Virusten käyttämä autofagiatie, esimerkkeinä EBV, VZV, poliovirus, coxackievirus

( Koska Sars-2 virus käyttää autofagiatien alkuosaa tehdäkseen replikaatio-organellin, katson tätä histokompatibiliteettialueen molekyylikatrasta. )

. 2017 Sep 22;8:1183.

doi: 10.3389/fimmu.2017.01183.    eCollection 2017. 

Autophagy Proteins in Phagocyte Endocytosis and Exocytosis

Christian Münz  ¹

• DOI: 10.3389/fimmu.2017.01183

Free PMC article

Abstract

Autophagy was initially described as a catabolic pathway that recycles nutrients of cytoplasmic constituents after lysosomal degradation during starvation. Since the immune system monitors products of lysosomal degradation via major histocompatibility complex (MHC) class II restricted antigen presentation, autophagy was found to process intracellular antigens for display on MHC class II molecules. In recent years, however, it has become apparent that the molecular machinery of autophagy serves phagocytes in many more membrane trafficking pathways, thereby regulating immunity to infectious disease agents. In this minireview, we will summarize the recent evidence that autophagy proteins regulate phagocyte endocytosis and exocytosis for myeloid cell activation, pathogen replication, and MHC class I and II restricted antigen presentation. Selective stimulation and inhibition of the respective functional modules of the autophagy machinery might constitute valid therapeutic options in the discussed disease settings.

Keywords: Epstein–Barr virus; IL-1; LC3-associated phagocytosis; coxsackievirus; major histocompatibility complex; poliovirus; varicella zoster virus. 

 

Sinkkiproteiinien ZXDA ja ZXDC osuutta histokompatibiliteettigeenisäätelyssä

 ZNF896, (Xp11.21), ZXDA,'

 Geeni  koodaa toista  kahdesta  kaksinkertaistuneesta sinkkisormigeenistä: Tämä X-kromosomin geeni (Xp11)  on telomeerinen kopio ja se, joka  on   sentromeerismpänä sijaitseva.  Ne kaksi geeniä omaavat 98%:sen nukleotidisekvenssien samankaltaisuuden  ja  oletetut proteiinit sisältävät 10 peräkkäistä sinkkisormimotiivia. Tähän geeniin ZXDA  liittyy monokromaattinen sinivärisokeus.  Tärkeä paralogi on se toinen geeni   ZXDB ( ZNF905,  X11.21).  

Lisänä tästä geenistä ZNF896 tärkeää tietoa:  Sillä on vaikutusta  immunologiseen  rakenteeseen: Se edistää MHC I ja MHC II luokkien geenitranskriptiota. Proteiinikoko 799 aminohappoa.

ZNF896 (GeneCards tietoa)
Aliases for ZXDA Gene , Zinc Finger X-Linked Duplicated A ^{2 3 5}  , Zinc Finger X-Linked Protein ZXDA ^{3 4} , Zinc Finger Protein 896 ^{2 3}  , ZNF896 ³

https://www.genecards.org/cgi-bin/carddisp.pl?gene=ZXDA&keywords=ZNF896

This gene encodes one of two duplicated zinc finger genes on chromosome Xp11. This gene is the telomeric copy; GeneID 158586 ZXDB is the more centromeric copy. The two genes have 98% nucleotide sequence similarity, and the predicted proteins contain 10 tandem zinc finger motifs.

GeneCards Summary for ZXDA Gene
ZXDA (Zinc Finger X-Linked Duplicated A) is a Protein Coding gene. Diseases associated with ZXDA include Blue Cone Monochromacy. Gene Ontology (GO) annotations related to this gene include nucleic acid binding and C2H2 zinc finger domain binding. An important paralog of this gene is ZXDB  (= ZNF905, Xp11.21).

UniProtKB/Swiss-Prot Summary for ZXDA Gene:Cooperates with CIITA to promote transcription of MHC class I and MHC class II genes ZXDA_HUMAN,P98168

[provided by RefSeq, Nov 2009]
Protein attributes for ZXDA Gene: Size:799 amino acids. Molecular mass: 84771 Da

Quaternary structure: Self-associates. Interacts with ZXDC (https://www.genecards.org/cgi-bin/carddisp.pl?gene=ZXDC&keywords=ZXDC )  and CIITA (https://www.genecards.org/cgi-bin/carddisp.pl?gene=CIITA&keywords=CIITA)

 

Tämä CIITA  (NOD like A) vasta erikoinen  geeni on.Siihen tekee interaktion sinkkisormiproteiinit  ZXD geenit  sekä A että  C.  ZXDA  edistää MCH luokkien I ja II geenien transkriptiota  ja ZXDC repressoi MCH luokka II transkriptiota, ainakin eräs sen  isoformi 3 tekee niin.    CIITA  taas edistää MHC II transkriptiota. 

