Pathogenicity and Virulence ofLegionella: Intracellular replication and host response

Virulence, Journal Year: 2021, Volume and Issue: 12(1), P. 1122 - 1144

Published: April 12, 2021

Bacteria of the genus Legionella are natural pathogens amoebae that can cause a severe pneumonia in humans called Legionnaires' Disease. Human disease results from inhalation Legionella-contaminated aerosols and subsequent bacterial replication within alveolar macrophages. pathogenicity has resulted extensive co-evolution with diverse genera amoebae. To replicate intracellularly, generates replication-permissive compartment Legionella-containing vacuole (LCV) through concerted action hundreds Dot/Icm-translocated effector proteins. In this review, we present collective overview including infection mechanisms, secretion systems, translocated function. We also discuss innate adaptive immune responses to L. pneumophila, implications genome diversity future avenues for field.

Language: Английский

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Deubiquitination of phosphoribosyl-ubiquitin conjugates by phosphodiesterase-domain–containingLegionellaeffectors

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(47), P. 23518 - 23526

Published: Nov. 5, 2019

Posttranslational protein modification by ubiquitin (Ub) is a central eukaryotic mechanism that regulates plethora of physiological processes. Recent studies unveiled an unconventional type ubiquitination mediated the SidE family Legionella pneumophila effectors, such as SdeA, catalyzes conjugation Ub to serine residue target proteins via phosphoribosyl linker (hence named PR-ubiquitination). Comparable deubiquitinases in canonical pathway, here we show 2 paralogous Lpg2154 (DupA; deubiquitinase for PR-ubiquitination) and Lpg2509 (DupB), reverse PR-ubiquitination specific removal phosphoribosyl-Ub from substrates. Both DupA DupB are fully capable rescuing Golgi fragmentation phenotype caused exogenous expression SdeA mammalian cells. We further deletion these genes results significant accumulation PR-ubiquitinated species host cells infected with In addition, have identified list targets play role modulating association Legionella-containing vacuoles. Together, our data establish complete deubiquitination cycle demonstrate intricate control has over this unusual Ub-dependent posttranslational modification.

Language: Английский

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There’s more to death than life: Noncatalytic functions in kinase and pseudokinase signaling

