Protein Quality Control in the Cytosol and the Endoplasmic Reticulum: Brothers in Arms

Abstract

In cells, both newly synthesized and pre-existing proteins are constantly endangered by misfolding and aggregation. The accumulation of damaged proteins can perturb cellular homeostasis and provoke aging, pathological states, and even cell death. To avert these dangers, cells have developed powerful quality control strategies that counteract protein damage in a compartment-specific way. Here, we compare the protein quality control systems of the eukaryotic cytosol and the endoplasmic reticulum, focusing on the principles of damage recognition, the triage decisions between chaperone-mediated refolding and proteolytic elimination of damaged proteins, the repair of misfolded and aggregated protein species, and the mechanisms by which perturbations of protein homeostasis are sensed to induce compartment-specific stress responses.

Tissue damage control in disease tolerance

“…Accumulation of misfolded proteins is a form of macromolecular damage associated with different forms of stress 51 . When misfolded proteins accumulate in the cytosol or in the ER these trigger two distinct damage-responses, namely the heat shock response 52,53 and the unfolded protein response (UPR) 51,54,55 , respectively (Fig.4).…”

“…When misfolded proteins accumulate in the cytosol or in the ER these trigger two distinct damage-responses, namely the heat shock response 52,53 and the unfolded protein response (UPR) 51,54,55 , respectively (Fig.4). The hallmarks of these proteotoxic responses are: i) broad suppression of protein synthesis and ii) transcriptional up-regulation of a subset of immediate early-responsive genes that escape translational repression, and repair protein damage and/or destroy unfolded proteins 29,51 . To what extent the heat shock and the UPR impact the severity of infectious diseases is not clear.…”

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

“…Among these proteins are several redox enzymes such as peroxiredoxins and superoxide dismutases, which are dysregulated in a large cohort of cancers (15,34). Moreover, endosomal redox stress response proteins (35,36) were identified including T-complex chaperones, heat shock proteins, protein-disulfide isomerases as well as co-chaperones. Furthermore, we identified mediators of posttranscriptional mRNA processing such as heterogeneous nuclear ribonucleoproteins, THO complex proteins, and eukaryotic translation initiation factors (Supplementary Table S4).…”

The proteasomal subunit Rpn6 is a molecular clamp holding the core and regulatory subcomplexes together

“…26S proteasome | cryoelectron microscopy | PSMD11 | S9 | PCI domain P rotein degradation is of vital importance for the maintenance of protein homeostasis, for the removal of misfolded proteins, and for the control of numerous regulatory processes (1,2). In eukaryotic cells, the main pathway for protein degradation is the ubiquitin-proteasome system (3).…”