ER-ASSOCIATED DEGRADATION

Newly made membrane and secretory proteins enter the ER unfolded via channels called translocons. When in the lumen, chaperones and modifying enzymes aid in post-translational modification to their native conformation where they'll exit the ER. Many factors affect the degree of misfolding, such as mutations, sub stochiometric levels of binding partners and chaperone shortages. Misfolded proteins are often retained in the ER, becoming clients of ER-associated degradation (ERAD). ERAD doesn't have one universal pathway, instead many branches for different misfolded protein classes sharing a universally similar sequence - substrate recognition, retrotranslocation, ubiquitination and degradation [1].

The recognition of misfolded proteins is dependent on their exposed hydrophobic regions, unbonded cysteine residues and immature glycans. Terminally misfolded proteins require removing from lectin-type chaperones such as calnexin and calreticulin (CNX/CRT, respectively). ER degradation enhancing α-mannosidase-like proteins (EDEM) and ER mannosidase 1. The latter protein de-mannosylates one mannose from glycoproteins so that EDEM can recognise it, as they can recognise when the misfolded protein displays 5-7 mannose residues as opposed to the usual 9. The EDEM will aid in the binding of misfolded glycoproteins to lectins such as osteosarcoma amplified 9 (OS9) and XTP3 transactivated gene B (XTP3-B) [2].

OS9 and XTP3-B associate in multimeric complexes, built around one of many E3 ubiquitin ligases of the ER membrane. These complexes functions, termed retrotranslocons, are to transport misfolded proteins into the cytosol for degradation in the 26S proteasome [2]. E3 ubiquitinates the misfolded protein at its cytosolic domain, ready for detection by the proteasome. The E3 ligase specificity depends on the location of the misfolded region on the secretory protein. If misfolded at the cytoplasmic region, it is degraded via the Doa10 complex, whereas if it's misfolded at the luminal or intramembrane regions, the Hrd1 complex is used [1].

When misfolded proteins fail to enter the ERAD, they enter the ER to lysosome associated degradation pathway (ERLAD). Not much is known about this particular pathway. Failure to enter the ERAD arises from many reasons; failure in alerting and engaging chaperones such as BiP and EDEMs, being too large or having tendencies to create aggregates incapable of being dislocated across the ER membrane [2]. These are collectively known as proteasome resistant proteins. They're delivered from the ER lumen or membrane, to degradative endo-lysosomal compartments. This is done either autophagically, where the endo-lysosme will engulf and degrade the ER or non-autophagically, where they'll deliver misfolded proteins to the endolysosome via membrane fusion [3].