NOTCH signaloinnista ja SARS2 interaktioproteiineista

SARS2 ORF8 interaktioproteiinit ovat POGLUT2 ja POGLUT3,
POFUT1 . katso alla olevaa kuvaa. Se on hiirellä tehty tutkimus.

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13251@10.1002/(ISSN)1873-3468.reviews
Review Article

Free Access

Multiple roles for O‐glycans in Notch signalling

Shweta Varshney

Pamela Stanley

First published: 12 September 2018

https://doi.org/10.1002/1873-3468.13251

Notch signalling regulates a plethora of developmental processes and is also essential for the maintenance of tissue homeostasis in adults. Therefore, fine‐tuning of Notch signalling strength needs to be tightly regulated. Of key importance for the regulation of Notch signalling are O‐fucose, O‐GlcNAc and O‐glucose glycans attached to the extracellular domain of Notch receptors. The EGF repeats of the Notch receptor extracellular domain harbour consensus sites for addition of the different types of O‐glycan to Ser or Thr, which takes place in the endoplasmic reticulum. Studies from Drosophila to mammals have demonstrated the multifaceted roles of O‐glycosylation in regulating Notch signalling. O‐glycosylation modulates different aspects of Notch signalling including recognition by Notch ligands, the strength of ligand binding, Notch receptor trafficking, stability and activation at the cell surface. Defects in O‐glycosylation of Notch receptors give rise to pathologies in humans. This Review summarizes the nature of the O‐glycans on Notch receptors and their differential effects on Notch signalling.

Abbreviations

ADAM , a disintegrin and metalloprotease
ANK , Ankyrin repeats
AOS4 , Adams‐Oliver syndrome 4
C2 domain , module at the N‐terminus of Notch ligands
CHO , Chinese hamster ovary
CSL , CBF‐1 suppressor of hairless‐LAG1
DDD , Dowling‐Degos disease
DLL , Delta‐like
EGF , epidermal growth factor‐like
EOGT , EGF‐domain‐specific O‐GlcNAc
ER , endoplasmic reticulum
ES , embryonic stem cells
Gal , galactose
GDP‐Fuc , GDP‐fucose
GlcNAc , N ‐acetylglucosamine
GSI , gamma‐secretase inhibitor
GXYLT1 , glucoside xylosyltransferase 1
GXYLT2 , glucoside xylosyltransferase 2
HD , heterodimerization domain
HEK , human embryonic kidney
HSC , haematopoietic stem cells
HS‐DDD4 , hidradenitis suppurativa‐Dowling‐Degos disease 4
JAG1 , Jagged 1
LFNG , Lunatic fringe
LGMD2Z , limb‐girdle muscular dystrophy type 2Z
MAML , mastermind‐like
MFNG , Manic fringe
NECD , Notch extracellular domain
NeuAc , N ‐acetylneuraminic acid
NEXT , Notch extracellular truncation
NICD , Notch intracellular domain
NRR , negative regulatory region
POFUT1 , protein O‐fucosyltransferase 1  ( =SARS2 interaction protein)
POGLUT1 , Protein O‐glucosyltransferase 1
RAM , RBP‐Jκ‐associated module
RFNG , Radical fringe
SCDO3 , spondylocostal dysostosis 3
Su(H) , suppressor of hairless
TAD , transcriptional activation domain
U2OS , human osteosarcoma cell line
XXYLT1 , xylose xylosyltransferase 1 

  

 

Representation of mouse NOTCH1 extracellular domain depicting EGF repeats with different O‐glycan consensus sites that may be modified with the O‐glycans shown. One of the EGF domains is magnified to show the consensus site for each type of O‐glycan. Different O‐glycans, their respective differential extension with sugars (+/−), and the glycosyltransferases responsible for the transfer of each sugar are shown below the diagram. The transfer of O‐glucose by POGLUT2 or POGLUT3 occurs only on EGF11 in NOTCH1. The consensus site is between Cys³ and Cys⁴, indicated by the different location of the glucose symbol in EGF11 in the diagram.

