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.
Zurek B1, Schoultz I, Neerincx A, Napolitano LM, Birkner K, Bennek E, Sellge G, Lerm M, Meroni G, Söderholm JD, Kufer TA.
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.
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.
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.
Annu Rev Biochem. 2005;74:355-83. Review.PMID:15952891Similar articles
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.
- PMID:15952891
- DOI:10.1146/annurev.biochem.74.082803.133347
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