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 296, P. 100705 - 100705

Published: Jan. 1, 2021

Protein kinases are present in all domains of life and play diverse roles cellular signaling. Whereas the impact substrate phosphorylation by protein has long been appreciated, it is becoming increasingly clear that also other, noncatalytic, functions. Here, we review recent developments understanding noncatalytic functions kinases. Many activities best exemplified devoid enzymatic activity altogether—known as pseudokinases. These dead proteins illustrate that, beyond conventional notions kinase function, catalytic can be dispensable for biological function. Through key examples mechanisms activity: allosteric modulators; protein-based switches; scaffolds complex assembly; competitive inhibitors signaling pathways. In common, these exploit nature fold a versatile protein–protein interaction module. intrinsically linked to ability switch between multiple states, function shared with Finally, consider contemporary landscape small molecules modulate kinases, which, although challenging, significant potential given scope health disease. quintessential proteins. Their posttranslationally modify amino acid side chains phosphoryl group underlies broad swath eukaryotic biology (1Hardman G. Perkins S. Brownridge P.J. Clarke C.J. Byrne D.P. Campbell A.E. Kalyuzhnyy A. Myall Eyers P.A. Jones A.R. C.E. Strong anion exchange-mediated phosphoproteomics reveals extensive human non-canonical phosphorylation.EMBO J. 2019; 38e100847Crossref PubMed Scopus (31) Google Scholar) regulates addition catalyzing transfer, roles, interacting other modifying their activity. A proportion even take extreme—lacking phosphoryl-transfer completely—and known pseudokinases (2Manning Whyte D.B. Martinez R. Hunter T. Sudarsanam The complement genome.Science. 2002; 298: 1912-1934Crossref (5717) Scholar, 3Zeqiraj E. van Aalten D.M.F. Pseudokinases-remnants evolution or regulators?.Curr. Opin. Struct. Biol. 2010; 20: 772-781Crossref (102) 4Eyers Murphy J.M. Dawn dead: signal new adventures cell biology.Biochem. Soc. Trans. 2013; 41: 969-974Crossref (60) Scholar). Originally thought evolutionary remnants, have since revealed remarkably pathways (5Jacobsen A.V. secret kinases: Insights into non-catalytic signalling from pseudokinases.Biochem. 2017; 45: 665-681Crossref (41) Importantly, zombie provide window often unheralded, nonenzymatic performed alive enzyme counterparts. Catalytically competent diverse, but means folds similar core elements show little variation (Fig. 1A). catalysis bind ATP, coordinate Mg2+, catalyze transfer. generally consist of: lysine residue within VAIK motif N-terminal lobe, glycine rich loop (Gly-loop), which features enabling ATP binding; an aspartate DFG-motif activation coordinates magnesium alongside ATP; HRD contributed C-terminal acts base during transfer 1B; 6Hanks S.K. Quinn A.M. family: Conserved deduced phylogeny domains.Science. 1988; 241: 42-52Crossref Scholar)). Any, multiple, lost (7Kung J.E. Jura N. Prospects pharmacological targeting pseudokinases.Nat. Rev. Drug Discov. 18: 501-526Crossref (28) 8Kwon Scott Taujale Yeung W. Kochut K.J. Kannan Tracing origin across tree life.Sci. Signal. 12eaav3810Crossref 9Murphy Zhang Q. Young S.N. Reese M.L. Bailey F.P. Ungureanu D. Hammarén H. Silvennoinen O. Varghese L.N. Chen K. Tripaydonis Fukuda Qin et al.A robust methodology subclassify based on nucleotide-binding properties.Biochem. 2014; 457: 323-334Crossref (0) Depending what lost, may unable nucleotides (Class I), not cations II), only III), both cations, still carry out IV) 1C) (9Murphy Analyses coding genes archaea, bacteria, eukaryotes identified pseudokinases, (8Kwon This focuses fold, predicted low abundance archaea bacteria (10Childers W.S. Shapiro L. pseudokinase couples enable asymmetric division bacterium.Microb. Cell. 2: 29-32Crossref 11Gee C.L. Papavinasasundaram K.G. Blair S.R. Baer Falick King D.S. Griffin Venghatakrishnan Zukauskas Wei J.