Chaperoning Endoplasmic Reticulum–Associated Degradation (ERAD) and Protein Conformational Diseases

Abstract

Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding compartment and whose function requires stringent protein quality-control systems. Multiprotein complexes in the ER are able to identify, remove, ubiquitinate, and deliver misfolded proteins to the 26S proteasome for degradation in the cytosol, and these events are collectively termed ERassociated degradation, or ERAD. Several steps in the ERAD pathway are facilitated by molecular chaperone networks, and the importance of ERAD is highlighted by the fact that this pathway is linked to numerous protein conformational diseases. In this review, we discuss the factors that constitute the ERAD machinery and detail how each step in the pathway occurs. We then highlight the underlying pathophysiology of protein conformational diseases associated with ERAD.

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

“…The ER is an important organelle where secreted and transmembrane proteins are synthesized and correctly folded into three-dimensional conformations. The above dynamic process requires highly precise regulation to maintain protein homeostasis [20]. Any stimuli that break the above equilibrium will trigger the unfolded protein response (UPR) and the occurrence of ER stress [21].…”

Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease

“…Under optimal biological conditions where the PN is highly dynamic, the level and balance of individual components are rapidly adjusted to compensate for changes in proteostatic load. This is accomplished by the coordinated activities of a suite of cell stress responses, including the HSR, the unfolded protein responses (UPRs) of the endoplasmic reticulum (UPR ER ) and mitochondria (UPR MT ) and their respective stress-responsive transcription factors HSF1, XBP1, ATF6, and ATFS-1, all with essential roles in the regulation of the PN (Preissler and Ron 2018;Karagöz et al 2019;Naresh and Haynes 2019;Needham et al 2019). In metazoans, these factors merge with the stress-signaling properties of the antioxidant factor SKN-1/NRF2, the insulin-signaling factor DAF-16/FOXO, and the tissue identity factor PHA-4/FOXA to more fully orchestrate organismal survival to diverse environmental and physiological stress conditions and to ensure tissue and compartment specific PN remodeling to prevent molecular damage.…”

N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases

“…The N-terminal and C-terminal sequences, which are rich in hydrophobic residues, are removed as a signal peptide sequence and a GPI-anchor signal sequence, respectively, in the ER ( Figure 1 A) [ 17 , 18 ]. PrP C also undergoes several post-translational modifications en route to the cell surface, including a GPI anchor attachment at the C-terminus, N -glycosylation at two sites, and formation of a disulfide bond in the C-terminal domain ( Figure 1 A) [ 19 , 20 , 21 , 22 , 23 , 24 ]. On the cell surface, PrP C is predominantly localized at the so-called “raft” domains and constitutively internalized via clathrin- and caveolae-dependent endocytosis ( Figure 1 B) [ 25 , 26 , 27 ].…”