Protein Quality Control in the Endoplasmic Reticulum

Abstract

The site of protein folding and maturation for the majority of proteins that are secreted, localized to the plasma membrane or targeted to endomembrane compartments is the endoplasmic reticulum (ER). It is essential that proteins targeted to the ER are properly folded in order to carry out their function, as well as maintain protein homeostasis, as accumulation of misfolded proteins could lead to the formation of cytotoxic aggregates. Because protein folding is an error-prone process, the ER contains protein quality control networks that act to optimize proper folding and trafficking of client proteins. If a protein is unable to reach its native state, it is targeted for ER retention and subsequent degradation. The protein quality control networks of the ER that oversee this evaluation or interrogation process that decides the fate of maturing nascent chains is comprised of three general types of families: the classical chaperones, the carbohydrate-dependent system, and the thiol-dependent system. The cooperative action of these families promotes protein quality control and protein homeostasis in the ER. This review will describe the families of the ER protein quality control network and discuss the functions of individual members.

Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery

“…Thus, they belong to that part of the cell proteome translocating into the endoplasmic reticulum (ER) for maturation and eventually entering the secretory pathway to reach the cell surface [9]. In this compartment, a stringent quality control system scrutinizes the newly synthetized proteins in order to: (i) allow the properly folded polypeptides to pass forward and (ii) deliver to degradation those folding-defective [36,37]. This ensures protein homeostasis avoiding, at the same time, the accumulation of potentially harmful species.…”

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

“…Of note, a considerable number of the nucleus-encoded mitochondrial proteins are transcriptionally regulated by -Pal NRF1 and GABP NRF2 (26,27), and also translationally monitored by -Pal NRF1 -targeted eIF2 (21)(22)(23). Particularly, another portion of those nucleus-encoded proteins localized within and around the outer and inner mitochondrial membranes are allowed for biosynthesis in proximity to the ribosome-budded ER, because the ER is central to biosynthesis of secretory and membrane proteins, their proper folding and processing into maturation by quality controls (31,32), before being transferred to the mitochondria and anchored within double mitochondrial membranes. Moreover, the mitochondrial intermembrane space is evolutionarily homologous to the most oxidizing ER lumen, with a lowest GSH/GSSG ratio of 1:1~3:1, than those in the relative reducing mitochondrial matrix and nuclear environments (with a higher GSH/GSSG ratio of ~100:1) (33)(34)(35).…”

“…Of note, mitochondria-targeting sequences (MTS), nuclear localization signal (NLS) and DNA-binding MHG-box were also indicated. Both MTS1 (aa 1-18) and MTS2 (aa[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] were wheeled into two similar α-helical structures. Basic arginine and lysine residues were placed on blue backgrounds, nucleophilic serine and threonine residues are on purple backgrounds, an unamiable proline residue was on a green background, and all hydrophobic amino acids were on yellow backgrounds, except for small alanine and glycine on grey backgrounds.…”

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

“…The ER is an essential organelle involved in protein synthesis, folding, and trafficking. As protein folding is an error-prone process, the PQC system of the ER is specialized in optimizing this process, thereby preserving cardiac protein quality and homeostasis [13]. As approximately 30% of the cardiomyocyte volume is comprised of mitochondria, the maintenance of a healthy and functional mitochondrial PQC system, which includes molecular chaperones (e.g., HSP60 and HSP10) and proteases (e.g., ClpP), is critical to conserve the energy balance and cardiomyocyte function.…”