuclease activity of the CARF domain is governed by aligned Trp14 and His132 side chains (insert, Figure 2E), with the His playing an autoinhibitory role (increased cleavage activity observed for the His132Ala mutant) in controlling the RNase activity of the HEPN domain. It remains to be demonstrated whether cleavage of cA4 in the CARF pocket is mediated by general acid-base catalysis or rather reflects mediation by steric factors that force the cA4 to adopt a conformation compatible with in-line nucleophilic substitution.27Garcia-Doval C. Schwede F. Berk C. Rostøl J.T. Niewoehner O. Tejero O. Hall J. Marraffini L.A. Jinek M. Activation and self-inactivation mechanisms of the cyclic oligoadenylate-dependent CRISPR ribonuclease Csm6.Nat. Commun. 2020; 11: 1596Crossref PubMed Scopus (45) Google Scholar By contrast, the structure of bound cA4 within the HEPN pocket of ToCsm6 provides insights into His-mediated in-line cleavage of target RNA by the ToCsm6 nuclease (insert, Figure 2G).12Jia N. Jones R. Yang G.L. Ouerfelli O. Patel D.J. CRISPR-Cas III-A Csm6 CARF domain is a ring nuclease triggering stepwise cA(4) cleavage with ApA>p formation terminating RNase activity.Mol. Cell. 2019; 75 (944–956.e6)Abstract Full Text Full Text PDF Scopus (58) Google Scholar It should be noted that cA4 degradation by the CARF domain is significantly slower than ssRNA degradation by the HEPN domain, thereby maintaining the antiviral response over a longer time period. A schematic model of cA4-mediated allosteric activation mechanism of accessory Csm6 accessory nuclease is depicted in Figure 2H with an outline of individual steps explained in the figure caption (adapted with modifications from Garcia-Doval et al.27Garcia-Doval C. Schwede F. Berk C. Rostøl J.T. Niewoehner O. Tejero O. Hall J. Marraffini L.A. Jinek M. Activation and self-inactivation mechanisms of the cyclic oligoadenylate-dependent CRISPR ribonuclease Csm6.Nat. Commun. 2020; 11: 1596Crossref PubMed Scopus (45) Google Scholar). Both CARF- and HEPN-domain-containing dimeric Csm6 and Csx1 accessory nucleases associated with type III CRISPR-Cas immunity function as ribonucleases. By contrast, Thermus thermophilus (Tt) Can1 is a monomeric protein composed of tandem alignment of a pair of CARF and a pair of nuclease/nuclease-like domains (Figure 3A), which exhibited metal-dependent DNase activity.30McMahon S.A. Zhu W.L. Graham S. Rambo R. White M.F. Gloster T.M. Structure and mechanism of a type III CRISPR defence DNA nuclease activated by cyclic oligoadenylate.Nat. Commun. 2020; 11: 500Crossref PubMed Scopus (57) Google Scholar In the crystal structure of cA4-bound TtCan1 (Figure 3B), the cA4 was enveloped at the interface between the pair of CARF domains (insert, Figure 3B), while the two nuclease domains are positioned in close proximity for generation of a postulated DNA-binding surface containing DNA cleavage sites. The proposed model positioning dsDNA on cA4-bound TtCan1 will require structure-based experimental validation. Light scattering data are consistent with a large conformational change on complex formation that brings the CARF domains in close proximity to form the cA4-binding site. Notably, it was shown that TtCan1 is not a ring nuclease and that cA4-activated Can1 nicks supercoiled dsDNA at elevated temperatures. Recent studies have identified cA4-activated Treponema succinifaciens (Ts) Card1 accessory nuclease containing CARF and REase domains (Figure 3C) that exhibits dual cleavage activities through its ability to cleave both ssRNA and ssDNA,31Rostøl J.T. Xie W. Kuryavyi V. Maguin P. Kao K. Froom R. Patel D.J. Marraffini L.A. The Card1 nuclease provides defence during type III CRISPR immunity.Nature. 2021; 590: 624-629Crossref PubMed Scopus (41) Google Scholar with the same system also independently investigated under the name Can2 from Sulfobacillus thermosulfidooxidans (Sts).32Zhu W.L. McQuarrie S. Grüschow S. McMahon S.A. Graham S. Gloster T.M. White M.F. The CRISPR ancillary effector Can2 is a dual-specificity nuclease potentiating type III CRISPR defence.Nucleic Acids Res. 2021; 49: 2777-2789Crossref PubMed Scopus (21) Google Scholar Crystal structures have been reported for apo- (Figure 3D) and cA4-bound (Figure 3E) TsCard1, highlighting a large cavity between the CARF and REase domains within the dimeric topology in the apo state. There is a large conformational change propagated to the REase domain upon cA4 binding to the CARF domain (compare Figures 3D with 3E), whereby individual monomers rotate relative to each other to form a more compact scaffold in which a Mn cation is coordinated to catalytic residues within the REase pocket.31Rostøl J.T. Xie W. Kuryavyi V. Maguin P. Kao K. Froom R. Patel D.J. Marraffini L.A. The Card1 nuclease provides defence during type III CRISPR immunity.Nature. 