Protein misfolding in the endoplasmic reticulum as a conduit to human disease

Wang, Miao; Kaufman, Randal J.

doi:10.1038/nature17041

Cited by 1,287 publications

(1,065 citation statements)

References 126 publications

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“…Thus, based on the composition of constituent genes, module responses were consistent with ER stress and then overload leading the cell death. 33,34 Module changes in rat hepatocyte treated with tunicamycin and ethionamide were similar including the four ER stress modules in C.I.b (Supplementary Figure S3). Treating rat primary hepatocytes with ethionamide increased Atf4, Hspa5 and Hsp90b1 protein and processing of Atf6 to the transcriptionally active form, evidence of ER stress (Figure 3d).…”

Section: Resultsmentioning

confidence: 81%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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Section: Resultsmentioning

confidence: 81%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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“…These findings revealed that the luminal ATF6 [Y567N] mutation resulted in the impairment of ATF6 signaling in ATF6 Y567N/Y567N fibroblasts during ER stress. ATF6 signaling is a key component of the unfolded protein response (UPR) and operates in parallel with UPR signal transduction pathways controlled by the inositol-requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK) proteins to ensure normal ER function in mammalian cells (11,12). We next examined whether the other branches of the UPR were also dysregulated in ATF6 Y567N/Y567N fibroblasts.…”

Section: Y567n/y567nmentioning

confidence: 99%

Achromatopsia mutations target sequential steps of ATF6 activation

Chiang

Chan

Wissinger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Achromatopsia is an autosomal recessive disorder characterized by cone photoreceptor dysfunction. We recently identified activating transcription factor 6 (ATF6) as a genetic cause of achromatopsia. ATF6 is a key regulator of the unfolded protein response. In response to endoplasmic reticulum (ER) stress, ATF6 migrates from the ER to Golgi to undergo regulated intramembrane proteolysis to release a cytosolic domain containing a basic leucine zipper (bZIP) transcriptional activator. The cleaved ATF6 fragment migrates to the nucleus to transcriptionally up-regulate protein-folding enzymes and chaperones. ATF6 mutations in patients with achromatopsia include missense, nonsense, splice site, and single-nucleotide deletion or duplication changes found across the entire gene. Here, we comprehensively tested the function of achromatopsia-associated ATF6 mutations and found that they group into three distinct molecular pathomechanisms: class 1 ATF6 mutants show impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity; class 2 ATF6 mutants bear the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress; and class 3 ATF6 mutants have complete loss of transcriptional activity because of absent or defective bZIP domains. Primary fibroblasts from patients with class 1 or class 3 ATF6 mutations show increased cell death in response to ER stress. Our findings reveal that human ATF6 mutations interrupt distinct sequential steps of the ATF6 activation mechanism. We suggest that increased susceptibility to ER stress-induced damage during retinal development underlies the pathology of achromatopsia in patients with ATF6 mutations.cone photoreceptor | achromatopsia | endoplasmic reticulum stress | ATF6 | unfolded protein response A chromatopsia is a heritable blinding disease caused by cone photoreceptor dysfunction that spares the rod system. Using next-generation whole-exome sequencing, we recently discovered autosomal recessive mutations in the activating transcription factor 6 (ATF6) gene in patients with achromatopsia (1). ATF6 mutations span the entire coding region and include missense, nonsense, splice site, and single-nucleotide deletion and duplication changes (1-3). We previously showed that a missense mutation that introduced an arginine-to-cysteine substitution at amino acid residue 324 of the ATF6 protein compromised ATF6 activity in patient fibroblasts obtained from an achromatopsia family (1). However, the functional consequences of the other ATF6 mutations found in patients with achromatopsia remain unknown.In humans, ATF6 is a 670-amino acid glycosylated transmembrane protein found in the endoplasmic reticulum (ER) (4). In response to protein misfolding in the ER or other forms of ER stress, ATF6 migrates from the ER to the Golgi apparatus, where the site 1 protease (S1P) and site 2 protease (S2P) cleave ATF6 in the transmembrane domain to liberate the cyt...

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“…Folding‐deficient proteins are labeled with specific mannose residues for ERAD degradation. Increased ER stress causes many human diseases,10 including cancers 11. Recent studies have demonstrated that the overexpression of α‐1,2‐mannosidase accelerates ERAD 12, 13…”

Section: Introductionmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

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α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)

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Protein misfolding in the endoplasmic reticulum as a conduit to human disease

Cited by 1,287 publications

References 126 publications

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

Achromatopsia mutations target sequential steps of ATF6 activation

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

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