scholarly journals The Unfolded Protein Response Is Induced by the Cell Wall Integrity Mitogen-activated Protein Kinase Signaling Cascade and Is Required for Cell Wall Integrity in Saccharomyces cerevisiae

2009 ◽  
Vol 20 (1) ◽  
pp. 164-175 ◽  
Author(s):  
Thomas Scrimale ◽  
Louis Didone ◽  
Karen L. de Mesy Bentley ◽  
Damian J. Krysan
Keyword(s):  
Cell Wall ◽  
Unfolded Protein Response ◽  
Wall Stress ◽  
Cell Wall Integrity ◽  
Double Mutation ◽  
Unfolded Protein ◽  
Cell Wall Stress ◽  
Mitogen Activated Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The yeast cell wall is an extracellular structure that is dependent on secretory and membrane proteins for its construction. We investigated the role of protein quality control mechanisms in cell wall integrity and found that the unfolded protein response (UPR) and, to a lesser extent, endoplasmic reticulum (ER)-associated degradation (ERAD) pathways are required for proper cell wall construction. Null mutation of IRE1, double mutation of ERAD components (hrd1Δ and ubc7Δ) and ire1Δ, or expression of misfolded proteins show phenotypes similar to mutation of cell wall proteins, including hypersensitivity to cell wall-targeted molecules, alterations to cell wall protein layer, decreased cell wall thickness by electron microscopy, and increased cellular aggregation. Consistent with its important role in cell wall integrity, UPR is activated by signaling through the cell wall integrity mitogen-activated protein (MAP) kinase pathway during cell wall stress and unstressed vegetative growth. Both cell wall stress and basal UPR activity is mediated by Swi6p, a regulator of cell cycle and cell wall stress gene transcription, in a manner that is independent of its known coregulatory molecules. We propose that the cellular responses to ER and cell wall stress are coordinated to buffer the cell against these two related cellular stresses.

scholarly journals Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

2015 ◽  
Vol 35 (8) ◽  
pp. 1414-1432 ◽  
Author(s):  
Hema Adhikari ◽  
Nadia Vadaie ◽  
Jacky Chow ◽  
Lauren M. Caccamise ◽  
Colin A. Chavel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Unfolded Protein Response ◽  
Mapk Pathway ◽  
Filamentous Growth ◽  
Proteolytic Processing ◽  
Mitogen Activated Protein Kinase ◽  
Unfolded Protein ◽  
Mitogen Activated Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Signaling mucins are evolutionarily conserved regulators of signal transduction pathways. The signaling mucin Msb2p regulates the Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. The cleavage and release of the glycosylated inhibitory domain of Msb2p is required for MAPK activation. We show here that proteolytic processing of Msb2p was induced by underglycosylation of its extracellular domain. Cleavage of underglycosylated Msb2p required the unfolded protein response (UPR), a quality control (QC) pathway that operates in the endoplasmic reticulum (ER). The UPR regulator Ire1p, which detects misfolded/underglycosylated proteins in the ER, controlled Msb2p cleavage by regulating transcriptional induction of Yps1p, the major protease that processes Msb2p. Accordingly, the UPR was required for differentiation to the filamentous cell type. Cleavage of Msb2p occurred in conditional trafficking mutants that trap secretory cargo in the endomembrane system. Processed Msb2p was delivered to the plasma membrane, and its turnover by the ubiquitin ligase Rsp5p and ESCRT attenuated the filamentous-growth pathway. We speculate that the QC pathways broadly regulate signaling glycoproteins and their cognate pathways by recognizing altered glycosylation patterns that can occur in response to extrinsic cues.

Repression of N-glycosylation triggers the unfolded protein response (UPR) and overexpression of cell wall protein and chitin in Aspergillus fumigatus

Microbiology ◽  
2011 ◽  
Vol 157 (7) ◽  
pp. 1968-1979 ◽  
Author(s):  
Kai Li ◽  
Haomiao Ouyang ◽  
Yang Lü ◽  
Jingnan Liang ◽  
Iain B. H. Wilson ◽  
...  
Keyword(s):  
Cell Wall ◽  
Aspergillus Fumigatus ◽  
Unfolded Protein Response ◽  
Cell Wall Protein ◽  
Signalling Pathway ◽  
Cell Wall Biosynthesis ◽  
Unfolded Protein ◽  
Cell Wall Biogenesis ◽  
The Unfolded Protein Response ◽  
Protein Response

Aspergillus fumigatus is the most common airborne fungal pathogen, causing fatal invasive aspergillosis in immunocompromised patients. The crude mortality is 60–90 % and remains around 29–42 % even with treatment. The main reason for patient death is the low efficiency of the drug therapies. As protein N-glycosylation is involved in cell wall biogenesis in A. fumigatus, a deeper understanding of its role in cell wall biogenesis will help to develop new drug targets. The Afstt3 gene encodes the essential catalytic subunit of oligosaccharyltransferase, an enzyme complex responsible for the transfer of the N-glycan to nascent polypeptides. To evaluate the role of N-glycosylation in cell wall biosynthesis, we constructed the conditional mutant strain CPR-stt3 by replacing the endogenous promoter of Afstt3 with the nitrogen-dependent niiA promoter. Repression of the Afstt3 gene in the CPR-stt3 strain led to a severe retardation of growth and a slight defect in cell wall integrity (CWI). One of the most interesting findings was that upregulation of the cell wall-related genes was not accompanied by an activation of the MpkA kinase, which has been shown to be a central element in the CWI signalling pathway in both Saccharomyces cerevisiae and A. fumigatus. Considering that the unfolded protein response (UPR) was found to be activated, which might upregulate the expression of cell wall protein and chitin, our data suggest that the UPR, instead of the MpkA-dependent CWI signalling pathway, is the major compensatory mechanism induced by repression but not abolition of N-glycosylation in A. fumigatus. Our finding is a key to understanding the complex compensatory mechanisms of cell wall biosynthesis and may provide a new strategy for drug development.