-R. Dhiman R.K. Crick D.C. Rubin E.J. Sassetti C.M. Alber phosphorylated controls wall synthesis mycobacteria.Sci. 2012; 5ra7Crossref Scholar), our more broadly prokaryotes emerging (12Kannan Taylor S.S. Zhai Y. Venter J.C. Manning Structural functional diversity microbial kinome.PLoS 2007; 5e17Crossref (195) 13Pérez Castañeda-García Jenke-Kodama Müller Muñoz-Dorado Eukaryotic-like myxobacterial kinome.Proc. Natl. Acad. Sci. U. 2008; 105: 15950-15955Crossref (83) proteome contain approximately 550 10% retained vertebrates, ∼10% kinomes designated 14Caenepeel Charydczak mouse kinome: Discovery comparative genomics kinases.Proc. 2004; 101: 11707-11712Crossref (237) More broadly, some species expanded complements. For instance, plants frequently comprise up ∼17% half kinase-like selected protists (Toxoplasma gondii Giardia lamblia) lack essential residues Such expansion concentrated specific classes example, undergone massive likely due important role innate immunity (15Jubic L.M. Saile Furzer O.J. El Kasmi F. Dangl J.L. Help wanted: Helper NLRs plant immune responses.Curr. Plant 50: 82-94Crossref (53) scale current analyses most classification sequence-based rather than experimentally verified. While computational approaches enlightening, several pertinent demonstrate need couple experimental characterization. seemingly degraded sequences nonetheless retain phosphorylate biomolecules (16Beraki Hu X. Broncel M. O'Shaughnessy W.J. Borek Treeck Divergent membrane ultrastructure Toxoplasma parasitophorous vacuole.Proc. 116: 6361-6370Crossref 17Zhu Venzke Walimbe A.S. Anderson M.E. Fu Kinch Wang Grishin N.V. Huang Yu Dixon K.P. Xiao Structure O-mannose unique active site architecture.Elife. 2016; 5e22238Crossref (19) 18Yoshida-Moriguchi Willer Muntoni Lee Nelson S.F. SGK196 glycosylation-specific required dystroglycan function.Science. 341: 896-899Crossref (139) 19Lopez V.A. Park B.C. Nowak Sreelatha Zembek P. Fernandez Servage K.A. Gradowski Hennig Tomchick D.R. Pawłowski Krzymowska Tagliabracci V.S. bacterial effector mimics host HSP90 client undermine immunity.Cell. 179: 205-218.e21Abstract Full Text PDF completely unanticipated distinct (20Black M.H. Osinski Bacterial catalyzes polyglutamylation inhibit SidE-family ubiquitin ligases.Science. 364: 787-792Crossref 21Sulpizio Minelli Wan Burrowes P.D. Wu Sanford Shin J.-H. Williams Goldberg Smolka M.B. Mao catalyzed calmodulin-dependent SidJ.Elife. 8e51162Crossref 22Bhogaraju Bonn Mukherjee Adams Pfleiderer M.M. Galej W.P. Matkovic V. Lopez-Mosqueda Kalayil Dikic I. Inhibition ligases SidJ-calmodulin catalysed glutamylation.Nature. 572: 382-386Crossref (34) 23Sreelatha Yee Lopez Pilch Jiou Karasiewicz-Urbańska Łobocka Orth Kucharczyk al.Protein AMPylation evolutionarily conserved pseudokinase.Cell. 2018; 175: 809-821.e19Abstract (54) Nonetheless, coupled bioinformatic will continued insight played throughout evolution. Pseudokinases led realization catalytically inactive enzymes (pseudoenzymes) almost facets (24Ribeiro A.J.M. Das Dawson Zaru Orchard Thornton Orengo C. Zeqiraj Emerging concepts pseudoenzyme classification, evolution, signaling.Sci. 12eaat9797Crossref (32) Across families kingdoms life, regulate processes through number different 25Murphy Mace Live let die: structure.Curr. 47: 95-104Crossref 26Murphy Farhan Bio-zombie: rise pseudoenzymes 537-544Crossref (47) Pseudoenzymes include pseudo-phosphatases, pseudoproteases, pseudoGTPases, among others. Broadly speaking, as: activators, inhibitors, assembly complexes, switches 2; (25Murphy Examples each categories regulatory surfaces evolved repurposed toward alternative versions same eschewed evolve Thus, while this does mean they nonfunctional. It note pseudogenes. Pseudogenes refer incomplete DNA lacking elements, whereas translated encoded genes. focus illustrative at molecular level. Because definition many clearest regulation pseudoenzymes. Noncatalytic particularly switches, because architecture domain encodes on- off-states. conformations though elements. activity, simultaneously scaffolds, activators. when freed constraints retaining elaborate develop novel enzymes. Accordingly, offer exemplars additional, unrecognized might conventional, enzymes—in keeping idea least case enzymes, there death life. One best-characterized modulation cognate either promoting attenuating binding partners. arisen gene duplication events, pathway partners owing common expression patterns subcellular localization, noted previously (26Murphy 27Adrain Freeman New lives old: Evolution illustrated iRhoms.Nat. Mol. Cell 13: 489-498Crossref 28Pils B. Schultz Inactive enzyme-homologues find processes.J. 340: 399-404Crossref (109) duplications bring enormous liberty; redundancy arises duplication, no necessity maintain geometry mediate striking Janus Kinase (JAK) family, where (termed JH2) occurs tandem, tyrosine JH1) attenuates its trans receptor-scaffolded dimers (29Brooks A.J. Dai O'Mara Abankwa Chhabra Pelekanos R.A. Gardon Tunny Blucher K.M. Morton Parker M.W. Sierecki Gambin Gomez G.A. Alexandrov al.Mechanism JAK2 growth hormone receptor.Science. 344: 1249783Crossref (231) 30Varghese Liau N.P.D. Laktyushin Lucet I.S. Nicola N.A. Babon J.J. Mechanistic insights SOCS3-mediated inhibition myeloproliferative neoplasm-associated mutants biochemical structural analyses.Biochem. 