TRIM9 (Kr. 14q22.1), SPRING, RNF91 (C_I, FNL2, PRYSPRY)
- Tällä geenillä on muita nimiä SPRING ja RNF91.
- Sen rakenne on RBCC (RING, Bbox1, Bbox2, Coiled-coil) ja C-terminaalin osalta alaluokkaa C_I (FNL, PRY-SPRY).
- Geeni koodaa kahta isoformia. Toisessa, pidemmässä, on 710 aminohappoa (isoformi1). Domeenien sijainnit ovat : RING( 9..38), Bbox (224..266), Bbox ( 273..398). FN3 domeenit sijoittuvat jaksoon 453..532. SPRY..PRY jakso on 529..700 ja se on samankaltainen myös TRIM67:ssä, joka myöskuuluu tähän alaluokaan C-I . FN3- domeeni tarkoittaa fibronektiini tyyppi3:n kaltaista domeenia.
- TRIM9 proteiini lokalisoituu sytoplasmisiin kappaleisiin. Sen funktiota ei ollut tunnistettu vielä 2008 mennessä, mutta paljon artikkelia on kertynyt sen jälkeen. Geeniä ilmenee eniten aivoissa, sappirakossa ja vielä hieman yhdessä kudoksessa. Alla on PubMed Gene lähteestä-tiedot 1-isoformista ja muutaman artikkelin suomennos.
- https://www.ncbi.nlm.nih.gov/gene/114088
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- RNF91; SPRING Summary.The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies. Its function has not been identified. Alternate splicing of this gene generates two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008] Expression Biased expression in brain (RPKM 15.3), gall bladder (RPKM 1.4) and 1 other tissue See more
Mielenkiintoisia artikkeleita TRIM9 funktioista netriini-1 säätelyjärjestelmässä
-
- https://www.semanticscholar.org/paper/TRIM9-dependent-ubiquitination-of-DCC-constrains-Plooster-Menon/2b55470e4402f16895685fa7ec5838bfa4adff15
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- TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branchingMelissa Plooster, Shalini Menon, +5 authors Stephanie L GuptonPublished 2017 in Molecular biology of the cell
Avainsanoja:
DCC tässä
yhteydessä tarkoittaa ”deleted in colorectal cancer”, ”puuttuu
kolorektaalisyövässä”. DCC on netriini-1 reseptori.
SNARE= soluble
N-ethylmaleimide attachment protein receptor
https://en.wikipedia.org/wiki/SNARE_(protein)
FAK= Focal Adhesion
Kinase, reseptori proteiinityrosiinikinaasi PRK2
(https://sv.wikipedia.org/wiki/PTK2)
src- family,
ei-reseptori-proteiinimtyrosiinikinaasi Non-receptor tyrosine
kinases, https://en.wikipedia.org/wiki/Src_family_kinase
KUVA:
(Suomennosta):
TRIM9:stä riippuva
netriini1-reseptorin (DDC) ubikitinaatio pitää aisoissa
kinaasisignalointia, exosytoosia ja aksonien haaroittumista.
Extrasellulaarinen netriini-1 ja sen reseptori DCC edistävät
aivokuoren kehittyvässä neuronissa neuroninjatkeen (aksonin)
haaroittumista. Netriinistä riippuvaa morfogeneesiä edeltää
netriinireseptorin (DCC) multimerisoituminen, Kinaasin
FAK-aktivaatio js Src-perheen kinaasien aktivoituminen – ja se
lisää exosyyttisten rakkuloiden fuusioitumista- mutta näiden
tapahtumien keskinäinen linkkiytyminen on ollut tuntematon seikka.
Tässä työssä
tutkijat osoittavat, että TRIM9:n tekemä netriinireseptorin (DCC)
ubikitinaatio estää FAK- interaktion ja fosforyloitumisen. Mutta
kun netriini-1 stimuloi tätä reseptoriaan DCC, niin TRIM9 edistää
reseptorin multimerisaatiota, mutta samalla vähenee DCC:n
ubikitinoitumisen aste, mistä taas fokaaliadheesiokinaasin (FAK)
interaktio pääsee edistymään ja samoin sen aktivaatio.
Tutkijat
havaitsivat, että FAK-aktiivisuuden inhibitio ( estäminen)
blokeerasi exosytoosin kohonneet frekvenssit koeputkessa ( in
vitro) ja aksonihaaroittumisen lisääntymisen in vitro ja in
vivo.
