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fredag 12 oktober 2018

NOD2 (NLR ) ja TRIM27 interaktio (Chronin tauti) . TLR ja NLR: hahmontunnistusreseptorien tärkeydestä.

PLoS One. 2012;7(7):e41255. doi: 10.1371/journal.pone.0041255. Epub 2012 Jul 19.

TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation.

Abstract

NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohn's disease.
We found that TRIM27 expression is increased in Crohn's disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus.We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases.
  • PMID:22829933
  • PMCID:PMC3400628
  • DOI:10.1371/journal.pone.0041255
  • [Indexed for MEDLINE]Free PMC Article
  • Toinen haku: NOD2 ja Legionella?  6 vastausta. Sitaatti.

    https://www.ncbi.nlm.nih.gov/pubmed/?term=Legionella%2C+NOD2

    Zhen Q, Cao X, Lu J, Yang Z.
    Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2018 Jun;34(6):488-494. Chinese.PMID: 30236199
    2.
    Liu M, Haenssler E, Uehara T, Losick VP, Park JT, Isberg RR.
    Cell Host Microbe. 2012 Aug 16;12(2):166-76. doi: 10.1016/j.chom.2012.06.004. PMID:22901537Successful pathogens have evolved to evade innate immune recognition of microbial molecules by pattern recognition receptors (PRR), which control microbial growth in host tissues. Upon Legionella pneumophila infection of macrophages, the cytosolic PRR Nod1 recognizes anhydro-disaccharide-tetrapeptide (anhDSTP) generated by soluble lytic transglycosylase (SltL), the predominant bacterial peptidoglycan degrading enzyme, to activate NF-κB-dependent innate immune responses. We show that L. pneumophila periplasmic protein EnhC, which is uniquely required for bacterial replication within macrophages, interferes with SltL to lower anhDSTP production. L. pneumophila mutant strains lacking EnhC (ΔenhC) increase Nod1-dependent NF-κB activation in host cells, while reducing SltL activity in a ΔenhC strain restores intracellular bacterial growth. Further, L. pneumophila ΔenhC is specifically rescued in Nod1- but not Nod2-deficient macrophages, arguing that EnhC facilitates evasion from Nod1 recognition. These results indicate that a bacterial pathogen regulates peptidoglycan degradation to control the production of PRR ligands and evade innate immune recognition.
    3.
    Berrington WR, Iyer R, Wells RD, Smith KD, Skerrett SJ, Hawn TR.
    Eur J Immunol. 2010 Dec;40(12):3519-27. doi: 10.1002/eji.201040518. Epub 2010 Nov 11.PMID:21108472   Together, our data suggest that although both NOD1 and NOD2 can detect Legionella, these receptors modulate the in vivo pulmonary immune response differently.
    4.
    Frutuoso MS, Hori JI, Pereira MS, Junior DS, Sônego F, Kobayashi KS, Flavell RA, Cunha FQ, Zamboni DS.
    Microbes Infect. 2010 Oct;12(11):819-27. doi: 10.1016/j.micinf.2010.05.006. Epub 2010 Jun 2.PMID:20685341

    5. TLR , NLR:  koordinoivaa yhteistyötä mikrobien erottelussa.
     
    Shin S, Case CL, Archer KA, Nogueira CV, Kobayashi KS, Flavell RA, Roy CR, Zamboni DS.
    PLoS Pathog. 2008 Nov;4(11):e1000220. doi: 10.1371/journal.ppat.1000220. Epub 2008 Nov 28.PMID:19043549