458: 395-405Crossref 31Babon activation.Biochem. 462: 1-13Crossref (143) mechanism debated (31Babon was clearly discovery activating mutations (32James Ugo Le Couédic J.-P. Staerk Delhommeau Lacout Garçon Raslova Berger Bennaceur-Griscelli Villeval Constantinescu Casadevall Vainchenker clonal mutation leading constitutive causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref (2692) promote induce hematopoietic malignancies. ancestors, pseudoactive sites do nucleotide, diminish loops, adopt discordant Any modifications allosterically. Via intermolecular interactions, able position element, αC helix N-lobe partner kinase. Several modes dimerization reported influence helix, illuminated detailed studies, highlight versatility 3; (33Lavoie Li Thevakumaran Therrien Sicheri Dimerization-induced allostery regulation.Trends Biochem. 39: 475-486Abstract 34Oliver M.R. Horne C.R. Shrestha Keown J.R. Liang L.-Y. Sandow Webb A.I. Goldstone Metcalf Granulovirus PK-1 relies side-to-side mode centered helix.Nat. Commun. 2021; 12: 1002Crossref (1) 35Horne whom bell tolls: structure kinase, IRAK3.Structure. 29: 197-199Abstract domain, including: back-to-back (as observed Ire1 RNase L homodimers (36Lee K.P.K. Dey Neculai Cao Dever T.E. dual basis nonconventional RNA splicing.Cell. 132: 89-100Abstract (238) 37Huang Dong Jha B.K. Duffy N.M. Orlicky Talukdar Pillon M.C. Ceccarelli D.F. L.C.K. Juang Y.-C. D.Y.L. Gaughan Brinton M.A. al.Dimeric bound 2-5A interferon-induced antiviral activity.Mol. 53: 221-234Abstract head-to-tail EGFR family proteins, such HER3 pseudokinase:EGFR (38Littlefield Liu Mysore Shan Shaw D.E. analysis EGFR/HER3 heterodimer mutations.Sci. 7ra114Crossref Scholar)), head-to-head found IRAK3 proposed pseudokinase:IRAK4 pairs (39Lange S.M. Nelen M.I. Cohen Kulathu Dimeric suggests negative regulation.Structure. 238-251.e4Abstract antiparallel (exemplified RAF:RAF KSR pseudokinase:RAF heterodimers (40Hu Stites E.C. Germino E.A. Meharena H.S. Stork P.J.S. Kornev A.P. Allosteric functionally RAF dimers.Cell. 154: 1036-1046Abstract (162) 41Hatzivassiliou Song Yen Brandhuber B.J. D.J. Alvarado Ludlam M.J.C. Stokoe Gloor S.L. Vigers Morales Aliagas Sideris Hoeflich al.RAF prime wild-type activate MAPK enhance growth.Nature. 464: 431-435Crossref (1177) 42Rajakulendran Sahmi Lefrançois dimerization-dependent drives activation.Nature. 2009; 461: 542-545Crossref Scholar)) modes. studies raise possibility exert those exerted recently parallel homodimerization granuloviral (34Oliver yet pseudokinase:kinase pairs, occupying synonymous Furthermore, currently poorly understood, allosterically nonkinase VRK3 to, of, VHR phosphatase (43Scheeff E.D. Eswaran Bunkóczi Knapp site, highly putative site.Structure. 17: 128-138Abstract (127) 44Kang T.-H. Kim K.-T. Negative ERK VRK3-mediated phosphatase.Nat. 2006; 8: 863-869Crossref (64) Overall, findings breadth mediated suggest underappreciated generally. Deducing precise remains major challenge. rely elegant chemical knockin approaches, deletion knockdown, reveal Over past 30 years, crystal structures captured N- C-lobes loop, pillars hydrophobic networks spines) continuum conformations, illustrating intrinsic dynamicity (45Kornev Dynamics-driven kinases.Trends 2015; 40: 628-647Abstract (136) 46Taylor dynamic proteins.Trends 2011; 36: 65-77Abstract (517) 47Modi Dunbrack Jr., R.L. Defining nomenclature 6818-6827Crossref flexibility associated Basally, apoenzyme exist uncommitted state until binding, galvanizes protein's internal poises catalysis. effectors oligomerization adoption conformation signified intact (R)-spine Glu engaged salt bridge β3-strand Lys However, if, range accessible reflect propensity serve switches? Recent via interactions. Consequently, attractive hypothesis interactions could governed pseudokinase, additionally, regulated posttranslational modifications. concept being employed Mixed Lineage domain-Like (MLKL) pseudokinase. Unlike solely thus interpretation conformational effects confounded additional MLKL terminal necroptosis pathway, lytic modality unlike cousin apoptosis, proteolytic Caspases (reviewed (48Samson A.L. Garnish S.E. Hildebrand Location, location, location: compartmentalized view TNF-induced necroptotic 14eabc6178Crossref (3) Instead, following insult, inflammatory receptor pathogen sensors, leads receptor-interacting kinase-3 (RIPK3) autophosphorylation (49Meng Czabotar P.E. post-translational modifications.Cell Death Differ. 28: 861-883Crossref (2) Activated RIPK3 then substrate, MLKL, ac