scholarly journals Chromatin remodeling by the SWI/SNF complex is essential for transcription mediated by the yeast cell wall integrity MAPK pathway

2012 ◽  
Vol 23 (14) ◽  
pp. 2805-2817 ◽  
Author(s):  
A. Belén Sanz ◽  
Raúl García ◽  
Jose Manuel Rodríguez-Peña ◽  
Sonia Díez-Muñiz ◽  
César Nombela ◽  
...  
Keyword(s):  
Cell Wall ◽  
Chromatin Remodeling ◽  
Mapk Pathway ◽  
Critical Role ◽  
Transcriptional Response ◽  
Wall Stress ◽  
Cell Wall Integrity ◽  
Mitogen Activated Protein Kinase ◽  
Cell Wall Stress ◽  
Mitogen Activated Protein

In Saccharomyces cerevisiae, the transcriptional program triggered by cell wall stress is coordinated by Slt2/Mpk1, the mitogen-activated protein kinase (MAPK) of the cell wall integrity (CWI) pathway, and is mostly mediated by the transcription factor Rlm1. Here we show that the SWI/SNF chromatin-remodeling complex plays a critical role in orchestrating the transcriptional response regulated by Rlm1. swi/snf mutants show drastically reduced expression of cell wall stress–responsive genes and hypersensitivity to cell wall–interfering compounds. On stress, binding of RNA Pol II to the promoters of these genes depends on Rlm1, Slt2, and SWI/SNF. Rlm1 physically interacts with SWI/SNF to direct its association to target promoters. Finally, we observe nucleosome displacement at the CWI-responsive gene MLP1/KDX1, which relies on the SWI/SNF complex. Taken together, our results identify the SWI/SNF complex as a key element of the CWI MAPK pathway that mediates the chromatin remodeling necessary for adequate transcriptional response to cell wall stress.

scholarly journals Identification of an Exceptionally Long Intron in theHAC1Gene ofCandida parapsilosis

mSphere ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Elise Iracane ◽  
Paul D. Donovan ◽  
Mihaela Ola ◽  
Geraldine Butler ◽  
Linda M. Holland
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Wall ◽  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Candida Parapsilosis ◽  
Calcofluor White ◽  
Content Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACTThe unfolded protein response (UPR) in the endoplasmic reticulum (ER) is well conserved in eukaryotes from metazoa to yeast. The transcription factorHAC1is a major regulator of the UPR in many eukaryotes. DeletingHAC1in the yeastCandida parapsilosisrendered cells more sensitive to DTT, a known inducer of the UPR. The deletion strain was also sensitive to Congo red, calcofluor white, and the antifungal drug ketoconazole, indicating thatHAC1has a role in cell wall maintenance. Transcriptomic analysis revealed that treatment of the wild type with DTT resulted in the increased expression of 368 genes. Comparison with mutant cells treated with DTT reveals that expression of 137 of these genes requiresHAC1. Enriched GO term analysis includes response to ER stress, cell wall biogenesis and glycosylation. Orthologs of many of these are associated with UPR inSaccharomyces cerevisiaeandCandida albicans. Unconventional splicing of an intron fromHAC1mRNA is required to produce a functional transcription factor. The spliced intron varies in length from 19 bases inC. albicansto 379 bases inCandida glabrata, but has not been previously identified inCandida parapsilosisand related species. We used RNA-seq data andin silicoanalysis to identify theHAC1intron in 12 species in the CTG-Ser1 clade. We show that the intron has undergone major contractions and expansions in this clade, reaching up to 848 bases. Exposure to DTT induced splicing of the long intron inC. parapsilosisHAC1, inducing the UPR.IMPORTANCEThe unfolded protein response (UPR) responds to the build-up of misfolded proteins in the endoplasmic reticulum. The UPR has wide-ranging functions from fungal pathogenesis to applications in biotechnology. The UPR is regulated through the splicing of an unconventional intron in theHAC1gene. This intron has been described in many fungal species and is of variable length. Until now it was believed that some members of the CTG-Ser1 clade such asC. parapsilosisdid not contain an intron inHAC1, suggesting that the UPR was regulated in a different manner. Here we demonstrate thatHAC1plays an important role in regulating the UPR inC. parapsilosis. We also identified an unusually long intron (626 bp) inC. parapsilosisHAC1. Further analysis showed thatHAC1orthologs in several species in the CTG-Ser1 clade contain long introns.

Oestrogen-driven changes in the bovine uterus are associated with activation of the unfolded protein response

2014 ◽  
Author(s):  
Mohammed A Alfattah ◽  
Paul Anthony McGettigan ◽  
John Arthur Browne ◽  
Khalid M Alkhodair ◽  
Katarzyna Pluta ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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