Reshaping endoplasmic reticulum quality control through the unfolded protein response

Wiseman, R. Luke; Mesgarzadeh, Jaleh; Hendershot, Linda M.

doi:10.1016/j.molcel.2022.03.025

Cited by 147 publications

(116 citation statements)

References 128 publications

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“…To determine whether GANAB was involved in the regulation of ERS signaling, we conducted experiments to quantitate the transcriptional activation of ATF6 by using siRNA-mediated GANAB knockdown in bladder cancer cell lines with/without tunicamycin (Tm) stimulation. According to previous studies, ATF6 activation is one of the critical signals of ERS [ 14 ] and G3BP1 is a marker of SG formation [ 15 ]. Interestingly, we found that Tm treatment induced the up-regulation of GANAB expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma

et al. 2022

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Background Urothelial carcinoma (UC) is among the most prevalent malignancies. The muscle-invasive bladder cancer (MIBC) shows an invasive feature and has poor prognosis, while the non-muscle invasive bladder cancer (NMIBC) shows a better prognosis as compared with the MIBC. However, a significant proportion (10%–30%) of NMIBC cases progress to MIBC. Identification of efficient biomarkers for the prediction of the course of UC remains challenging nowadays. Recently, there is an emerging study showed that post-translational modifications (PTMs) by glycosylation is an important process correlated with tumor angiogenesis, invasion and metastasis. Herein, we reported a data-driven discovery and experimental validation of GANAB, a key regulator of glycosylation, as a novel prognostic marker in UC. Methods In the present study, we conducted immunohistochemistry (IHC) assay to evaluate the correlation between the expression levels of GANAB protein and the prognosis of UC in our cohort of 107 samples using whole slide image (WSI) analysis. In vitro experiments using RNAi were also conducted to investigate the biological functions of GANAB in UC cell lines. Results We observed that positive GANAB protein expression was significantly correlated with poor prognosis of UC in our cohort, with p-value of 0.0017 in Log-rank test. Notably, tumor cells at the invasive front of the tumor margin showed stronger GANAB expression than the tumor cells inside the tumor body in UCs. We further validated that the elevated expression levels of GANAB were significantly correlated with high grade tumors (p-values of 1.72 × 10–10), advanced stages (6.47 × 10–6), and elevated in luminal molecular subtypes. Moreover, knocking-down GANAB using RNAi in UM-UC-3 and T24 cells inhibited cell proliferation and migration in vitro. Knockdown of GANAB resulted in cell cycle arrest at G1 phase. We demonstrated that GANAB mediated HIF1A and ATF6 transcriptional activation in the ER stress signaling, and regulated the gene expression of cell cycle-related transcriptional factors E2F7 and FOXM1. Conclusions The elevated expression of GANAB is a novel indicator of poorer prognosis of UC. Our data suggests that GANAB is not only a new and promising prognostic biomarker for UC, but also may provide important cues for the development of PTM-based therapeutics for UC treatment.

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Section: Resultsmentioning

confidence: 99%

Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma

et al. 2022

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“…The coordinate downregulation of at least ten ER chaperone genes, including Hspa5 and Hsp90b1, in PWS β-cells, but not the whole suite of UPR genes, supports the hypothesis that a PWS-imprinted gene or genes governs a pathway that coordinately regulates ER chaperones in a unique gene regulatory network (GRN). Although many of the DEGs that encode ER chaperones in PWS INS-1 β-cells are known ATF6 and/or XBP1 targets, numerous ATF6, IRE1α/XBP1, and ATF4/CHOP (PERK pathway) target genes [80][81][82][83][84][85][86][87][88][89] are not dysregulated in PWS INS-1 lines, suggesting a novel GRN in PWS β-cells. Candidate transcription factors (TFs) within the PWS-ER chaperone GRN are those with binding site motifs enriched in the promoters of DEGs in PWS β-cells, including, but not limited to the known ATF6 co-factor NFYA, which has roles in insulin secretion and glucose homeostasis [90], as well as PPARB/D also with known roles in βcell mass and insulin secretion [91].…”

Section: A Putative Pws-er Chaperone Gene Regulatory Network (Grn)mentioning

confidence: 99%

Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones

Koppes

Johnson

Moresco

et al. 2021

Preprint

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Prader-Willi syndrome (PWS) is a multisystem disorder caused by loss of expression of a cluster of paternally-expressed, imprinted genes. Neonatal failure to thrive is followed by childhood-onset hyperphagia, obesity, neurobehavioral abnormalities, and hormonal deficits. Prior evidence from a mouse model with a deletion of the orthologous PWS-gene domain identified abnormal pancreatic islet development with deficient insulin secretion, hypoglucagonemia, and postnatal onset of progressive, lethal hypoglycemia. To investigate the role of PWS-genes in β-cell secretory function, we used CRISPR/Cas9 genome-editing to generate isogenic, clonal INS-1 insulinoma lines with 3.16 Mb deletions of the silent, maternal (control) or active, paternal (PWS) alleles. PWS β-cells showed a significant reduction in basal and glucose-stimulated insulin secretion, signifying a deficiency in cell-autonomous insulin secretion. Parallel proteome and transcriptome studies revealed reduced levels of secreted peptides and twelve endoplasmic reticulum (ER) chaperones, including HSPA5 and HSP90B1. In contrast to the dosage compensation previously seen for ER chaperones in Hspa5 or Hsp90b1 gene knockouts, compensation is precluded by the widespread deficiency of ER chaperones in PWS β-cells. Consistent with the reduced ER chaperone levels, PWS INS-1 β-cells are more sensitive to ER stress, leading to earlier activation of all three arms of the unfolded protein response. These results suggest that a chronic deficit of ER chaperones in PWS β-cells leads to a delay in ER transit and/or folding of insulin and other cargo along the secretory pathway. The findings illuminate the pathophysiological basis of hormone deficits in PWS and implicate PWS-imprinted genes in β-cell secretory pathway function.

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“…Providing sufficient space to prevent protein overcrowding has been shown to alleviate the stress ( Schuck et al., 2009 ). Along with promoting chaperone and lipid biogenesis, the UPR also signals for the production of some autophagy-related genes, thereby inducing ER-phagy ( Bernales et al., 2007 ) (for more details on UPR, please refer to Wiseman et al, [2022] in this issue of Molecular Cell ). ER-phagy is hypothesized to fulfill different functions in the course of ER stress—initially, it might facilitate degradation of luminal protein aggregates, and later, it might aid the ER in shrinking back to its original size by degrading excess membranes.…”

Section: Introductionmentioning

confidence: 99%

ER remodeling via ER-phagy

Gubaš

Đikić

2022

Molecular Cell

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Reshaping endoplasmic reticulum quality control through the unfolded protein response

Cited by 147 publications

References 128 publications

Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma

Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma

Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones

ER remodeling via ER-phagy

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