Language: Английский

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A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling

Cell, Journal Year: 2022, Volume and Issue: 185(13), P. 2354 - 2369.e17

Published: May 13, 2022

Interferons (IFNs) induce an antimicrobial state, protecting tissues from infection. Many viruses inhibit IFN signaling, but whether bacterial pathogens evade responses remains unclear. Here, we demonstrate that the Shigella OspC family of type-III-secreted effectors blocks signaling independently its cell death inhibitory activity. Rather, inhibition was mediated by binding OspC1 and OspC3 to Ca2+ sensor calmodulin (CaM), blocking CaM kinase II downstream JAK/STAT signaling. The growth lacking attenuated in epithelial cells a murine model This phenotype rescued both models depletion receptors. homologs conserved additional not only bound also inhibited IFN, suggesting widespread virulence strategy. These findings reveal previously undescribed molecular mechanism critical role targeting pathogenesis.

Language: Английский

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Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

mBio, Journal Year: 2020, Volume and Issue: 11(5)

Published: Oct. 5, 2020

Through coevolution with host cells, microorganisms have acquired mechanisms to avoid the detection by surveillance system and use cell’s supplies establish themselves. Indeed, certain pathogens evolved proteins that imitate specific eukaryotic cell proteins, allowing them manipulate pathways, a phenomenon termed molecular mimicry. Bacterial “eukaryotic-like proteins” are remarkable example of They defined as strongly resemble or carry domains predominantly present in eukaryotes generally absent from prokaryotes.

Language: Английский

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Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Nov. 2, 2020

Legionella pneumophila extensively modulates the host ubiquitin network to create Legionella-containing vacuole (LCV) for its replication. Many of virulence factors function as ligases or deubiquitinases (DUBs). Here, we identify Lem27 a DUB that displays preference diubiquitin formed by K6, K11, K48. is associated with LCV where it regulates Rab10 ubiquitination in concert SidC and SdcA, two bacterial E3 ligases. Structural analysis complex an active fragment substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals harbors fold resembling those OTU1 subfamily Cys-His catalytic dyad recognizes via extensive hydrogen bonding at six contact sites. Our results establish functions regulate protein on L. phagosomes counteracting activity

