Protein folding and quality control in the endoplasmic reticulum: Recent lessons from yeast and mammalian cell systems

Abstract

Summary The evolution of eukaryotes was accompanied by an increased need for intracellular communication and cellular specialization. Thus, a more complex collection of secreted and membrane proteins had to be synthesized, modified, and folded. The endoplasmic reticulum (ER) thereby became equipped with devoted enzymes and associated factors that both catalyze the production of secreted proteins and remove damaged proteins. A means to modify ER function to accommodate and destroy misfolded proteins also evolved. Not surprisingly, a growing number of human diseases are linked to various facets of ER function. Each of these topics will be discussed in this article, with an emphasis on recent reports in the literature that employed diverse models.

Sterol-induced dislocation of 3-Hydroxy-3-methylglutaryl coenzyme A reductase from membranes of permeabilized cells

“…It is widely accepted that after their selection, soluble ERAD substrates are transported across the ER membrane into the cytosol through a protein-conducting channel formed by Sec61, a component of the translocation channel that imports nascent polypeptides into the ER, the polytopic Derlin proteins, or the membrane domain of ubiquitin ligases that initiate substrate ubiquitination (Lilley and Ploegh, 2004;Ye et al, 2004;Meusser et al, 2005;Brodsky and Skach, 2011). The ER-to-cytosol dislocation of membrane-bound ERAD substrates, especially of those with multiple membrane-spanning segments like reductase, is less well understood.…”

“…Cytosolic dislocation is a key step in the ERAD of substrates that are not only entirely soluble within the lumen of the ER, but also integrated into ER membrane through one or more transmembrane helices (Brodsky and Skach, 2011). It is widely accepted that after their selection, soluble ERAD substrates are transported across the ER membrane into the cytosol through a protein-conducting channel formed by Sec61, a component of the translocation channel that imports nascent polypeptides into the ER, the polytopic Derlin proteins, or the membrane domain of ubiquitin ligases that initiate substrate ubiquitination (Lilley and Ploegh, 2004;Ye et al, 2004;Meusser et al, 2005;Brodsky and Skach, 2011).…”

A Shared Endoplasmic Reticulum-associated Degradation Pathway Involving the EDEM1 Protein for Glycosylated and Nonglycosylated Proteins

“…A pathway has been delineated, which involves lectin chaperones, glycosidases, and components of a putative retrotranslocation machinery, some of which also possess lectin activity, for delivery to the cytosolic proteasomes (1)(2)(3)(4)(5). The chain of events that leads a nascent glycoprotein through ER quality control and toward proper folding or ERAD involves processing of its N-glycans and their interactions.…”

How Viruses Use the Endoplasmic Reticulum for Entry, Replication, and Assembly

“…Once a newly synthesized protein is translated and folded properly in the ER lumen, it exits the ER to reach the Golgi apparatus via membrane budding mediated by the COPII complex. By contrast, should a protein misfold in the ER, an endogenous ER quality control system called ER-associated degradation (ERAD) alleviates the build-up of misfolded ER proteins (Brodsky and Skach 2011;Smith et al 2011). To do so, a network of ER factors recognizes and retrotranslocates the misfolded protein to the cytosol.…”