Nämä Histokompatibiliteettiin   vaikuttavat taustalla olevat säätelevät   geenitekijät sijaitsevat  eri kromosomeissa.  ZXDA sijaitsee  siinä tuplageenissä X-kromosomissa  ja sen läheinen ZXDB:n  ehkä  ilmeinen tukitekijä tärkeän ZXDA:n  olemassaololle.

 

  Repressorityyppinen  ZXDC sijaitsee  kromosomissa 3q21.3.

Sekä  ZXDA:n että  ZXDC:n   molempien  interaktiopartneri  CIITA  (NODA)   "Master Control Factor"  on  tumassa toimiva ja   koodautuu kromosomista  16p13.13.

 

(UniProtKB/Swiss-Prot Summary for CIITA Gene

Tästä on  tietoa on  sen oman  otsikon alla enemmän: 

• Essential for transcriptional activity of the HLA class II promoter; activation is via the proximal promoter. No DNA binding of in vitro translated CIITA was detected. May act in a coactivator-like fashion through protein-protein interactions by contacting factors binding to the proximal MHC class II promoter, to elements of the transcription machinery, or both. Alternatively it may activate HLA class II transcription by modifying proteins that bind to the MHC class II promoter. Also mediates enhanced MHC class I transcription; the promoter element requirements for CIITA-mediated transcription are distinct from those of constitutive MHC class I transcription, and CIITA can functionally replace TAF1 at these genes. Activates CD74 transcription (PubMed:32855215). Exhibits intrinsic GTP-stimulated acetyltransferase activity. Exhibits serine/threonine protein kinase activity: can phosphorylate the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF, histone H2B at 'Ser-37' and other histones (in vitro). Has antiviral activity against Ebola virus and coronaviruses, including SARS-CoV-2. Induces resistance by up-regulation of the p41 isoform of CD74, which blocks cathepsin-mediated cleavage of viral glycoproteins, thereby preventing viral fusion (PubMed:32855215).

  • C2TA_HUMAN,P33076

MHC luokka I- ja MHCluokka II- geenien ja proteiinien säätelystä

 

NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module.

Ludigs K, Seguín-Estévez Q, Lemeille S, Ferrero I, Rota G, Chelbi S, Mattmann C, MacDonald HR, Reith W, Guarda G. PLoS Genet. 2015 Mar 26;11(3):e1005088. doi: 10.1371/journal.pgen.1005088. eCollection 2015 Mar. PMID: 25811463 Free PMC article.

MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) family member CIITA, which is recruited to SXY enhancers of MHCII promoters via a DNA-binding "enhanceosome" complex. NLRC5, another NLR protein, was recently found to cont …

control transcription of MHC class I (MHCI) genes. However, detailed understanding of NLRC5's target gene specificity and mechanism of action remained lacking. We performed ChIP-sequencing experiments to gain comprehensive information on NLRC5-regulated genes. In addition to classical MHCI genes, we exclusively identified novel targets encoding non-classical MHCI molecules having important functions in immunity and tolerance. ChIP-sequencing performed with Rfx5(-/-) cells, which lack the pivotal enhanceosome factor RFX5, demonstrated its strict requirement for NLRC5 recruitment. Accordingly, Rfx5-knockout mice phenocopy Nlrc5 deficiency with respect to defective MHCI expression. Analysis of B cell lines lacking RFX5, RFXAP, or RFXANK further corroborated the importance of the enhanceosome for MHCI expression. Although recruited by common DNA-binding factors, CIITA and NLRC5 exhibit non-redundant functions, shown here using double-deficient Nlrc5(-/-)CIIta(-/-) mice. These paradoxical findings were resolved by using a "de novo" motif-discovery approach showing that the SXY consensus sequence occupied by NLRC5 in vivo diverges significantly from that occupied by CIITA. These sequence differences were sufficient to determine preferential occupation and transactivation by NLRC5 or CIITA, respectively, and the S box was found to be the essential feature conferring NLRC5 specificity. These results broaden our knowledge on the transcriptional activities of NLRC5 and CIITA, revealing their dependence on shared enhanceosome factors but their recruitment to distinct enhancer motifs in vivo. Furthermore, we demonstrated selectivity of NLRC5 for genes encoding MHCI or related proteins, rendering it an attractive target for therapeutic intervention. NLRC5 and CIITA thus emerge as paradigms for a novel class of transcriptional regulators dedicated for transactivating extremely few, phylogenetically related genes.