NOTCH signalointi keuhkojen pienissä tiehyeissä

LÄHDE: 
 Down-regulation of the Notch Pathway in HumanAirway Epithelium in Association with Smokingand Chronic Obstructive Pulmonary DiseaseAnn E. Tilley1, Ben-Gary Harvey1, Adriana Heguy2*, Neil R. Hackett2, Rui Wang2, Timothy P. O’Connor2, andRonald G. Crystal1,21Division of Pulmonary and Critical Care Medicine and2Department of Genetic Medicine, Weill Medical College of Cornell University,New York, New York

...  One such differentiation control system is the Notch signaling pathway. Originally discovered in Drosophila, there is evidencein experimental animals that the Notch pathway plays an important role in the determination of cell fate in multiple organsystems (7, 13, 15, 16) including the lung (7, 12–14). The classical role of Notch signaling is the prevention of cell differentiation and the maintenance of an undifferentiated state in stem cells invarious organs (7, 15, 37). 

When Notch is ‘‘on,’’ differentiation is suppressed,
 whereas when Notch is ‘‘off,’’ cells are allowed to proceed to a specific differentiation fate (13, 15, 16). 

Notch typically acts locally to define boundaries between different celltypes with divergent fates; for example, it can act following division of a stem cell to induce differentiation in one daughter cell and keep the other as a stem cell (13, 16). 
Notch signaling is simple in concept, but multiple regulatory components at every stage of the pathway add a level of complexity (13, 15–17).

 Notch signaling in humans is initiatedby interaction of one of the five Notch ligands, Delta-like (DLL1,3, or 4) or Jagged (JAG1 or 2) with one of the four receptors(NOTCH1, 2, 3, or 4). Both ligand and receptor are single-passmembrane proteins, and therefore Notch signaling typically involves cell-to-cell contact.



  Literature searches and Ingenuity Pathways software were used to identify components of the Notch signaling pathway, which were assigned to functional groups.Microarray data on small airway epithelial samples from the HG-U133 Plus 2.0 (n= 20 nonsmokers) were examined for the selected genes.†Expressed as P call percentage (%), which is defined as the percentage of normal nonsmoker samples for which the Affymetrix algorithm determined that the gene  was expressed or ‘‘Present’’ (P).‡Genes were categorized as expressed in human airway epithelium if the P call percentage was at least 50% in normal nonsmokers; for genes with more than one probe set, the percentage of P call listed is the highest value among the probe se


