ERAD koneisto on monen viruksen kaappaama, myös SARS2 CoV omaa tekijöitä, jotka tekevät siihen interaktiota

•  https://www.researchgate.net/profile/Timothy_Bergmann/publication/309439006/figure/fig3/AS:716405699784706@1547815837565/Folding-and-quality-control-of-glycosylated-proteins-within-the-ER-N-glycans-are.ppm

 

• ERAD koneistosta  artikkeleita.
•  ERAD  tarkoittaa endoplasmiseen retikulumiin(ER)  assosioitunutta hajoitusjärjestelmää, joka on solutalouden kannalta eräänlainen tarkka hyödynnyslaitos  tekovikamaterialle, jota ei onnistuta korjaamaan. 
• Virukset ja toksiinit kaappaavat tätä  järjestelmää.

https://www.sciencedirect.com/science/article/pii/S1097276515004499

ER-associated degradation (ERAD) is a protein clearance mechanism by which misfolded, misassembled, or metabolically regulated proteins are specifically dislocated from the ER into the cytosol and degraded by the ubiquitin proteasome system. 

 ERAD very likely evolved to maintain proteostasis and sterol homeostasis in the ER. 

However, the ironic truth is that membrane-penetrating transportation and protein degradation machineries in ERAD are preferably hijacked by exogenous pathogens such as viruses and toxins for their invasion and evasion from immunological surveillance. In this Review, we provide an overview of our current understanding of the pathogenic hijacking of the host cell ERAD, in which pathogens exploit the complex ERAD machinery in a variety of manners for their own use, suggesting flexibility and plasticity of the molecular machinery of ERAD.

• ERAD koneisto  toimii endoplasmisen retikulumin (ER)    syntetisoimien  proteiinin laadunkontrollijärjestelmänä (QC)  (Quality Control ) 
• Tämä ERQC käsittää  useita vaiheita ja lukuisia  komponentteja.

ERAD functions in ER protein quality control (ERQC) and sterol regulation (Ruggiano et al., 2014). Over the past two decades, it has been elucidated that ERQC-related ERAD is a multi-step and branched process that has numerous components (Araki and Nagata, 2011, Christianson and Ye, 2014).

 ERQC kolme akselia.

Three Axes of ERQC

I akseli  on proteiinien laskostuminen.  Useimmat  Endoplasmisessa retikulumissa (ER)  syntetisoituneista proteiineista  ovat modifioitu kovalenttisesti  molekyylien nsisäisten ja välisten disulfidisiltojen (-S-S-)   ja oligosakkaridiketjujen avulla  (OS) samanaikaisesti kun peptidiä syntetuisoidaan ja laskostetaan. Näitten modifikaatioitten avulla proteiinit saavat  sellaista kestokykyä, jolla  ne pysyvät elossa myös solun ulkopuolisessa miljöössä.  Tähän modifikaatioon kytkeytyneeseein proteiinien laskostumiseen osallistuu  kolme molekulaarista kaitsijaproteiiniryhmää
(Chaperoneproteiini = kaitsijaproteiini).
I chaperone-proteiiniryhmä  on immunoglobuliinin raskaan ketjun sisältävä BiP, joka kuuluu  HSP70-proteiiniperheeseen ja se edistää proteiinin laskostumista sisäisellä ATP.ta hydroplysoivalla aktiivisuudella.
II chaperoneproteiiniryhmä  ovat ER oxidoreduktaasit, kuten
PDI, proteiinidisulfidi-isomeraasi;
ERO1, ER oxidoreductiini-1.
ja ERp57, joka oksidoi cysteiinitähteitä , siis muodostaa niissä  disulfidisiltoja (-S-S-).
III chaperoniproteiiniryhmä ovat kalnexiini (CNX)  ja kalretikuliini(CRT). Ne ovat lektiinien kaltaisia kaitsijoita ja ne tunnistavat  oligosakkaridiketjuja vastasyntetisoituneissa  glykoproteiineissa ja edistävät proteiinin laskostumista.
Eräät näistä mainituista tekijöistä osallistuvat myös ERAD.iin ja moni patogeeni hyödyntää niitä. ( Esim SARSc  tekee interaktion ER- kalvoon integroituneeseen   kalnexiiniin , mutta  välttää interaktiota luminaaliseen  kalretikuliiniin, jolloin se häiritsee  CRT/CNX toimintasykliä). 
https://kyushu-u.pure.elsevier.com/en/publications/monitoring-of-s-protein-maturation-in-the-endoplasmic-reticulum-b

• Monitoring of s protein maturation in the endoplasmic reticulum by calnexin is important for the infectivity of severe acute respiratory syndrome coronavirus  Masaya Fukushi, Yoshiyuki Yoshinaka et al    Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of SARS, a fatal pulmonary disorder with no effective treatment. We found that SARS-CoV spike glycoprotein (S protein), a key molecule for viral entry, binds to calnexin, a molecular chaperone in the endoplasmic reticulum (ER), but not to calreticulin, a homolog of calnexin. . These findings demonstrated that calnexin strictly monitors the maturation of S protein by its direct binding, resulting in conferring infectivity on SARS-CoV.

