ERAD, physiological machinery of normal degradation of new unfolded and misfolded, failed to fold - proteins

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

Most newly synthesized proteins at the ER are N-glycosylated with oligosaccharide chains possessing G3M9 (three glucoses and nine mannoses) (Figure 2) (Helenius and Aebi, 2004). 

Glucoses in the N-glycan chains are subsequently trimmed off by glucosidases I and II, resulting in the mono-glucose form of N-glycans. This form of N-glycan chain is recognized by lectin-like chaperones, calnexin and calreticulin, which support folding of the carrier glycoprotein in conjunction with UDP-glucose glycoprotein glucosyltransferase.

 After the final glucose is trimmed off by glucosidase II, nine mannoses are further processed into five or six mannoses by ER mannosidases for successive ERAD processes.

 Although the exact mechanism that links protein misfolding and mannose trimming remains unclear, the hypothetical “timer model” may explain this. Mannose trimming takes time, and thus could work as a biological timer.

 When the mannose portion is processed into the M5–8 forms and the protein is still not properly folded, the protein is deemed to be terminally misfolded and is recruited into the ERAD pathway by specific lectins (Helenius and Aebi, 2001). 

How mannose residues are trimmed, how they are recognized, the responsible factors, and the mechanism underlying recruitment to ERAD machinery are matters of debate, but current understanding is depicted in Figure 2.

 ERAD-enhancing mannosidase-like protein 1 (EDEM1) was identified as a potential lectin that specifically recognizes a misfolded glycoprotein with an oligosaccharide chain of the M8 form, receives it from calnexin, and moves it into the ERAD pathway (Figure 3) (Oda et al., 2003).

 A recent study by Mori and colleagues raises a new model: EDEM2, one of three EDEM homologs, serves as a mannosidase that predominantly trims mannose in the B branch of oligosaccharide chains from M9 to M8;

 the other homolog, EDEM3, trims mannose in the A branch from M8 to M5–7; and the mannosidase activity of EDEM1 is modest (Ninagawa et al., 2014) (Figure 2). 

 Osteosarcoma 9 (OS9), another lectin, recognizes the M5–7 forms and recruits them to membrane penetration machinery through a direct interaction with a core component of the machinery, SEL1L (Figure 3) (Christianson et al., 2008; Denic et al., 2006).

 It should also be noted that EDEM1 forms a complex with the first-identified ER reductase, ERdj5, which reduces disulfide bonds of misfolded substrates and is believed to generate an extended form of the polypeptide to facilitate its membrane translocation (Figure 3) (Hagiwara et al., 2011; Ushioda et al., 2008).