TABLE 2. NOTCH PATHWAY GENES EXPRESSED (%)  IN THE SMALL AIRWAY EPITHELIUM OF NONSMOKER (n=20)
LIGANDS  
 Delta-like ligand 1 , DLL1, 100, yes
 Delta-like ligand 3, DLL3,      5, no 
Delta-like ligand 4,  DLL4,       0, no 
Jagged 1,  JAG1,                100, yes
Jagged 2, JAG2          100  yes
RECEPTORS
Notch 1, NOTCH1      100, yes 
Notch 2, NOTCH2,      100, yes 
Notch 3, NOTCH3       100 , yes
 Notch 4, NOTCH4        90,  yes
PROTEASES
Disintegrin and metalloprotease 10,  ADAM10,   100, yes.
Disintegrin and metalloprotease 17, ADAM17, 100 yes.
Presenilin 1, PSEN1,   100, yes.
Presenilin 2, PSEN2,  100, yes.
Anterior pharynx defective 1 homolog,  AAPH1A,  100, yes.
Anterior pharynx defective 1 homolog,  BAPH1B,  100, yes.
Presenilin enhancer 2  homolog, PSENEN,    100, yes. 
 Nicastrin,  NCSTN, 100, yes.
TRANSCRIPTION FACTORS
 CBF1;
 CSL; 
recombining binding protein suppressor of hairless RBPSUH  100,  yes.
COACTIVATORS 
 Mastermind-like 1, MAML1,  100, yes.
 Mastermind-like 2,  MAML2,  100, yes.
 Mastermind-like 3,  MAML3,  100, yes.
 Lymphocyte-activation gene 3, LAG3,  5,  no.
Nuclear receptor co-repressor 2,  NCOR2,   100, yes.
DOWNSTREAM EFFECTORS
 Hairy & enhancer of split 1, HES1, 100,  yes.
Hairy & enhancer of split 2, HES2,  90, yes.
Hairy & enhancer of split 5, HES5,  50,  yes.
Hairy/enhancer-of-split related with YRPW motif 1,HEY1, 100, yes.
Hairy/enhancer-of-split related with YRPW motif 2, HEY2, 100, yes. 
Hairy/enhancer-of-split related with YRPW motif-like, HEYL, 90, yes. 
MODULATORS
Positive MODULATORS
Neuralized-like, NEURL,(RNF67,  RING Finger Protein 67   45, no.
Neuralized-like 2,  NEURL2 (Neuralized E3 Ubiquitin Protein Ligase 2),   0, no.
Mindbomb homolog 1, MIB1,( E3 ub ligase) ,ZZZ6, ZZANK2 100,  yes. (SARS2 nsp9 interaction protein)
Mindbomb homolog 2, MIB2,( ZZZ5),  100, yes. 
Protein O-fucosyltransferase 1, POFUT1,  40, no.
Protein O-fucosyltransferase 2,  POFUT2, 100, yes.
Ligand of numb-protein X,  LNX ,(RING-Type E3 Ubiquitin Transferase LNX;  PDZRN2), ,  100, yes.
Seven in absentia homolog 1, SIAH1,RINGtype E3 ubiquitin ligase,   100, yes.  
Musashi homolog 1, MSI1,    0, no. 
Musashi homolog 2, MSI2, 100, yes.
Dynamin 1, DNM1,   15, no.
Dynamin 2, DNM2,   95,  yes.
Dynamin 3, DNM3,  35, no.
Negative MODULATORS 
Hairy & enhancer of split 6, HES6,  95, yes.
 ITCHY homolog, ITCH, 100, yes.
 Neural precursor cell expressed, developmentally, down-regulated 4, NEDD4, 90, yes.
NUMB homolog, NUMB, 100, yes.
 Adaptor-related protein complex 2, a2 subunit [ora2]AP2A2,  100, yes.(SARS-2 nsp10 interaction protein)
 F-box & WD-40 protein 7, FBXW7, 100, yes.
SPEN homolog, SPEN, 100, yes.
MIXED/unknown MODULATORS
Radical fringe, RFNG, 90, yes.
 Lunatic fringe,LFNG, 60, yes.
 Manic fringe, MFNG, 75, yes.
Deltex homolog 1, DTX1, 0,no.
 Deltex homolog 2, DTX2, 100, yes, 
 Furin, FURIN, 75, yes. 

Geeni POFUT1 vaikuttaa NOTCH, EGF- signalointialueella

"Six signal transduction system, notch, EGF, FGF, TGFbeta, Hedgehog, and Wnt, are utilized to provide spatial inputs in a myriad of diverse subcircuits in the development of any bilaterian, and in different contents  in different bilaterians. Though in their internal biochemical interactions these signal transduction cassetes are higly conserved across the bilateria, they are indeed "plugged in" at all levels of gene regulatory networks, in all sorts of regulatory spatial  specification processes.
Lähde:
Eric H. Davidson. 2006.
The Regulatory genome:Gene regulatory network in Development and Evolution.  p. 194."


Otan tänään  23.6. 2020  lisätietoja eräästä SARS-2 viruksen  interaktioproteiinista POFUT1.  se mainitaan listassa ORF8 interaktioproteiinina.  Olen tänään nimittäin ktomassa glycocalicasiaa ja veriryhmäepitooppeja. Niissä on FUT- entsyymeitä mainittu.  Tässä on eri joukon FUT, POFUT1 entsyymi siirtää fukoosia jonkin proteiinin seriini- tai threoniinin tähteeseen O-välitteisesti .  Vain seriinillä ja threoniinilla on - OH ryhmä ja siihen sivuhaaraan voi tapahtua  glycocalix epitooppien kertymää, niitä oligosakkarideja. 