The first axis of ERQC is protein folding (Araki and Nagata, 2011). Most newly synthesized proteins in the ER are covalently modified with intra- and/or inter-molecular disulfide bonds and oligosaccharide chains in parallel with their synthesis and folding. These modifications reinforce the structure of these proteins such that they can survive in the extracellular environment. Three groups of molecular chaperones and folding enzymes majorly contribute to modification-coupled protein folding. The first group includes classic molecular chaperones, such as immunoglobulin heavy chain-binding protein (BiP), which belongs to the heat shock protein 70 family and promotes protein folding with an intrinsic ATP-hydrolyzing activity (Otero et al., 2010). The second group consists of ER oxidoreductases, such as protein disulfide isomerase (PDI), ER oxidoreductin 1 (ERO1), and ERp57, which oxidize substrate cysteine residues (synonymous with the formation of a disulfide bond) and isomerize improperly oriented disulfide bonds in parallel with de novo protein synthesis and folding (Ellgaard and Ruddock, 2005). The third group consists of lectin-like chaperones such as calnexin and calreticulin, which recognize oligosaccharide chains attached to newly synthesized glycoproteins and promote protein folding (Helenius and Aebi, 2004). 

Some of these factors also participate in ERAD and are occasionally utilized by pathogens, as discussed later.

II akseli on vaste proteiinin laskostumattomuuteen. (UPR,  Unfolded protein response). 

Jos jostain syystä proteiinit eivät laskostu  tai laskostuvat väärin ja jos  tällaista materiaalia kertyy endoplasmiseen verkostoon  ylen määrin, ylittyy   kapasiteetti  saada  tätä materiaalia  pois endoplasmisesta   verkostosta.
 Näitä proteiineja, joiden  tehtäviin kuluu tunnistaa  laskostumattomien proteiinien   ylikuormitusta,   ovat  PERK, ATF6 ja IRE1, ja ne pystyvät  kukin  tiettyä  tietään  aloittamaan alavirran tapahtumia kuten translaation vaimentamista ja  laskostavien entsyymien ERAD- tekijöiden   ylössäätämistä jotta ER  ylikuormitus tila korjautuisi ja ER  proteostaasi palautuisi. ESIM: https://www.frontiersin.org/articles/10.3389/fendo.2018.00210/full
https://www.frontiersin.org/files/Articles/364990/fendo-09-00210-HTML/image_m/fendo-09-00210-g001.jpg 

The second axis of ERQC is the unfolded protein response (UPR). When the level of unfolded or misfolded proteins accumulated in the ER exceeds the folding and clearance capacity of the ER for any reason, particular ER membrane proteins such as PERK, ATF6, and IRE1 sense the overloaded state and initiate downstream events, including translation attenuation and upregulation of folding enzymes and ERAD factors, which comprehensively reduce the protein burden in the ER and restore ER proteostasis (see previous review articles, e.g., Walter and Ron, 2011). The UPR also involves an apoptotic pathway, which is activated when the cell fails to resolve the stress conditions (Walter and Ron, 2011).

III akseli on varsinainen ERAD. 

Finally, the third axis of ERQC is ERAD, which is described in the next section.

(Tähän laitan  ERAD  kohtaan kuuluvia SARS interaktioproteiineja sitä mukaa kuin löydän. Selenos eli VIMP on yksi näitä.

https://www.researchgate.net/publication/307442236/figure/fig1/AS:403388127825920@1473186632494/ER-associated-degradation-ERAD-pathway-ERAD-is-an-ER-quality-control-pathway-that.png

SELENOS (15q26.2 Aliases for SELENOS Gene, VIMP

Selenoprotein S ^{2 3 4 5}
VCP-Interacting Membrane Protein ^{2 3 4} Valosin-Containing Protein-Interacting Membrane Protein ^{2 3} VCP Interacting Membrane Selenoprotein ^{2 3}
VIMP ^{3 4}, AD-015 ³, ADO15 ³, SBBI8 ³ SEPS1 ³, Tanis ³ , SelS ⁴, SELS ^{3 4}

 https://api.intechopen.com/media/chapter/65506/media/F2.png
 

This gene  SELENOS encodes a transmembrane protein that is localized in the endoplasmic reticulum (ER). It is involved in  ERAD, the degradation process of misfolded proteins in the ER, and may also have a role in inflammation control. This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Two additional phylogenetically conserved stem-loop structures (Stem-loop 1 and Stem-loop 2) in the 3' UTR of this mRNA have been shown to function as modulators of Sec insertion. An alternatively spliced transcript variant, lacking the SECIS element and encoding a non-Sec containing shorter isoform, has been described for this gene (PMID:23614019). [provided by RefSeq, Jul 2017]