scholarly journals The impact of the unfolded protein response on human disease

2012 ◽  
Vol 197 (7) ◽  
pp. 857-867 ◽  
Author(s):  
Shiyu Wang ◽  
Randal J. Kaufman
Keyword(s):  
Unfolded Protein Response ◽  
Human Disease ◽  
Intracellular Signaling ◽  
Central Function ◽  
Intracellular Signaling Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

scholarly journals Two Distinctly Localized P-Type ATPases Collaborate to Maintain Organelle Homeostasis Required for Glycoprotein Processing and Quality Control

2002 ◽  
Vol 13 (11) ◽  
pp. 3955-3966 ◽  
Author(s):  
Shilpa Vashist ◽  
Christian G. Frank ◽  
Claude A. Jakob ◽  
Davis T.W. Ng
Keyword(s):  
Quality Control ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Ion Homeostasis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Coa Reductase ◽  
Protein Response ◽  
P Type ◽  
Er Homeostasis

Membrane transporter proteins are essential for the maintenance of cellular ion homeostasis. In the secretory pathway, the P-type ATPase family of transporters is found in every compartment and the plasma membrane. Here, we report the identification of COD1/SPF1(control of HMG-CoA reductase degradation/SPF1) through genetic strategies intended to uncover genes involved in protein maturation and endoplasmic reticulum (ER)-associated degradation (ERAD), a quality control pathway that rids misfolded proteins. Cod1p is a putative ER P-type ATPase whose expression is regulated by the unfolded protein response, a stress-inducible pathway used to monitor and maintain ER homeostasis. COD1 mutants activate the unfolded protein response and are defective in a variety of functions apart from ERAD, which further support a homeostatic role.COD1 mutants display phenotypes similar to strains lacking Pmr1p, a Ca2+/Mn2+pump that resides in the medial-Golgi. Because of its localization, the previously reported role of PMR1 in ERAD was somewhat enigmatic. A clue to their respective roles came from observations that the two genes are not generally required for ERAD. We show that the specificity is rooted in a requirement for both genes in protein-linked oligosaccharide trimming, a requisite ER modification in the degradation of some misfolded glycoproteins. Furthermore, Cod1p, like Pmr1p, is also needed for the outer chain modification of carbohydrates in the Golgi apparatus despite its ER localization. In strains deleted of both genes, these activities are nearly abolished. The presence of either protein alone, however, can support partial function for both compartments. Taken together, our results reveal an interdependent relationship between two P-type ATPases to maintain homeostasis of the organelles where they reside.

scholarly journals Phosphorylation of Pal2 by the protein kinases Kin1 and Kin2 modulates HAC1 mRNA splicing in the unfolded protein response in yeast

2021 ◽  
Vol 14 (684) ◽  
pp. eaaz4401
Author(s):  
Chandrima Ghosh ◽  
Jagadeesh Kumar Uppala ◽  
Leena Sathe ◽  
Charlotte I. Hammond ◽  
Ashish Anshu ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Protein Kinases ◽  
Cellular Stress ◽  
Mrna Processing ◽  
Mrna Splicing ◽  
Cellular Stress Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

During cellular stress in the budding yeast Saccharomyces cerevisiae, an endoplasmic reticulum (ER)–resident dual kinase and RNase Ire1 splices an intron from HAC1 mRNA in the cytosol, thereby releasing its translational block. Hac1 protein then activates an adaptive cellular stress response called the unfolded protein response (UPR) that maintains ER homeostasis. The polarity-inducing protein kinases Kin1 and Kin2 contribute to HAC1 mRNA processing. Here, we showed that an RNA-protein complex that included the endocytic proteins Pal1 and Pal2 mediated HAC1 mRNA splicing downstream of Kin1 and Kin2. We found that Pal1 and Pal2 bound to the 3′ untranslated region (3′UTR) of HAC1 mRNA, and a yeast strain lacking both Pal1 and Pal2 was deficient in HAC1 mRNA processing. We also showed that Kin1 and Kin2 directly phosphorylated Pal2, and that a nonphosphorylatable Pal2 mutant could not rescue the UPR defect in a pal1Δ pal2Δ strain. Thus, our work uncovers a Kin1/2-Pal2 signaling pathway that coordinates HAC1 mRNA processing and ER homeostasis.

Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency

2008 ◽  
Vol 45 (10) ◽  
pp. 2990-2997 ◽  
Author(s):  
Juliana S. Kuribayashi ◽  
Cíntia R. Bombardieri ◽  
Gisele V. Baracho ◽  
Júlio Aliberti ◽  
Fabiana S. Machado ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Common Variable Immunodeficiency ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Common Variable

scholarly journals The Unfolded Protein Response Regulates Multiple Aspects of Secretory and Membrane Protein Biogenesis and Endoplasmic Reticulum Quality Control

2000 ◽  
Vol 150 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Davis T.W. Ng ◽  
Eric D. Spear ◽  
Peter Walter
Keyword(s):  
Membrane Protein ◽  
Unfolded Protein Response ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Yeast Saccharomyces Cerevisiae ◽  
Regulatory Pathways ◽  
Unfolded Protein ◽  
Protein Biogenesis ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is an intracellular signaling pathway that relays signals from the lumen of the ER to activate target genes in the nucleus. We devised a genetic screen in the yeast Saccharomyces cerevisiae to isolate mutants that are dependent on activation of the pathway for viability. Using this strategy, we isolated mutants affecting various aspects of ER function, including protein translocation, folding, glycosylation, glycosylphosphatidylinositol modification, and ER-associated protein degradation (ERAD). Extending results gleaned from the genetic studies, we demonstrate that the UPR regulates trafficking of proteins at the translocon to balance the needs of biosynthesis and ERAD. The approach also revealed connections of the UPR to other regulatory pathways. In particular, we identified SON1/RPN4, a recently described transcriptional regulator for genes encoding subunits of the proteasome. Our genetic strategy, therefore, offers a powerful means to provide insight into the physiology of the UPR and to identify novel genes with roles in many aspects of secretory and membrane protein biogenesis.

scholarly journals The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily M. Nakada ◽  
Rui Sun ◽  
Utako Fujii ◽  
James G. Martin
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Lung Structure ◽  
Selective Translation ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

scholarly journals Loss of BOK Has a Minor Impact on Acetaminophen Overdose-Induced Liver Damage in Mice

2021 ◽  
Vol 22 (6) ◽  
pp. 3281
Author(s):  
Samara Naim ◽  
Yuniel Fernandez-Marrero ◽  
Simone de Brot ◽  
Daniel Bachmann ◽  
Thomas Kaufmann
Keyword(s):  
Liver Injury ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Western World ◽  
Liver Necrosis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
A Minor ◽  
Protein Response ◽  
The Impact

Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury. We therefore investigated the impact of the loss of BOK following APAP overdosing in mice. Surprisingly, we observed sex-dependent differences in the activation of the unfolded protein response (UPR) in both wildtype (WT) and Bok-/- mice, with increased activation of JNK in females compared with males. Loss of BOK led to a decrease in JNK activation and a reduced percentage of centrilobular necrosis in both sexes after APAP treatment; however, this protection was more pronounced in Bok-/- females. Nevertheless, serum ALT and AST levels of Bok-/- and WT mice were comparable, indicating that there was no major difference in the overall outcome of liver injury. We conclude that after APAP overdosing, loss of BOK affects initiating signaling steps linked to ER stress, but has a more minor impact on the outcome of liver necrosis. Furthermore, we observed sex-dependent differences that might be worthwhile to investigate.

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