Language: Английский

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ADP-ribosylation systems in bacteria and viruses

Computational and Structural Biotechnology Journal, Journal Year: 2021, Volume and Issue: 19, P. 2366 - 2383

Published: Jan. 1, 2021

ADP-ribosylation is an ancient posttranslational modification present in all kingdoms of life. The system likely originated bacteria where it functions inter- and intra-species conflict, stress response pathogenicity. It was repeatedly adopted via lateral transfer by eukaryotes, including humans, has a pivotal role epigenetics, DNA-damage repair, apoptosis, other crucial pathways the immune to pathogenic viruses. In words, same ammunition used pathogens adapted eukaryotes fight back. While we know quite lot about eukaryotic system, expanding rather patchy knowledge on bacterial viral would give us not only better understanding as whole but fighting advantage this constant arms race. By writing review hope put into focus available information perspective how works can be exploited search for therapeutic targets future. relevance subject especially highlighted current situation being amid world pandemic caused virus harbouring dependent representative such system.

Language: Английский

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The Legionella pneumophila Dot/Icm type IV secretion system and its effectors

Microbiology, Journal Year: 2022, Volume and Issue: 168(5)

Published: May 23, 2022

To prevail in the interaction with eukaryotic hosts, many bacterial pathogens use protein secretion systems to release virulence factors at host–pathogen interface and/or deliver them directly into host cells. An outstanding example of complexity and sophistication diversity their substrates, effectors, is Defective organelle trafficking/Intracellular multiplication (Dot/Icm) Type IVB system (T4BSS) Legionella pneumophila related species. species are facultative intracellular environmental protozoa opportunistic human respiratory pathogens. The Dot/Icm T4BSS translocates an exceptionally large number more than 300 per L. strain, essential for evasion phagolysosomal degradation exploitation macrophages as replicative niches. Recent technological advancements imaging complexes have provided new insight architecture allowed us propose models transport mechanism. At same time, significant progress has been made assigning functions about a third discovering unprecedented enzymatic activities concepts subversion. In this review, we describe current knowledge workings machinery provide overview to-date characterized effectors

Language: Английский

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Ubiquitin‐targeted bacterial effectors: rule breakers of the ubiquitin system

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(18)

Published: Aug. 9, 2023

Language: Английский

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The Legionella Effector SdjA Is a Bifunctional Enzyme That Distinctly Regulates Phosphoribosyl Ubiquitination

mBio, Journal Year: 2021, Volume and Issue: 12(5)

Published: Sept. 7, 2021

Legionella pneumophila promotes its survival and replication in phagocytes by actively modulating cellular processes using effectors injected into host cells Dot/Icm type IV secretion system. Many of these function to manipulate the ubiquitin network infected cells, thus contributing biogenesis Legionella-containing vacuole (LCV), which is permissive for bacterial replication. Among these, members SidE effector family (SidEs) catalyze ubiquitination functionally diverse proteins a mechanism that chemically distinct from canonical three-enzyme cascade. The activity SidEs regulated two mechanisms: reversal phosphoribosyl DupA DupB direct inactivation SidJ, calmodulin-dependent glutamylase. In many L. strains, SidJ belongs two-member protein family. Its homolog SdjA appears differently despite high-level similarity their primary sequences. Here, we found bifunctional enzyme exhibits activities toward It inhibits SdeB SdeC glutamylation. Unexpectedly, it also functions as deglutamylase reverses SidJ-induced glutamylation on SdeA. Our results reveal an can completely opposite biochemical reactions, highlights regulation IMPORTANCE One unique feature existence families with similarity. Whereas some are redundant, suggested sequences, relationship between SdjA, family, has remained mysterious. Despite sharing 57% identity, sdjA cannot complement defects virulence displayed mutant lacking sidJ. calmodulin (CaM)-dependent glutamylase activity. dual protein: CaM-dependent against but SdeA been modified indicating fine-tune SidEs. These findings have paved way future structural functional analysis may novel isopeptide bond cleavage provide insights study evolution.

Language: Английский

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