All cellular proteins are subject to quality control “decisions,” which help to prevent or delay a myriad of diseases. Quality control within the secretory pathway creates a special challenge, as ...aberrant polypeptides are recognized and returned to the cytoplasm for proteasomal degradation. This process is termed endoplasmic-reticulum (ER)-associated degradation (ERAD).
Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur ...quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.
The endoplasmic reticulum (ER) serves as a warehouse for factors that augment and control the biogenesis of nascent proteins entering the secretory pathway. In turn, this compartment also harbors the ...machinery that responds to the presence of misfolded proteins by targeting them for proteolysis via a process known as ER-associated degradation (ERAD). During ERAD, substrates are selected, modified with ubiquitin, removed from the ER, and then degraded by the cytoplasmic 26S proteasome. While integral membrane proteins can directly access the ubiquitination machinery that resides in the cytoplasm or on the cytoplasmic face of the ER membrane, soluble ERAD substrates within the lumen must be retrotranslocated from this compartment. In either case, nearly all ERAD substrates are tagged with a polyubiquitin chain, a modification that represents a commitment step to degrade aberrant proteins. However, increasing evidence indicates that the polyubiquitin chain on ERAD substrates can be further modified, serves to recruit ERAD-requiring factors, and may regulate the ERAD machinery. Amino acid side chains other than lysine on ERAD substrates can also be modified with ubiquitin, and post-translational modifications that affect substrate ubiquitination have been observed. Here, we summarize these data and provide an overview of questions driving this field of research.
Protein folding is a complex, error-prone process that often results in an irreparable protein by-product. These by-products can be recognized by cellular quality control machineries and targeted for ...proteasome-dependent degradation. The folding of proteins in the secretory pathway adds another layer to the protein folding "problem," as the endoplasmic reticulum maintains a unique chemical environment within the cell. In fact, a growing number of diseases are attributed to defects in secretory protein folding, and many of these by-products are targeted for a process known as endoplasmic reticulum-associated degradation (ERAD). Since its discovery, research on the mechanisms underlying the ERAD pathway has provided new insights into how ERAD contributes to human health during both normal and diseases states. Links between ERAD and disease are evidenced from the loss of protein function as a result of degradation, chronic cellular stress when ERAD fails to keep up with misfolded protein production, and the ability of some pathogens to coopt the ERAD pathway. The growing number of ERAD substrates has also illuminated the differences in the machineries used to recognize and degrade a vast array of potential clients for this pathway. Despite all that is known about ERAD, many questions remain, and new paradigms will likely emerge. Clearly, the key to successful disease treatment lies within defining the molecular details of the ERAD pathway and in understanding how this conserved pathway selects and degrades an innumerable cast of substrates.
Lysosomal degradation of endoplasmic reticulum (ER) fragments by autophagy, termed ER-phagy or reticulophagy, occurs under normal as well as stress conditions. The recent discovery of multiple ...ER-phagy receptors has stimulated studies on the roles of ER-phagy. We discuss how the ER-phagy receptors and the cellular components that work with these receptors mediate two important functions: ER homeostasis and ER quality control. We highlight that ER-phagy plays an important role in alleviating ER expansion induced by ER stress, and acts as an alternative disposal pathway for misfolded proteins. We suggest that the latter function explains the emerging connection between ER-phagy and disease. Additional ER-phagy-associated functions and important unanswered questions are also discussed.
The selective degradation of the endoplasmic reticulum (ER), termed ER-phagy or reticulophagy, has multiple physiological functions.Many different types of cell stress can induce ER-phagy, including starvation and misfolded protein accumulation.ER-phagy pathways participate in ER homeostasis and ER quality control.ER-phagy performs functions that are independent of the unfolded protein response (UPR) and ER-associated degradation (ERAD).ER-phagy pathways, that play a role in ER quality control, are cytoprotective.
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 ER-associated 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.
To maintain protein homeostasis (i.e., “proteostasis”) and withstand the toxic effects brought about by the presence of misfolded proteins, eukaryotes have evolved a hierarchy of quality control ...checkpoints along the secretory pathway. The most prominent quality control step in this pathway, which acts during or soon after proteins are synthesized, is endoplasmic reticulum associated degradation (ERAD). The importance of this pathway is underscored by the fact that ~80 different protein substrates of the ERAD pathway have been linked to human disease. Although most misfolded proteins in the secretory pathway are eliminated by ERAD, others can exit the ER in COPII vesicles and are instead turned over by lysosomal proteases. This post‐ER quality control event requires the ESCRT machinery. A different class of secreted proteins, particularly those that are aggregation‐prone, can alternatively be degraded by ER‐phagy. To date, it remains elusive how these diverse misfolded proteins‐‐which can trigger various stress responses‐‐are selected for different fates. However, by constructing a collection of model substrates and examining wild‐type and disease‐associated mutant forms of various proteins, we are beginning to define the requirements for the targeted selection of misfolded proteins in the secretory pathway for one fate versus another. This pursuit represents a vital step toward the development of pharmaceuticals that might one day repair folding‐defective proteins. Indeed, a growing number of clinical and pre‐clinical drugs that repair ERAD and other quality control substrates have shown efficacy in various disease models. In this presentation, each of these topics will be discussed and future research directions defined.
In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the ...cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.
Protein folding in the endoplasmic reticulum (ER) is monitored by ER quality control (ERQC) mechanisms. Proteins that pass ERQC criteria traffic to their final destinations through the secretory ...pathway, whereas non-native and unassembled subunits of multimeric proteins are degraded by the ER-associated degradation (ERAD) pathway. During ERAD, molecular chaperones and associated factors recognize and target substrates for retrotranslocation to the cytoplasm, where they are degraded by the ubiquitin-proteasome machinery. The discovery of diseases that are associated with ERAD substrates highlights the importance of this pathway. Here, we summarize our current understanding of each step during ERAD, with emphasis on the factors that catalyse distinct activities.
Cystic fibrosis (CF) is the most common lethal inherited disease among Caucasians in North America and a significant portion of Europe. The disease arises from one of many mutations in the gene ...encoding the cystic fibrosis transmembrane conductance regulator, or CFTR. The most common disease-associated allele, F508del, along with several other mutations affect the folding, transport, and stability of CFTR as it transits from the endoplasmic reticulum (ER) to the plasma membrane, where it functions primarily as a chloride channel. Early data demonstrated that F508del CFTR is selected for ER associated degradation (ERAD), a pathway in which misfolded proteins are recognized by ER-associated molecular chaperones, ubiquitinated, and delivered to the proteasome for degradation. Later studies showed that F508del CFTR that is rescued from ERAD and folds can alternatively be selected for enhanced endocytosis and lysosomal degradation. A number of other disease-causing mutations in CFTR also undergo these events. Fortunately, pharmacological modulators of CFTR biogenesis can repair CFTR, permitting its folding, escape from ERAD, and function at the cell surface. In this article, we review the many cellular checkpoints that monitor CFTR biogenesis, discuss the emergence of effective treatments for CF, and highlight future areas of research on the proteostatic control of CFTR.
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