The unfolded protein response is required for dendrite morphogenesis

Precise patterning of dendritic fields is essential for the formation and function of neuronal circuits. During development, dendrites acquire their morphology by exuberant branching. How neurons cope with the increased load of protein production required for this rapid growth is poorly understood. Here we show that the physiological unfolded protein response (UPR) is induced in the highly branched Caenorhabditis elegans sensory neuron PVD during dendrite morphogenesis. Perturbation of the IRE1 arm of the UPR pathway causes loss of dendritic branches, a phenotype that can be rescued by overexpression of the ER chaperone HSP-4 (a homolog of mammalian BiP/ grp78). Surprisingly, a single transmembrane leucine-rich repeat protein, DMA-1, plays a major role in the induction of the UPR and the dendritic phenotype in the UPR mutants. These findings reveal a significant role for the physiological UPR in the maintenance of ER homeostasis during morphogenesis of large dendritic arbors.

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

Molecular Biology of the Cell ◽

10.1091/mbc.02-06-0090 ◽

2002 ◽

Vol 13 (11) ◽

pp. 3955-3966 ◽

Cited By ~ 61

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.

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

Science Signaling ◽

10.1126/scisignal.aaz4401 ◽

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.

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Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function

International Journal of Molecular Sciences ◽

10.3390/ijms20071792 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1792 ◽

Cited By ~ 4

Author(s):

Kyeorda Kemp ◽

Cody Poe

Keyword(s):

Endoplasmic Reticulum ◽

T Cell ◽

Unfolded Protein Response ◽

T Cell Development ◽

Cell Development ◽

Secretory Cells ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

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

Molecular Immunology ◽

10.1016/j.molimm.2008.01.013 ◽

2008 ◽

Vol 45 (10) ◽

pp. 2990-2997 ◽

Cited By ~ 6

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

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

Frontiers in Physiology ◽

10.3389/fphys.2021.665622 ◽

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.

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Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide

Human & Experimental Toxicology ◽

10.1177/0960327120937049 ◽

2020 ◽

Vol 39 (12) ◽

pp. 1690-1699

Author(s):

H Yu ◽

K Wen ◽

X Zhou ◽

Y Zhang ◽

Z Yan ◽

...

Keyword(s):

Unfolded Protein Response ◽

Messenger Rna ◽

Hypoxia Inducible Factor ◽

Reproductive Organs ◽

Pregnant Mouse ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

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ER homeostasis and autophagy

Essays in Biochemistry ◽

10.1042/ebc20170092 ◽

2017 ◽

Vol 61 (6) ◽

pp. 625-635 ◽

Cited By ~ 69

Author(s):

Matthew Smith ◽

Simon Wilkinson

Keyword(s):

Secretory Proteins ◽

Unfolded Protein ◽

Effector Pathway ◽

Autophagy Pathway ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response ◽

Er Homeostasis ◽

Effector Mechanisms

The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis.

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The impact of the unfolded protein response on human disease

The Journal of Cell Biology ◽

10.1083/jcb.201110131 ◽

2012 ◽

Vol 197 (7) ◽

pp. 857-867 ◽

Cited By ~ 567

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.

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Recent advances in signal integration mechanisms in the unfolded protein response

F1000Research ◽

10.12688/f1000research.19848.1 ◽

2019 ◽

Vol 8 ◽

pp. 1840 ◽

Cited By ~ 5

Author(s):

G. Elif Karagöz ◽

Tomás Aragón ◽

Diego Acosta-Alvear

Keyword(s):

Unfolded Protein Response ◽

New Developments ◽

Cellular Processes ◽

Unfolded Protein ◽

Integration Mechanisms ◽

Physiological Demands ◽

The Unfolded Protein Response ◽

Protein Response ◽

Er Homeostasis ◽

Made In

Since its discovery more than 25 years ago, great progress has been made in our understanding of the unfolded protein response (UPR), a homeostatic mechanism that adjusts endoplasmic reticulum (ER) function to satisfy the physiological demands of the cell. However, if ER homeostasis is unattainable, the UPR switches to drive cell death to remove defective cells in an effort to protect the health of the organism. This functional dichotomy places the UPR at the crossroads of the adaptation versus apoptosis decision. Here, we focus on new developments in UPR signaling mechanisms, in the interconnectivity among the signaling pathways that make up the UPR in higher eukaryotes, and in the coordination between the UPR and other fundamental cellular processes.

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