Endoplasmic Reticulum Stress in Disease Pathogenesis

Lin, Jonathan H.; Walter, Peter; Yen, T. S. Benedict

doi:10.1146/annurev.pathmechdis.3.121806.151434

Cited by 704 publications

(538 citation statements)

References 156 publications

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“…Our sequence analysis, however, suggests that the CL1 amino acid sequence represents a frameshifted region of the yeast PMD1 gene. 3 Additionally, we find that the SL17 degron and the other CL degrons identified by Gilon and co-workers (1) also represent out of frame sequences from yeast ORFs. Frameshift mutations often eliminate gene function, and study of CL1 and other degrons in yeast may thus reveal mechanisms for the removal of improper translation products.…”

Section: Discussionsupporting

confidence: 63%

“…Protein "quality control" is an essential process monitoring protein folding, ultimately targeting misfolded proteins for degradation via the ubiquitin-proteasome system. The importance of protein quality control is best exemplified by the numerous human diseases that can result from protein misfolding due to mutational or physiological causes and include cystic fibrosis, Parkinson disease, and ␣ 1 -antitrypsin deficiency (2,3).…”

mentioning

confidence: 99%

“…Additionally, our sequence analysis suggests that CL1 is an out of frame region of the yeast PMD1 gene. 3 Thus, studies of CL1 may also reveal insight into the fate of improper translation products.…”

mentioning

confidence: 99%

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Degradation of a Cytosolic Protein Requires Endoplasmic Reticulum-associated Degradation Machinery

Metzger

Maurer

Dancy

et al. 2008

Journal of Biological Chemistry

128

169

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Protein misfolding is monitored by a variety of cellular "quality control" systems. Endoplasmic reticulum (ER) quality control handles misfolded secretory and membrane proteins and is well characterized. However, less is known about the quality control of misfolded cytosolic proteins (CytoQC). To study CytoQC, we have employed a genetic system in Saccharomyces cerevisiae using a transplantable degron, CL1 (1). Attachment of CL1 to the cytosolic protein Ura3p destabilizes Ura3p, targeting it for rapid proteasomal degradation. We have performed a comprehensive analysis of Ura3p-CL1 degradation requirements. As shown previously, we observe that the ER-localized ubiquitin E2 (Ubc6p, Ubc7p, and Cue1p) and E3 (Doa10p) machinery involved in ER-associated degradation (ERAD) are also responsible for the degradation of the cytosolic substrate Ura3p-CL1. Importantly, we find that the cytosol/ER membrane-localized chaperones Ydj1p and Ssa1p, known to be necessary for the ERAD of membrane proteins with misfolded cytosolic domains, are also required for the ubiquitination and degradation of Ura3p-CL1. In addition, we show a role for the Cdc48p-Npl4p-Ufd1p complex in the degradation of Ura3p-CL1. When ubiquitination is blocked, a portion of Ura3p-CL1 is ER membrane-localized. Furthermore, access to the cytosolic face of the ER is required for the degradation of CL1 degroncontaining proteins. The ER is distributed throughout the cytosol, and our data, together with previous studies, suggest that the cytosolic face of the ER membrane serves as a "platform" for the degradation of Ura3p-CL1, which may also be the case for other CytoQC substrates.Mutation, errors in transcription or translation, and cellular stress can cause alterations in amino acids that may prevent proteins from attaining their properly folded, native conformations. Protein "quality control" is an essential process monitoring protein folding, ultimately targeting misfolded proteins for degradation via the ubiquitin-proteasome system. The importance of protein quality control is best exemplified by the numerous human diseases that can result from protein misfolding due to mutational or physiological causes and include cystic fibrosis, Parkinson disease, and ␣ 1 -antitrypsin deficiency (2, 3).Distinct protein quality control systems appear to exist in various cellular compartments, including the nucleus, mitochondria, and endoplasmic reticulum (ER), 2 with the bestcharacterized system being ER quality control (4 -7). Studies of ER quality control and, in particular, ER-associated degradation (ERAD) have revealed discrete chaperone and ubiquitination machinery required for the recognition and ubiquitination of different classes of misfolded secretory or membrane proteins. Much of this work has been greatly aided by the use of "model" ER quality control substrates, such as CPY* or Ste6p*, in the yeast Saccharomyces cerevisiae (8 -12). For example, it has become clear that model membrane proteins with misfolded cytosolic domains (called ERAD-C substrates), such as St...

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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

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Degradation of a Cytosolic Protein Requires Endoplasmic Reticulum-associated Degradation Machinery

Metzger

Maurer

Dancy

et al. 2008

Journal of Biological Chemistry

128

169

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“…Secretory cells and the products they manufacture are often at the center of these systems, facilitating the generation and release of response molecules ranging from digestive enzymes to antibodies and hormones. Appropriate safeguards to monitor synthesis, processing, and exocytosis in these cells are critical to human health as they prevent and mitigate multiple disease states resulting from ineffective quality control (e.g., Alzheimer's, Huntington's, and irritable bowel syndrome) or failure to execute apoptotic programs in response to stress (e.g., malignancy) (6,(63)(64)(65). These safety mechanisms are driven by response systems coupling protein stress sensors with downstream transcriptional networks.…”

Section: Discussionmentioning

confidence: 99%

“…A greater understanding of the regulation of the unfolded protein response has already proved critical in designing enhanced therapies for the prevention of tumor development and for generating new chemotherapeutics (69)(70)(71). Indeed, multiple approaches have investigated the XBP1 branch and its targets as a means to control human diseases (7,64,72,73). The inclusion of MIST1 as both an XBP1 target with wide-ranging effects and as a potential negative regulator of Xbp1 expression greatly augments the number of possibilities for developing novel therapeutics for treating protein-processing diseases and disorders.…”

Section: Discussionmentioning

confidence: 99%

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Hess

Strelau

Karki

et al. 2016

Molecular and Cellular Biology

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Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

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The role of sphingolipids in endoplasmic reticulum stress

Park

2020

FEBS Letters

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The endoplasmic reticulum (ER) is an important intracellular compartment in eukaryotic cells and has diverse functions, including protein synthesis, protein folding, lipid metabolism and calcium homeostasis. ER functions are disrupted by various intracellular and extracellular stimuli that cause ER stress, including the inhibition of glycosylation, disulphide bond reduction, ER calcium store depletion, impaired protein transport to the Golgi, excessive ER protein synthesis, impairment of ER-associated protein degradation and mutated ER protein expression. Distinct ER stress signalling pathways, which are known as the unfolded protein response, are deployed to maintain ER homeostasis, and a failure to reverse ER stress triggers cell death. Sphingolipids are lipids that are structurally characterized by long-chain bases, including sphingosine or dihydrosphingosine (also known as sphinganine). Sphingolipids are bioactive molecules long known to regulate various cellular processes, including cell proliferation, migration, apoptosis and cell-cell interaction. Recent studies have uncovered that specific sphingolipids are involved in ER stress. This review summarizes the roles of sphingolipids in ER stress and human diseases in the context of pathogenic events.

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Endoplasmic Reticulum Stress in Disease Pathogenesis

Cited by 704 publications

References 156 publications

Degradation of a Cytosolic Protein Requires Endoplasmic Reticulum-associated Degradation Machinery

Degradation of a Cytosolic Protein Requires Endoplasmic Reticulum-associated Degradation Machinery

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

The role of sphingolipids in endoplasmic reticulum stress

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