Histokompatibiliteetti " Master Control factor" CIITA Immuunivasteen tärkeää geenivarustetta.

 Immuunivasteelle  tärkeää  genomivarustetta: 

GeneCards: https://www.genecards.org/cgi-bin/carddisp.pl?gene=CIITA&keywords=CIITA

Aliases for CIITA Gene

• GeneCards Symbol: CIITA ²
• Class II Major Histocompatibility Complex Transactivator ^{2 3 5}
• MHC Class II Transactivator ^{2 3 4}
• MHC2TA ^{3 4 5}
• C2TA ^{2 3 5}
• NLRA ^{2 3 5}
• Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Acid Domain Containing ^{2 3}

• NLR Family, Acid Domain Containing ^{2 3}
• Class II, Major Histocompatibility Complex, Transactivator ²
• MHC Class II Transactivator Type III ³
• MHC Class II Transactivator Type I ³
• EC 2.7.11.1 ⁴
• EC 2.3.1.- ⁴
• CIITAIV ³

External Ids for CIITA Gene

. 2020 Oct 9;370(6513):241-247.

doi: 10.1126/science.abb3753. Epub 2020 Aug 27.

MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses

Anna Bruchez ^{#  1} , Ky Sha ^{#  1} , Joshua Johnson  ² , Li Chen  ³ , Caroline Stefani  ¹ , Hannah McConnell  ¹ , Lea Gaucherand  ¹ , Rachel Prins  ¹ , Kenneth A Matreyek  ⁴ , Adam J Hume  ^{5   6} , Elke Mühlberger  ^{5   6} , Emmett V Schmidt  ⁷ , Gene G Olinger  ^{2   5   6   8} , Lynda M Stuart  ^{1   9} , Adam Lacy-Hulbert  ^{10   11}

Affiliations

• PMID: 32855215
• PMCID: PMC7665841
• DOI: 10.1126/science.abb3753

Free PMC article

UniProtKB/Swiss-Prot Summary for CIITA Gene

• Essential for transcriptional activity of the HLA class II promoter; activation is via the proximal promoter. No DNA binding of in vitro translated CIITA was detected. May act in a coactivator-like fashion through protein-protein interactions by contacting factors binding to the proximal MHC class II promoter, to elements of the transcription machinery, or both. Alternatively it may activate HLA class II transcription by modifying proteins that bind to the MHC class II promoter. Also mediates enhanced MHC class I transcription; the promoter element requirements for CIITA-mediated transcription are distinct from those of constitutive MHC class I transcription, and CIITA can functionally replace TAF1 at these genes. Activates CD74 transcription (PubMed:32855215). Exhibits intrinsic GTP-stimulated acetyltransferase activity. Exhibits serine/threonine protein kinase activity: can phosphorylate the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF, histone H2B at 'Ser-37' and other histones (in vitro). Has antiviral activity against Ebola virus and coronaviruses, including SARS-CoV-2. Induces resistance by up-regulation of the p41 isoform of CD74, which blocks cathepsin-mediated cleavage of viral glycoproteins, thereby preventing viral fusion (PubMed:32855215).

  • C2TA_HUMAN,P33076

Solutuman sinkki (Zn) ja geeni (2001). Sinkkisormiproteiinit ZNF(2017)

Dreosti I.1. Zinc and gene (2001)

Suom  Sinkistä  ja geenistä.

2001 Apr 18;475(1-2):161-7.

 doi: 10.1016/s0027-5107(01)00067-7. Zinc and the gene  I E Dreosti  1

Affiliations PMID: 11295161 DOI: 10.1016/s0027-5107(01)00067-7

TIIVISTELMÄN  suomennosta:

Merkitsevä osa soluperäisestä sinkistä (Zn)  on solutuman (nucleus)  puolella ja siellä se näyttää olevan kriittinen geneettisen vakauden ylläpidossa ja geeniekspressioprosessissa. Geenien ilmentämisessä sinkki (Zn) toimii mekanistisesti useissa tasoissa, joista nykyään kiinnostaa erityisesti sinkin osuus DNA:n transkriptiossa. Siinä toimii useita transkriptiofaktoreita (TF), joista osalla on DNA:ta sitovia erityisiä sinkkisormialueita rakenteessaan ja ne pystyvät kontrolloimaan solunproliferoitumsita, erilaistumista ja solukuolemaa. Huomattavaa mielenkiintoa on kohdistunut sinkkiin essentiellinä mineraalina juuri siksi, kun se on keskeisen tärkeä solun jakautumiselle ja kasvulle. On paljon kirjallisuutta sinkin (Zn) ravintolähteistä ja sinkkimineraalin ravintoperäisen saannin suosituksista.