POFUT1 (20q11.219

Aliases for POFUT1 Gene

Protein O-Fucosyltransferase 1 ^{2 3 5}
GDP-Fucose Protein O-Fucosyltransferase 1 ^{2 3 4}
Peptide-O-Fucosyltransferase 1 ^{3 4}
EC 2.4.1.221 ^{4 52}
O-FucT-1 ^{3 4}
FUT12 ^{3 4}

O-Fucosyltransferase Protein ³
Peptide-O-Fucosyltransferase ²
KIAA0180 ⁴
O-Fuc-T ³
OFUCT1 ³
O-FUT ³
DDD2 ³

 POFUT1 Gene. This gene encodes a member of the glycosyltransferase O-Fuc family. This enzyme adds O-fucose through an O-glycosidic linkage to conserved serine or threonine residues in the epidermal growth factor-like (EGFL)  repeats of a number of cell surface and secreted proteins. O-fucose glycans are involved in ligand-induced receptor signaling. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

GeneCards Summary for POFUT1 Gene

POFUT1 (Protein O-Fucosyltransferase 1) is a Protein Coding gene. Diseases associated with POFUT1 include Dowling-Degos Disease 2 and Dowling-Degos Disease. Among its related pathways are Notch Signaling Pathway (WikiPathways) and Pre-NOTCH Expression and Processing. Gene Ontology (GO) annotations related to this gene include fucosyltransferase activity and peptide-O-fucosyltransferase activity.

UniProtKB/Swiss-Prot Summary for POFUT1 Gene

Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs). OFUT1_HUMAN,Q9H488

Kerään  tään mainitut   vaikutuskohteet.

NOTCH,  EGEF repeats https://www.genecards.org/cgi-bin/carddisp.pl?gene=NOTCH1&keywords=NOTCH1

FRINGE/RFNG, acetylglucosaminyltransferase

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

FRINGE,  https://www.genecards.org/cgi-bin/carddisp.pl?gene=LFNG&keywords=FRINGE

DLL1, (Delta like canonical Notch ligand 1), https://www.genecards.org/cgi-bin/carddisp.pl?gene=DLL1&keywords=DLL1

JAGGED1,  ( Notch 1ligand) , https://www.genecards.org/cgi-bin/carddisp.pl?gene=JAG1&keywords=JAGGED1

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

AChR, https://www.genecards.org/cgi-bin/carddisp.pl?gene=CHRNE&keywords=ACHR

• Kuva NOTCH signalointikartasta. modulaattorien joukossa n-kyy tämä POFUT1.Fukosylaation merkitys on signaalitien tarkennuksessa ja viitoituksessa.
   KUVA netistä: https://www.researchgate.net/profile/Adriana_Heguy/publication/23687986/figure/fig1/AS:341171915247620@1458353131550/The-Notch-pathway-in-mammals-The-pathway-is-triggered-by-the-Delta-like-or-Jagged.png

The Notch pathway in mammals. The pathway is triggered by the Delta-like or Jagged ligands interacting with one or more of the Notch receptors. The pathway is activated by intracellular cleavage of a Notch receptor, releasing the Notch intracellular domain, which translocates to the nucleus where it activates CBF1 (gene symbol, RBPSUH), the primary transcription factor to activate downstream Notch effector pathways (Hes1, 2, 5; Hey1, 2 and L). A variety of transcriptional coactivators and cytoplasmic and nuclear modulators tune the pathway, providing multiple points of control. When Notch signaling is active, differentiation is suppressed . When Notch signaling is turned ''off,'' differentiation to specific cell fates is allowed to proceed.

