Protein quality control in the ER: balancing the ubiquitin checkbook

Abstract

Protein maturation in the endoplasmic reticulum (ER) is subject to stringent quality control. Terminally misfolded polypeptides are usually ejected into the cytoplasm and targeted for destruction by the proteasome. Ubiquitin conjugation is essential for both extraction and proteolysis. We discuss the role of the ubiquitin conjugation machinery in this pathway and focus on the role of ubiquitin ligase complexes as gatekeepers for membrane passage. We then examine the type of ubiquitin modification applied to the misfolded ER protein and the role of de-ubiquitylating enzymes in the extraction of proteins from the ER.

Figure 1. Protein folding in the ER

Schematic overview of a nascent polypeptide entering the ER lumen co-translationally, where it engages folding machinery to obtain its final conformation (folding cycle). Quality control check-point(s) establish the folding status of the poly-peptide which then either proceeds to its final destination or is selectively degraded, either via the dislocation pathway or via a bulk degradation mechanism (e.g. autophagy or lipid droplet formation).

Figure 2. Protein dislocation and/or degradation

Left panel: A proposed model of a dislocated protein that is ubiquitylated at the ER membrane and consequently engaged by p97 via NFD1/NPL4. A de-ubiquitylating enzyme cleaves ubiquitin to allow threading of the polypeptide through the central pore of p97. A hypothesized re-ubiquitylation step post-p97 then facilitates proteasomal targeting. Right panel: A poly-ubiquitin tag targets the protein for proteasomal degradation. The poly-ubiquitin chain is probably modified before it is finally removed to allow threading of the polypeptide through the central pore of the base of the 19S cap and into the proteolytic chamber of the 20S proteasome core particle.