Vaikka
fokaaliadheesiokinaasin vähensi SNARE- välitteistä exosytoosia,
SNARE-kompleksien ja rakkuloiden kokoontuminen plasmakalvon
läheisyyteen lisääntyi , mikä viittaisi siihen, että FAK omaa
jonkin uuden roolin SNARE-kompleksien kokoontumisen progressiossa
ja rakkuloiden fuusioitumisessa koe-eläimen kehittyvässä
neuronissa.
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TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching. Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. Netrin-dependent morphogenesis is preceded by multimerization of DCC, activation of FAK and Src family kinases, and increases in exocytic vesicle fusion, yet how these occurrences are linked is unknown.
-
Here we demonstrate that tripartite motif protein 9 (TRIM9)-dependent ubiquitination of DCC blocks the interaction with and phosphorylation of FAK. Upon netrin-1 stimulation TRIM9 promotes DCC multimerization, but TRIM9-dependent ubiquitination of DCC is reduced, which promotes an interaction with FAK and subsequent FAK activation.
-
We found that inhibition of FAK activity blocks elevated frequencies of exocytosis in vitro and elevated axon branching in vitro and in vivo. Although FAK inhibition decreased soluble N-ethylmaleimide attachment protein receptor (SNARE)-mediated exocytosis, assembled SNARE complexes and vesicles adjacent to the plasma membrane increased, suggesting a novel role for FAK in the progression from assembled SNARE complexes to vesicle fusion in developing murine neurons.
Toinen artikkeli ja kuva netriini-1 signaloinnista ja TRIM9 osuudesta
Tunnettuja TRIM9-
interaktioita.
Sanastoa: F-actin,
on filamenttimuotoinen aktiini.
VASP =
prosessiivinen aktiinipolymeraasi
https://www.ncbi.nlm.nih.gov/pubmed/21041447
Kuva A.
Netriini-1:n poissaollessa TRIM9 inhiboi SNARE kompleksin jäseniä
(kuten SNAP25) ligaasifunktiostaan riippumattomalla tavalla estäen
rakkuloiden exosytoosia. TRIM9 toimii filopodia rakenteille ”OFF”
vaihteen tavoin ubikitinoimalla VASP-polymeraasin. Ubikitinoitu
prosessiivinen aktiinipolymeraasi VASP irtoaa aktiinifilamenttien
päistä jolloin aktiinipolymerisaatio vähenee.
Kuva B. Kun
netriini-1 on läsnä, TRIM9 tekee interaktion netriini-1-reseptorin
(DCC) kanssa ligaasista riippuvalla tavalla. TRIM9:n interaktio
SNAP25:n kanssa estyy, kun netriini-1 tulee reseptoriinsa. Ja nyt
pääsee tapahtumaan exosytoosivälitteistä kalvon laajenemista ja
filopodia ”ON” vaihde, sillä TRIM9:n tekemä VASP-ubikitinaatio
estyy ja VASP ( aktiinipolymeraasi ) pääsee assosioitumaan
aktiinifilamentteihin ja aktiinifilamentit alkavat polymerisoitua ja
filopodiamuodostus edistyy.
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Figure 1. Known TRIM9 interactions. A, In the absence of Netrin-1, TRIM9 inhibits SNAP25 in a ligase-independent manner to inhibit exocytosis. TRIM9 also acts as a filopodia " off " switch by ubiquitinating actin polymerase VASP. Ubiquitinated VASP is dissociated from the ends of actin filaments, leading to decreased actin polymerization. B, When Netrin-1 is present, TRIM9 interacts with Netrin-1 receptor DCC in a ligase-dependent manner. TRIM9's interaction with SNAP25 is inhibited upon Netrin-1 introduction, leading to exocytosis-mediated membrane expansion. TRIM9 ubiquitination of VASP is also inhibited, leading to VASP association with actin filaments, increased actin filament polymerization, and promotion of filopodia formation. F-actin, filamentous actin; Ub, ubiquitination.Cell Res. 2016 May;26(5):613-28. doi: 10.1038/cr.2016.27. Epub 2016 Feb 26.
Lyhempi TRIM9 isoformi omaa kaksoisvaikutuksia antivirusimmuunivasteessa.
(Suomennosta) .
Avainsanoja:
MAVS =Mitochondrial
Anti-Viral Signaling-protein
STING=double-strand
(ds) DNA receptors activate the adaptor molecule STimulator of
IFN Genes (STING) at the endoplasmic reticulum (ER)
Kuva tässä
linkissä osoittaa MAVS ja STING proteiinien sijainnin. MAVS on
mitokondriaan assosioitunut ja STING endoplasmiseen retikulumiin.
