Ubiquitin C-terminal Hydrolase-L1 Protects Cystic Fibrosis Transmembrane Conductance Regulator from Early Stages of Proteasomal Degradation

Henderson, Mark J.; Vij, Neeraj; Zeitlin, Pamela L.

doi:10.1074/jbc.m109.044057

Cited by 15 publications

(8 citation statements)

References 60 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is well known that F508del-CFTR protein degradation involves Ubiquitin modification. It was previoulsy shown that the de-ubiquitinating enzyme, Ubiquitin C-terminal hydrolase-L1 (UCH-L1), is highly expressed in CF airway epithelial cells and that there is a positive correlation between UCH-L1 expression and steady state levels of Wt-CFTR protein and F508del-CFTR [101]. Although it is not sufficient to rescue F508del-CFTR, the effect of UCH-L1 upon CFTR processing shows its potential roles in CF.…”

Section: Resultsmentioning

confidence: 99%

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

2017

View full text Add to dashboard Cite

Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

show abstract

Section: Resultsmentioning

confidence: 99%

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

2017

View full text Add to dashboard Cite

show abstract

“…For example, whereas the J-domain protein DNAJB12 facilitates Hsc70 and Rma1-dependent ubiquitination of the non-native N-terminus cotranslationally [53–55], CHIP (C-terminal Hsc70 interacting protein) preferentially recognizes the misfolded full-length CFTR. Gp78, an E4 ER Ub ligase [55], assists in poly-Ub chain extension, whereas UCH-L1 (ubiquitin C-terminal hydrolyse-L1) and Usp19 (ubiquitin specific protease 19) stabilize the ΔF508 CFTR nascent chain by catalyzing Ub cleavage [56, 57]. The cytosolic Nedd4-2 and Fbs1 E3 ligases have also been implicated in the ERAD of ΔF508 CFTR [58, 59].…”

Section: Membrane Trafficking and Functional Defects Of δF508 Cftrmentioning

confidence: 99%

CFTR: folding, misfolding and correcting the ΔF508 conformational defect

Lukacs

Verkman

2012

Trends in Molecular Medicine

335

322

View full text Add to dashboard Cite

Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is caused by loss-of-function mutations of the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated plasma membrane chloride channel. The most common mutation, deletion of phenylalanine 508 (ΔF508), impairs CFTR folding and, consequently, its biosynthetic and endocytic processing as well as chloride channel function. Pharmacological treatments may target the ΔF508 CFTR structural defect directly by binding to the mutant protein and/or indirectly by altering cellular protein homeostasis (proteostasis) to promote ΔF508 CFTR plasma membrane targeting and stability. This review discusses recent basic research aimed at elucidating the structural and trafficking defects of ΔF508 CFTR, a prerequisite for the rational design of CF therapy to correct the loss-of-function phenotype.

show abstract

“…ERAD is the key protective mechanism to maintain ER protein homeostasis in case of accumulation of misfolded proteins in the ER. Indeed, more than 99% of dF508CFTR protein can be degraded by ERAD, while only 25% of wild-type CFTR is degraded by the same pathway [23]. However, as shown in this study, human tracheal cells stably expressing the misfolded CFTR protein, dF508CFTR, exhibited significantly increased sumoylation of ATF6, a major transcriptional activator of ERAD program.…”

Section: Discussionmentioning

confidence: 62%

SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6

Hou

Zhao

Zhang

et al. 2017

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

The Unfolded Protein Response (UPR) is a cascade of intracellular stress signaling from the endoplasmic reticulum (ER) that protect the cells from the stress caused by accumulation of unfolded or misfolded proteins in the ER. Activating transcription factor 6 (ATF6) is one of primary UPR transducers that remodels the stressed cells through transcriptional regulation. Although the activation mechanism and biological roles of ATF6 have been well studied, the understanding of the negative or feedback regulation of ATF6 remains elusive. In this report, we showed that ATF6 protein can be modified by small ubiquitin-like modification (SUMOylation) and that the transcriptional activity of ATF6 is negatively regulated by SUMOylation. We identified that SUMOylation of ATF6 is significantly increased in the cells expressing misfolded cystic fibrosis transmembrane conductance regulator (CFTR) encoded by the mutant human CFTR gene (dF508CFTR). Further analyses revealed two highly conserved SUMOylation motifs within the trans-activation domain of ATF6 protein of human, mouse, or rat specie. The human ATF6 protein can be SUMOylated mediated through the small ubiquitin-like modifier protein 1 (SUMO-1) and E3 SUMO-protein ligase 1 (PIAS1) at the conserved sumoylation residue Lys149 that is located at the N-terminal of the activated form of ATF6 protein. Bimolecular fluorescence complementation (BiFC) analysis confirmed that the activated ATF6 protein can be SUMOylated and that the ATF6 sumoylation occurs in the nuclei. Moreover, trans-activation reporter analysis demonstrated that SUMOylation of the ATF6 protein at the conserved residue Lys14 represses the transcriptional activity of ATF6. In summary, our study revealed a negative regulation of the UPR transducer ATF6 through post-translational SUMOylation. The information from this study will not only increase our understanding of the fine-tuning regulation of the UPR signaling but will also be informative to the modulation of the UPR for therapeutic benefits.

show abstract

Ubiquitin C-terminal Hydrolase-L1 Protects Cystic Fibrosis Transmembrane Conductance Regulator from Early Stages of Proteasomal Degradation

Cited by 15 publications

References 60 publications

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

CFTR: folding, misfolding and correcting the ΔF508 conformational defect

SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6

Contact Info

Product

Resources

About