Abstract
In response to environmental stimuli, cells make a series of adaptive changes to combat the injury, repair the damage, and increase the tolerance to the stress. However, once the damage is too serious to repair, the cells will undergo apoptosis to protect the overall cells through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions to form protein aggregation, which may ultimately produce serious damage to the cells. Ubiquitin plays an important role in the degradation of these unnatural proteins by tagging with ubiquitin chains in the ubiquitin–proteasome or autophagy system. If the two processes fail to eliminate the abnormal protein aggregates, the cells will move to apoptosis and death. Dysregulation of ubiquitin–proteasome system (UPS) and autophagy may result in the development of numerous diseases. This review focuses on the molecular mechanisms of UPS and autophagy in clearance of intracellular protein aggregates, and the relationship between dysregulation of ubiquitin network and diseases.
Highlights
Under environmental stimuli, cell maintains the cellular homeostasis by increasing tolerance to damage and repairing damaged macromolecules and organelles
When folded proteins gather in the endoplasmic reticulum, GRP78 binds to the unfolded protein, and activating transcription factor 6 (ATF6), PKR-like ER kinase (PERK), and inositol requiring enzyme 1 (IRE1) are released and activated; the unfolded protein signal is transduced across the endoplasmic reticulum to the cytoplasm and nucleus (Figure 1)
Maintaining the homeostasis of ubiquitin pools is very crucial for protein quality control, and transcription factors which respond to external stimuli and deubiquitination enzymes play an important role in ubiquitin pool homeostasis
Summary
Cell maintains the cellular homeostasis by increasing tolerance to damage and repairing damaged macromolecules and organelles. Common stimuli include heat stress, oxidative stress, hypoxic stress, and DNA damage, which will quickly destroy the protein-folding ability of the endoplasmic reticulum (ER) and induce accumulation of misfolded and unfolded proteins in the ER [2]. To deal with this situation, the stressed cells activate the unfolded protein response (UPR) [3–5]. Abnormal proteins are cleared by the endoplasmic-reticulum-associated degradation pathway (ERAD), which transports the unfolded and misfolded proteins out of the ER by retro-translocation and is further degraded by the ubiquitin–proteasome system and autophagy [3,4,6]. The PERK/ATF4 axis induces the expression of chaperones and proteins involved in autophagy [7], apoptosis, and redox homeostasis. We first briefly summarize the ubiquitin pool, UPS, and autophagy and discuss, in detail, various examples of coordination and crosstalk between them and dysregulation of UPS and ubiquitin-mediated autophagy pathways in human diseases, neurodegenerative diseases, and cancer, in particular
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