Niitten avulla solu lajittelee virusvihollisiaan.
”
Antivirusimmuunivasteessa on tyypin 1 interferoni(IFN)
signaalinvälittäjäna ja sen sanomana on, että solun
virussensorijärjestelmä (DNA-sensori cGAS ja RNA-sensorit RIG-1
ja MDA5) ovat tunnistaneet DNA ja RNA virusta. Näiden DNA ja
RNA-sensoreiden aktivoituminen johtaa STING- ja vastaavasti MAVS-
proteiinien rekrytoitumiseen- ja nämä herätteet konvergoituvat
TBK1- signalointitiehen ja siitä seuraa IRF3- fosforyloituminen (
ja aktivoituminen) ja 1 tyypin IFN:n tuotto ( katso kuva)
-
Type I interferon (IFN) is an important component of antiviral innate immune signaling mediated by viral DNA and RNA recognition by the DNA sensor cGAS and RNA sensors RIG-I and MDA5. Activation of these DNA and RNA sensors leads to the recruitment of STING and MAVS, respectively, and converges on TANK-binding kinase 1 (TBK1) signaling for subsequent phosphorylation of IFN regulatory factor 3 (IRF3).
(TANK= TRAF family
member associated NfkB activator)
(TRAF = TNR receptor
associated factor)
(TNR = tumor
necrosis factor, proinflamamtorinen sytokiini)
(GSK3beta
=glykogeenisyntaasikinaasi , 3 beta
https://en.wikipedia.org/wiki/GSK-3,
kiinnsotava entsyymi ja ilmenee monessa patologiassa)
”TBK1 kinaasin
aktivaatio ei ole täysin yksityiskohtaisesti selvitetty. Tässä
työssä on tunnistettu TRIM9 geenin koodaama lyhempi isoformi
1-tyypin interferonisignaloinnin positiiviseksi säätelijäksi.
Virusinfektion aikana TRIM9 autopolyubikitinoituu K63 asemaan ja
toimii alustana, jolla GSK3beta liittyy TBK1 entsyymiin ja tätä
tietä pääsee IRF3-siganlointi aktivoitumaan. Tutkijat
havaitsivat, että TRIM9 pystyy selektiivisesti inhiboimaan
proinflammatoristen sytokiinien tuotantoa, mutta lisää 1- tyypin
interferonin ja interferonilla stimuloituvien geenien ilmenemistä.
Tutkijoitten löytönä on TRIM9:n kaksoisvaikutukset
antivirusimmuniteetissä ja ne tasapainottavat proinflammatorisia
vasteita ja 1- tyypin interferonien tuotantoa”.
-
However, the mechanisms that control TBK1 activation are still poorly defined. Here, we identify tripartite motif 9 short isoform (TRIM9s) as a positive regulator in type I IFN signaling. Upon viral infection, TRIM9s undergoes Lys-63-linked auto-polyubiquitination and serves as a platform to bridge GSK3β to TBK1, leading to the activation of IRF3 signaling. Interestingly, we found that TRIM9s selectively inhibits the production of pro-inflammatory cytokines, but enhances the expression of type I IFNs as well as IFN-stimulated genes, in response to viral infection. Our findings reveal novel dual functions of TRIM9s in antiviral immunity, which serve to balance pro-inflammatory response and production of type I IFNs.
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TRIM9 pitempi isoformi 16-393X/5/3/23/htm
TRIM9 on aivospesifinen NF-kB:n negatiivinen säätelijä.
- TRIM9 as a brain-specific negative regulator of the NF-κB pro-inflammatory signalling pathway.