2021; 590: 624-629Crossref PubMed Scopus (41) Google Scholar The bound cA4 is embedded deep within its CARF domain pocket and anchored in place through adenosine-specific hydrogen bond formation (Figure 3F). The REase pocket of cA4-bound TsCard1 cleaves ssRNA faster than ssDNA,31Rostøl J.T. Xie W. Kuryavyi V. Maguin P. Kao K. Froom R. Patel D.J. Marraffini L.A. The Card1 nuclease provides defence during type III CRISPR immunity.Nature. 2021; 590: 624-629Crossref PubMed Scopus (41) Google Scholar but the mechanistic basis for this relative difference remains unknown, given that structures are unavailable of cA4-bound Card1 with ssRNA or ssDNA bound within the REase pocket. Though TtCan1 and TsCard1/StsCan2 are not ring nucleases, differences of opinion remain regarding their nuclease activities. Thus, while TsCard1 was unable to cleave supercoiled or linearized dsDNA at ambient temperature,31Rostøl J.T. Xie W. Kuryavyi V. Maguin P. Kao K. Froom R. Patel D.J. Marraffini L.A. The Card1 nuclease provides defence during type III CRISPR immunity.Nature. 2021; 590: 624-629Crossref PubMed Scopus (41) Google Scholar StsCan2 nicked supercoiled dsDNA at elevated, but not ambient, temperatures.32Zhu W.L. McQuarrie S. Grüschow S. McMahon S.A. Graham S. Gloster T.M. White M.F. The CRISPR ancillary effector Can2 is a dual-specificity nuclease potentiating type III CRISPR defence.Nucleic Acids Res. 2021; 49: 2777-2789Crossref PubMed Scopus (21) Google Scholar Notably, structural studies on TsCard1 were complemented by in vivo studies, where it was shown that activation of TsCard1 induces dormancy of the infected hosts to provide immunity against plasmids and phage infection.31Rostøl J.T. Xie W. Kuryavyi V. Maguin P. Kao K. Froom R. Patel D.J. Marraffini L.A. The Card1 nuclease provides defence during type III CRISPR immunity.Nature. 2021; 590: 624-629Crossref PubMed Scopus (41) Google Scholar The cO second messenger can also be degraded by trans-acting ring nucleases composed solely of a dimeric CARF domain.33Athukoralage J.S. Rouillon C. Graham S. Grüschow S. White M.F. Ring nucleases deactivate type III CRISPR ribonucleases by degrading cyclic oligoadenylate.Nature. 2018; 562: 277-280Crossref PubMed Scopus (75) Google Scholar Thus, it has been demonstrated that the dimeric CARF domain of Sulfolobus solfataricus Crn1 degrades cA4 to ApA>p using a metal-independent mechanism with a single turnover rate constant of 0.23 min−1, thereby deactivating the accessory ribonuclease Csx1 in trans and switching off the antiviral state. Archaeoglobus fulgidus (Af) Csx3 is another trans-acting ring nuclease, which cleaves cA4 in a Mn2+-dependent manner.34Athukoralage J.S. McQuarrie S. Grüschow S. Graham S. Gloster T.M. White M.F. Tetramerisation of the CRISPR ring nuclease Crn3/Csx3 facilitates cyclic oligoadenylate cleavage.eLife. 2020; 9 (e5762710)Crossref Scopus (15) Google Scholar Structural studies of cA4 bound to the AfCx3 dimer (Figure 3G) revealed a head-to-tail filament topology with cA4 bound between adjacent dimers (Figure 3H) in a pocket containing His and Arg residues (Figure 3I). Additional ring nucleases are anticipated based on evolutionary and functional classification of the CARF domain superfamily.22Makarova K.S. Timinskas A. Wolf Y.I. Gussow A.B. Siksnys V. Venclovas Č. Koonin E.V. Evolutionary and functional classification of the CARF domain superfamily, key sensors in prokaryotic antivirus defense.Nucleic Acids Res. 2020; 48: 8828-8847Crossref PubMed Scopus (40) Google Scholar Expanding on the above, additional studies identified a metal-independent viral ring nuclease AcrIII-1, with this anti-CRISPR protein found to be widely distributed in archaeal and bacterial viruses, as well as proviruses, where it rapidly degrades cA4 to ApA>p.35Athukoralage J.S. McMahon S.A. Zhang C.Y. Grüschow S. Graham S. Krupovic M. Whitaker R.J. Gloster T.M. White M.F. An anti-CRISPR viral ring nuclease subverts type III CRISPR immunity.Nature. 2020; 577: 572-575Crossref PubMed Scopus (86) Google Scholar Crystal structures have been reported for AcrIII-1 in the apo- and cA4-bound (Figure 3J) states, thereby identifying conformational changes of the dimeric topology on complex formation (see black arrows, Figure 3K), with the bound cA4 completely encapsulated by loop-closing elements at the dimeric interface (insert, Figure 3J). Notably, a key histidine in the cA4-binding pocket (insert, Figure 3J) contributes to the catalytic cleavage rate of AcrIII-1, which exceeds 5 per min, a factor of 60-fold faster than observed for Crn1. In conclusion, second messengers such as cA4 ca" @default.
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• W4310522711 date "2022-12-01" @default.
• W4310522711 modified "2023-10-03" @default.
• W4310522711 title "Bacterial origins of cyclic nucleotide-activated antiviral immune signaling" @default.
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• W4310522711 doi "https://doi.org/10.1016/j.molcel.2022.11.006" @default.

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