    Käännös: 
    Immuunijärjestelmän on pystyttävä tekemään ero ( eli diskriminaatio)  patogeenisten ja ei-patogeenisten mikrobien välillä. Toll-reseptorien kaltaiset reseptorit (TLR) havaitsevat  mikrobiaalisia komponentteja (hahmoja)  sekä patogeenisistä että ei-patogeenisistä bakteereista. Sen sijaan NOD- reseptorien kaltaiset reseptorit (NLR) aistivat isäntäsolun sytosoliin  johtuneita mikrobiaalisia komponentteja, joita mikrobit pystyvät  johtamaan erikoistuneella eritesysteemillään tai  reikiä tekevillä myrkyillään ( toksiineilla). Aimmein ei ole  oikein hyvin  ymmärretty niitä signaaliteitä, joilla isäntäsolu vastaa  bakteerien eritejärjestelmiin.  Tässä käsitellään Legionellaa: 
     Patogeeninen Legionella pneumophila-bakteeri hyödyntää  T4SS- nimistä  eritesysteemiä ( tyypin 4 eritysjärjestelmä')  ja vertailtaessa apatogeeniin ( ei-patogeeniseen)  bakteeriin, jolla ei ole T4SS -järjestelmää, on havaittu, että patogeeninen Legionella  indusoi (sai  aikaan)  lisääntyneen  proinflammatorisen vasteen. 
    Lisääntyneessä tulehduksellisessa  vasteessa li kysymys  NF-kB-aktivoitumisesta  TLR signaloinnista  ja  myös  NOD1:n  ja NOD2:n havaitsemasta T4SS erityksestä.
     Lisäksi havaittiin, että  isäntasolujen vasteessa  virulentille  Legionella pneumofilalle  oli  yhta suurta merkitystä  TLR- ja RIP-2 - teistä riippumattomalla  signaalitiellä, joka myös  johtaa  p38 ja SAPK/JNK MAPK-aktivaatioon . Tämä  MAPK-aktivaatio oli riippuvainen T4SS  sekreetiosysteemistä  ja se  koordinoitui   TLR- signaloinnin kanssa saaden aikaan  L. pneumphilaa kohtaan  proinflammatoristen  sytokiinien vankkaa vastetta. 
    Nämä löydöt  määrittävät aiemmin karakterisoimattoman isäntäsolu vasteen bakteeriperäiselle  T4SS sekreetiojärjestelmälle, josta MAPK signalointi aktivoituu. Näillä löydöillä  osoitetaan, että solun tekemät monien bakteerikomponenttien  samanaikaishavaitsemiset ( simultaanitunnistukset) mahdollistavat immuunidiskriminaation  virulenttein ja ei-virulenttein bakteerien välillä.
    • The immune system must discriminate between pathogenic and nonpathogenic microbes in order to initiate an appropriate response. Toll-like receptors (TLRs) detect microbial components common to both pathogenic and nonpathogenic bacteria, whereas Nod-like receptors (NLRs) sense microbial components introduced into the host cytosol by the specialized secretion systems or pore-forming toxins of bacterial pathogens. The host signaling pathways that respond to bacterial secretion systems remain poorly understood. Infection with the pathogen Legionella pneumophila, which utilizes a type IV secretion system (T4SS), induced an increased proinflammatory cytokine response compared to avirulent bacteria in which the T4SS was inactivated. 
    • This enhanced response involved NF-kappaB activation by TLR signaling as well as Nod1 and Nod2 detection of type IV secretion. 
    • Furthermore, a TLR- and RIP2-independent pathway leading to p38 and SAPK/JNK MAPK activation was found to play an equally important role in the host response to virulent L. pneumophila. 
    • Activation of this MAPK pathway was T4SS-dependent and coordinated with TLR signaling to mount a robust proinflammatory cytokine response to virulent L. pneumophila. 
    • These findings define a previously uncharacterized host response to bacterial type IV secretion that activates MAPK signaling and demonstrate that coincident detection of multiple bacterial components enables immune discrimination between virulent and avirulent bacteria.
    6.
    Inohara, Chamaillard, McDonald C, Nuñez G.

     https://www.ncbi.nlm.nih.gov/pubmed/15952891Abstract

    Nods are cytosolic proteins that contain a nucleotide-binding oligomerization domain (NOD). These proteins include key regulators of apoptosis and pathogen resistance in mammals and plants. A large number of Nods contain leucine-rich repeats (LRRs), hence referred to as NOD-LRR proteins. Genetic variation in several NOD-LRR proteins, including human Nod2, Cryopyrin, and CIITA, as well as mouse Naip5, is associated with inflammatory disease or increased susceptibility to microbial infections. Nod1, Nod2, Cryopyrin, and Ipaf have been implicated in protective immune responses against pathogens. Together with Toll-like receptors, Nod1 and Nod2 appear to play important roles in innate and acquired immunity as sensors of bacterial components. Specifically, Nod1 and Nod2 participate in the signaling events triggered by host recognition of specific motifs in bacterial peptidoglycan and, upon activation, induce the production of proinflammatory mediators. Naip5 is involved in host resistance to Legionella pneumophila through cell autonomous mechanisms, whereas CIITA plays a critical role in antigen presentation and development of antigen-specific T lymphocytes. Thus, NOD-LRR proteins appear to be involved in a diverse array of processes required for host immune reactions against pathogens.

     (Huom: nämä  luonnollisen immuunijärjestelmämme reseptorit  ovat kaikki luonnollisesti valkuaisaineita, proteiineja.  Leusiinia on runsaasti esim kalaravinnosa ja palkokasveissa).

     


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