E3 ubiquitin-protein ligase TRIM9 isoform 1 [Homo sapiens]
NCBI Reference Sequence: NP_055978.4Identical Proteins FASTA Graphics
LOCUS NP_055978 710 aa linear PRI 08-APR-2018 DEFINITION E3 ubiquitin-protein ligase TRIM9 isoform 1 [Homo sapiens]. ACCESSION NP_055978 VERSION NP_055978.4 DBSOURCE REFSEQ: accession NM_015163.5 KEYWORDS RefSeq. SOURCE Homo sapiens (human) ORGANISM Homo sapiens Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo. REFERENCE 1 (residues 1 to 710) AUTHORS Plooster M, Menon S, Winkle CC, Urbina FL, Monkiewicz C, Phend KD, Weinberg RJ and Gupton SL. TITLE TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. JOURNAL Mol. Biol. Cell 28 (18), 2374-2385 (2017) PUBMED 28701345 REMARK GeneRIF: Authors demonstrate that tripartite motif protein 9 (TRIM9)-dependent ubiquitination of DCC blocks the interaction with and phosphorylation of FAK. REFERENCE 2 (residues 1 to 710) AUTHORS Qin Y, Liu Q, Tian S, Xie W, Cui J and Wang RF. TITLE TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3beta to TBK1 JOURNAL Cell Res. 26 (5), 613-628 (2016) PUBMED 26915459 REMARK GeneRIF: TRIM9s undergoes Lys-63-linked auto-polyubiquitination and serves as a platform to bridge GSK3beta to TBK1, leading to the activation of IRF3 signaling. REFERENCE 3 (residues 1 to 710) AUTHORS Yang X, Coulombe-Huntington J, Kang S, Sheynkman GM, Hao T, Richardson A, Sun S, Yang F, Shen YA, Murray RR, Spirohn K, Begg BE, Duran-Frigola M, MacWilliams A, Pevzner SJ, Zhong Q, Trigg SA, Tam S, Ghamsari L, Sahni N, Yi S, Rodriguez MD, Balcha D, Tan G, Costanzo M, Andrews B, Boone C, Zhou XJ, Salehi-Ashtiani K, Charloteaux B, Chen AA, Calderwood MA, Aloy P, Roth FP, Hill DE, Iakoucheva LM, Xia Y and Vidal M. TITLE Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing JOURNAL Cell 164 (4), 805-817 (2016) PUBMED 26871637 REFERENCE 4 (residues 1 to 710) AUTHORS Shi M, Cho H, Inn KS, Yang A, Zhao Z, Liang Q, Versteeg GA, Amini-Bavil-Olyaee S, Wong LY, Zlokovic BV, Park HS, Garcia-Sastre A and Jung JU. TITLE Negative regulation of NF-kappaB activity by brain-specific TRIpartite Motif protein 9 JOURNAL Nat Commun 5, 4820 (2014) PUBMED 25190485 REMARK GeneRIF: TRIM9 is a brain-specific negative regulator of the NF-kappaB pro-inflammatory signalling pathway. Publication Status: Online-Only REFERENCE 5 (residues 1 to 710) AUTHORS Kanazawa T, Ikeda M, Glatt SJ, Tsutsumi A, Kikuyama H, Kawamura Y, Nishida N, Miyagawa T, Hashimoto R, Takeda M, Sasaki T, Tokunaga K, Koh J, Iwata N and Yoneda H. TITLE Genome-wide association study of atypical psychosis JOURNAL Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B (7), 679-686 (2013) PUBMED 24132900 REFERENCE 6 (residues 1 to 710) AUTHORS Tanji K, Kamitani T, Mori F, Kakita A, Takahashi H and Wakabayashi K. TITLE TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson's disease and dementia with Lewy bodies JOURNAL Neurobiol. Dis. 38 (2), 210-218 (2010) PUBMED 20085810 REMARK GeneRIF: These results suggest that TRIM9 plays an important role in the regulation of neuronal functions and participates in pathological process of Lewy body disease through its ligase activity. REFERENCE 7 (residues 1 to 710) AUTHORS Li Y, Chin LS, Weigel C and Li L. TITLE Spring, a novel RING finger protein that regulates synaptic vesicle exocytosis JOURNAL J. Biol. Chem. 276 (44), 40824-40833 (2001) PUBMED 11524423 REFERENCE 8 (residues 1 to 710) AUTHORS Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG and Ballabio A. TITLE The tripartite motif family identifies cell compartments JOURNAL EMBO J. 20 (9), 2140-2151 (2001) PUBMED 11331580 REFERENCE 9 (residues 1 to 710) AUTHORS Ohara O, Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N and Nomura N. TITLE Construction and characterization of human brain cDNA libraries suitable for analysis of cDNA clones encoding relatively large proteins JOURNAL DNA Res. 4 (1), 53-59 (1997) PUBMED 9179496 REFERENCE 10 (residues 1 to 710) AUTHORS Dawson SJ and White LA. TITLE Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin JOURNAL J. Infect. 