Abstract:A significant portion of cellular zinc is found in the nucleus where it appears to be critically involved in maintaining genetic stability and in the process of gene expression. With regard to gene expression zinc functions mechanistically at several levels but recent interest has focussed especially on the involvement of zinc in DNA transcription through the activity of transcription factors (Tfs) which contain specific zinc-finger regions (Znf) which bind to DNA and, in conjunction with other families of transcription factors (Tfs) , control cell proliferation, differentiation and cell death. Because of the central importance of zinc in cell division and growth, considerable attention is paid to zinc as an essential trace element and much has been written concerning dietary sources of zinc and recommended dietary intakes of the metal. 

Kommenttini:  Sinkkisormiproteiineista  on kirjoittanut M.Cassandri artikkelin 2017 : Hän kokosi artiikeliinsa 30  ryhmää.   Tässä blogissa kirjoitin  niistä  toukokuussa 2018  Toistan otsikkoni:  Zinc Finger proteins (ZNF). M.Cassandri et al (2017) . 

Toistan linkin  PubMed hakulaitteen kautta: 

 eCollection 2017. Zinc-finger proteins in health and disease

Matteo Cassandri  ¹ , Artem Smirnov  ¹ , Flavia Novelli  ¹ , Consuelo Pitolli  ¹ , Massimiliano Agostini  ¹ , Michal Malewicz  ² , Gerry Melino  ^{1   2} , Giuseppe Raschellà  ³

Affiliations

• PMID: 29152378
• PMCID: PMC5683310
• DOI: 10.1038/cddiscovery.2017.71

Free PMC article

Abstract

Zinc-finger proteins (ZNFs) are one of the most abundant groups of proteins and have a wide range of molecular functions. Given the wide variety of zinc-finger domains, ZNFs are able to interact with DNA, RNA, PAR (poly-ADP-ribose) and other proteins. Thus, ZNFs are involved in the regulation of several cellular processes. In fact, ZNFs are implicated in transcriptional regulation, ubiquitin-mediated protein degradation, signal transduction, actin targeting, DNA repair, cell migration, and numerous other processes. The aim of this review is to provide a comprehensive summary of the current state of knowledge of this class of proteins. Firstly, we describe the actual classification of ZNFs, their structure and functions. Secondly, we focus on the biological role of ZNFs in the development of organisms under normal physiological and pathological conditions.

Suomennan  7.8. 2022   PubMed tekstin:

Sinkkisormiproteiinit (ZNFs) ovat yksi kaikkein runsaimmista proteiiniryhmistä ja  niillä on laaja kirjo erilaisia funktioita. Ottaen huomioon sinkkisormidomeenin (znf domain)  suuren vaihtelevaisuuden  sinkkisormiproteiineilla   on kykyä tehdä interaktioita DNA-, RNA- ja PAR-proteiineihin ja muihin proteiineihin. (PAR tarkoittaa polyadenosyyliriboosia). Tällä tavalla  sinkkisormiproteiinit (ZNF)  osallistuvat useiden soluproteiiniprosessien säätelyyn. Todellakin niitä on  osoitettavissa transkription säädössä, ubikitiinivälitteisessä  proteosomaalisessa silppuroinnissa, signaalien välityksessä, aktiiniin kohdistamisessa, DNA:n korjauksessa, solumigraatiossa ja lukuisissa muissa prosessesssa.  Tämän katsauksen tarkoituksena on tarjota  laaja yhteenveto tästä proteiiniluokasta saadusta nykytietämyksestä. Ensinnä tässä selostetaan sinkkisormien  (ZNF) ajanmukainen luokitus , niiden rakenne ja  funktio. Toiseksi kohdistetaan  sinkkisormiproteiinien  biologiseen osuuteen organismien kehityksessä  normaaliolosuhteissa ja patologisissa tiloissa.