•  Otan netistä toisenkin kuvan  Agrin proteiinin  ja asetylkoliinireseptorin  ryhmittyminen (AchR)  näkyy siinä. 

https://www.researchgate.net/figure/Agrin-Lrp4-MuSK-pathways-leading-to-AChR-clustering-See-text-for-details_fig2_279750836 
Arnab Barik

Muscle-specific kinase (MuSK) is a RTK that is specifically expressed in skeletal muscle fibers and critical for the formation and maintenance of the neuromuscular junction (NMJ), a peripheral synapse formed between motoneurons and muscle fibers (1, 2). The acetylcholine receptors (AChRs) are concentrated at the crest of junctional folds on muscle...

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Siisrsin tämän SARS-2 proteiini-proteiini-interaktioproteiinin asian  Solusykli blogiini, koska  tänmä interaktioalue  on   NOTCh signalointikartasta, joten vaikutus ulottuu transkriptiotasoon.

Pneumosyytti I ei lisäänny mutta Pneumosyytti II voi tuottaa myös tyyppi I solua.

https://pubmed.ncbi.nlm.nih.gov/30865885/

Abstract

Lung alveolar type I cells (AT1) and alveolar type II cells (AT2) regulate the structural integrity and function of alveoli. AT1, covering ∼95% of the surface area, are responsible for gas exchange, whereas AT2 serve multiple functions, including alveolar repair through proliferation and differentiation into AT1. However, the signaling mechanisms for alveolar repair remain unclear. Here, we demonstrate, in Pseudomonas aeruginosa-induced acute lung injury in mice, that non-canonical Notch ligand Dlk1 (delta-like 1 homolog, DLL1) is essential for AT2-to-AT1 differentiation. Notch signaling was activated in AT2 at the onset of repair but later suppressed by Dlk1. Deletion of Dlk1 in AT2 induced persistent Notch activation, resulting in stalled transition to AT1 and accumulation of an intermediate cell population that expressed low levels of both AT1 and AT2 markers. Thus, Dlk1 expression leads to precisely timed inhibition of Notch signaling and activates AT2-to-AT1 differentiation, leading to alveolar repair.

Keywords: Dlk1; Notch; alveoli; lung; progenitor type II cell.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reser


Dlk1 (14q32.2 )

Entrez Gene Summary for DLK1 Gene

This gene encodes a transmembrane protein that contains multiple epidermal growth factor (EGF) repeats that functions as a regulator of cell growth. The encoded protein is involved in the differentiation of several cell types including adipocytes. This gene is located in a region of chromosome 14 frequently showing unparental disomy, and is imprinted and expressed from the paternal allele. A single nucleotide variant in this gene is associated with child and adolescent obesity and shows polar overdominance, where heterozygotes carrying an active paternal allele express the phenotype, while mutant homozygotes are normal. [provided by RefSeq, Nov 2015] GeneCards Summary for DLK1 (Delta Like Non-Canonical Notch Ligand 1) is a Protein Coding gene. Diseases associated with DLK1 include Idiopathic Central Precocious Puberty and Temple Syndrome. Among its related pathways are Notch Signaling Pathway (WikiPathways) and Signaling by GPCR. Gene Ontology (GO) annotations related to this gene include calcium ion binding. An important paralog of this gene is PEAR1.

 https://www.genecards.org/cgi-bin/carddisp.pl?gene=DLK1&keywords=Dlk1  
 Aliases for DLK1 Gene

• Delta Like Non-Canonical Notch Ligand 1 ^{2 3 5}
• Protein Delta Homolog 1 ^{3 4}
• DLK-1 ^{3 4}
• DLK ^{3 4}
• PG2 ^{3 4}
• Delta-Like 1 Homolog (Drosophila) ²
• Delta-Like Homolog (Drosophila) ²
• Preadipocyte Factor 1 ³

• Delta-Like 1 Homolog ³
• Fetal Antigen 1 ³
• Secredeltin ³
• Delta1 ³
• Pref-1 ³
• PREF1 ³
• FA1 ³
• ZOG ³