24 (3), 317-320 (1992) PUBMED 1602151 COMMENT REVIEWED REFSEQ: This record has been curated by NCBI staff. The reference sequence was derived from BC063872.1, DA101991.1, DA173440.1 and D87458.2. On Jun 13, 2008 this sequence version replaced NP_055978.3. Summary: The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies. Its function has not been identified. Alternate splicing of this gene generates two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]. Transcript Variant: This variant (1) represents the longest transcript and encodes the longer isoform (1). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: BC063872.1, SRR1660807.103429.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support SAMEA1965299, SAMEA1966682 [ECO:0000350] ##Evidence-Data-END## FEATURES Location/Qualifiers source 1..710 /organism="Homo sapiens" /db_xref="taxon:9606" /chromosome="14" /map="14q22.1" Protein 1..710 /product="E3 ubiquitin-protein ligase TRIM9 isoform 1" /EC_number="2.3.2.27" /note="homolog of rat RING finger Spring; tripartite motif-containing protein 9; E3 ubiquitin-protein ligase TRIM9; RING finger protein 91; RING-type E3 ubiquitin transferase TRIM9" /calculated_mol_wt=79046 Region 9..>38 /region_name="RING" /note="RING-finger (Really Interesting New Gene) domain, a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc; defined by the 'cross-brace' motif C-X2-C-X(9-39)-C-X(1-3)- H-X(2-3)-(N/C/H)-X2-C-X(4-48)C-X2-C; probably involved in...; cd00162" /db_xref="CDD:238093" Site 41 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphothreonine. {ECO:0000250|UniProtKB:Q8C7M3}; propagated from UniProtKB/Swiss-Prot (Q9C026.1)" Site 44 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphoserine. {ECO:0000250|UniProtKB:Q8C7M3}; propagated from UniProtKB/Swiss-Prot (Q9C026.1)" Site 46 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphoserine. {ECO:0000250|UniProtKB:Q8C7M3}; propagated from UniProtKB/Swiss-Prot (Q9C026.1)" Site 49 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphoserine. {ECO:0000250|UniProtKB:Q8C7M3}; propagated from UniProtKB/Swiss-Prot (Q9C026.1)" Region 163..211 /region_name="BBOX" /note="B-Box-type zinc finger; smart00336" /db_xref="CDD:197662" Region 224..266 /region_name="BBOX" /note="B-Box-type zinc finger; smart00336" /db_xref="CDD:197662" Region 273..399 /region_name="BBC" /note="B-Box C-terminal domain; smart00502" /db_xref="CDD:128778" Region 453..532 /region_name="FN3" /note="Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all...; cd00063" /db_xref="CDD:238020" Site order(521..522,524..525) /site_type="other" /note="Cytokine receptor motif" /db_xref="CDD:238020" Region 529..700 /region_name="SPRY_PRY_TRIM67_9" /note="PRY/SPRY domain in tripartite motif-containing proteins, TRIM9 and TRIM67; cd12889" /db_xref="CDD:293947" CDS 1..710 /gene="TRIM9" /gene_synonym="RNF91; SPRING" /coded_by="NM_015163.5:766..2898" /note="isoform 1 is encoded by transcript variant 1" /db_xref="CCDS:CCDS9703.1" /db_xref="GeneID:114088" /db_xref="HGNC:HGNC:16288" /db_xref="MIM:606555" ORIGIN 1 meemeeelkc pvcgsfyrep iilpcshnlc qacarnilvq tpesespqsh raagsgvsdy 61 dyldldkmsl yseadsgygs yggfasaptt pcqkspngvr vfppampppa thlspalapv 121 prnscitcpq chrslilddr glrgfpknrv legvidryqq skaaalkcql cekapkeatv 181 mceqcdvfyc dpcrlrchpp rgplakhrlv ppaqgrvsrr lsprkvstct dhelenhsmy 241 cvqckmpvcy qcleegkhss hevkalgamw klhksqlsqa lnglsdrake akeflvqlrn 301 mvqqiqensv efeaclvaqc dalidalnrr kaqllarvnk ehehklkvvr dqishctvkl 361 rqttglmeyc levikendps gflqisdali rrvhltedqw gkgtltprmt tdfdlsldns 421 pllqsihqld fvqvkasspv patpilqlee ccthnnsatl swkqpplstv padgyileld 481 dgnggqfrev yvgketmctv dglhfnstyn arvkafnktg vspysktlvl qtsevawfaf 541 dpgsahsdii lsndnltvtc ssyddrvvlg ktgfskgihy weltvdrydn hpdpafgvar 601 mdvmkdvmlg kddkawamyv dnnrswfmhn nshtnrtegg itkgatigvl ldlnrknltf 661 findeqqgpi afdnveglff pavslnrnvq vtlhtglpvp dfyssrasia
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