Valaiseva artikkeli ERAD koneistosta ja proteiinin laadun kontrollista ERQC

Artikkeli valaisee myös syitä, miksi patogeenit kaappaavat tämän järjestelmän   kehittäessään evaasiomentelemiään.
https://www.sciencedirect.com/science/article/pii/S1097276515004499

• ERAD, Endoplasmiseen retikuluumiin assosioitunut  proteiininhajoitustyö 

  Artikkelissa asnnetaan esimerkkejä  proteiinien ja toksiinien tavasta hyödyntää ERAD- järjestelmää. samlal tutkijat kuvaavat imettäväisissä ilmenevän ERAD järjestelmän ja  sen palstiset ja mahdolliset mekaaniset joustavuudet, mikä auttaa ymmärtämään paremmin ERAD-fysioliogiaa ja patologiaa.

 A number of studies revealed various instances of pathogenic hijacking of host cell ERAD. In this Review, we describe physiological mammalian ERAD and the colorful modalities of pathogenic hijacking of ERAD, in which pathogens exploit the complex ERAD machinery in a variety of manners, and discuss the plasticity and potential mechanical flexibility of the ERAD machinery for a better understanding of physiological and pathological ERAD.

• Proteiinin laadunkontrollijärjestelmän (ERQC) kolme akselia   endoplasmisessa retikulumissa

ERQC

Secreted or membrane proteins are first synthesized at the ER and are subsequently transported along the secretory pathway. Protein synthesis at the ER is highly active and accounts for more than one-third of total protein synthesis in the cell, whereas the ER presumably occupies only one-tenth of the total cell volume, indicating that the ER is extremely crowded with newly synthesized proteins. Nascent and unfolded proteins are unstable because their hydrophobic moieties are yet to be embedded in the inner surface of the target structure and tend to be entangled with each other via non-specific hydrophobic interactions. Even after protein folding is completed, matured proteins are continuously exposed to cellular stresses, including heat stress and ER stress, and are often denatured within the cell, resulting in the exposure of hydrophobic moieties to molecular surfaces. This further leads to polypeptide aggregation and cytotoxicity (Hartl and Hayer-Hartl, 2002). ERQC is a comprehensive maintenance system for the highly crowded proteins in the ER and consists of three axes.

•  Kolme  ER-akselia proteiinin laadunkontrollissa  (ERQC)

  I. Ensimmäinen  akseli koskee proteiinien laskostumista (folding)  ja siinä mainitaan kaitsijaproteiinien (chaperone)  ja entsyymien  kolme ryhmäa . 1) B1P, joka edistää proteiinin laskostumista, 2) ER- oksidoreduktasit:  PDI,  proteiinidisulfidi-isomeraasi, ERO1, ER oxidoreduktaasi ja ERp57, joka oksidoi  cysteiiniä ja oikaisee  disulfidisillat  paralleeleiksi tuoreissa proteiineissa ja 3) lektiinin kaltaiset kaitsijaproteiinit  calnexiini (CNX ja calretikuliini.

  II. Toinen kvaliteettikontrollin  akseli  on   laskostumattomien (unfolded) tai viallisesti laskostuneiden (missfolded)   proteiinien vaste (UPR) . Kun laskostuamttomien proteiinien taso endoplasmisessa verkostossa (ER) ylittää laskostuskapasiteetin , alkaa (stressinä ) kertyä endoplasmiseen retikulumiin  kuormaa ja   ER turpoa a- kolme  eri proteiinia  ER kalvossa tunnistaa tilanteen IRE1, PERK ja ATF6 ja niistä triggeröityy alavirran tapahtumia,  ja samalla  translaatiota  vähennetään ja  laskostavia proteiinejä teetetään lisää   ja myös  hajoittavia  tekijöitä, ERAD -koneiston jäseniä, aletaan tuottaa.

  III. akseli on varsinainen ERAD-koneiston funktio, josta  erikseen-.

Three Axes of ERQC

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.

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).

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