scholarly journals Impact of cellular health conditions on the protein folding state in mammalian cells

2017 ◽  
Vol 53 (81) ◽  
pp. 11245-11248 ◽  
Author(s):  
Kohsuke Inomata ◽  
Hajime Kamoshida ◽  
Masaomi Ikari ◽  
Yutaka Ito ◽  
Takanori Kigawa
Keyword(s):  
Protein Folding ◽  
Mammalian Cells ◽  
Health Conditions ◽  
Folding State

Cellular health conditions severely affect the protein folding state in mammalian cells.

scholarly journals Network measures for protein folding state discrimination

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Giulia Menichetti ◽  
Piero Fariselli ◽  
Daniel Remondini
Keyword(s):  
Protein Folding ◽  
Network Measures ◽  
State Discrimination ◽  
Folding State

scholarly journals Monitoring cotranslational protein folding in mammalian cells at codon resolution

2012 ◽  
Vol 109 (31) ◽  
pp. 12467-12472 ◽  
Author(s):  
Y. Han ◽  
A. David ◽  
B. Liu ◽  
J. G. Magadan ◽  
J. R. Bennink ◽  
...  
Keyword(s):  
Protein Folding ◽  
Mammalian Cells

scholarly journals Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes

2011 ◽  
Vol 22 (18) ◽  
pp. 3277-3288 ◽  
Author(s):  
Xingqian Zhang ◽  
Shu-Bing Qian
Keyword(s):  
Protein Folding ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Hierarchical Control ◽  
Dominant Negative ◽  
Misfolded Proteins ◽  
Interacting Protein ◽  
Aggresome Formation

Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Despite the well-established role of chaperones in both protein folding and degradation, how chaperones regulate the aggregation process remains controversial. Here we investigate the molecular mechanisms underlying aggresome formation in mammalian cells. Analysis of the chaperone requirements for the fate of misfolded proteins reveals an unexpected role of heat shock protein 70 (Hsp70) in promoting aggresome formation. This proaggregation function of Hsp70 relies on the interaction with the cochaperone ubiquitin ligase carboxyl terminal of Hsp70/Hsp90 interacting protein (CHIP). Disrupting Hsp70–CHIP interaction prevents the aggresome formation, whereas a dominant-negative CHIP mutant sensitizes the aggregation of misfolded protein. This accelerated aggresome formation also relies on the stress-induced cochaperone Bcl2-associated athanogene 3. Our results indicate that a hierarchy of cochaperone interaction controls different aspects of the intracellular protein triage decision, extending the function of Hsp70 from folding and degradation to aggregation.

scholarly journals ER-Resident Transcription Factor Nrf1 Regulates Proteasome Expression and Beyond

2020 ◽  
Vol 21 (10) ◽  
pp. 3683 ◽  
Author(s):  
Jun Hamazaki ◽  
Shigeo Murata
Keyword(s):  
Transcription Factor ◽  
Protein Folding ◽  
Mammalian Cells ◽  
Current Knowledge ◽  
Complex Structure ◽  
Molecular Assembly ◽  
26S Proteasome ◽  
Misfolded Proteins ◽  
Related Factor ◽  
Dependent Manner

Protein folding is a substantively error prone process, especially when it occurs in the endoplasmic reticulum (ER). The highly exquisite machinery in the ER controls secretory protein folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol; these misfolded proteins are then degraded by the ubiquitin–proteasome system termed as the ER-associated degradation (ERAD). The 26S proteasome is a multisubunit protease complex that recognizes and degrades ubiquitinated proteins in an ATP-dependent manner. The complex structure of the 26S proteasome requires exquisite regulation at the transcription, translation, and molecular assembly levels. Nuclear factor erythroid-derived 2-related factor 1 (Nrf1; NFE2L1), an ER-resident transcription factor, has recently been shown to be responsible for the coordinated expression of all the proteasome subunit genes upon proteasome impairment in mammalian cells. In this review, we summarize the current knowledge regarding the transcriptional regulation of the proteasome, as well as recent findings concerning the regulation of Nrf1 transcription activity in ER homeostasis and metabolic processes.

scholarly journals Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1

2021 ◽  
Author(s):  
Vy Ngo ◽  
Nadun C. Karunatilleke ◽  
Anne Brickenden ◽  
Wing-Yiu Choy ◽  
Martin L. Duennwald
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Protein Folding ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Inclusion Formation ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Antioxidant Proteins ◽  
Cysteine Content

Cells that experience high levels of oxidative stress respond with the induction of antioxidant proteins through the activation of the transcription factor Nrf2. Nrf2 is negatively regulated by Keap1 which binds to Nrf2 to facilitate its ubiquitination and ensuing proteasomal degradation under basal conditions. Here, we study protein folding and misfolding in Nrf2 and Keap1 in yeast, mammalian cells, and purified proteins under oxidative stress conditions. Both Nrf2 and Keap1 are susceptible to protein misfolding and inclusion formation upon oxidative stress. We propose that the intrinsically disordered regions within Nrf2 and the high cysteine content of Keap1 contribute to their oxidation and the ensuing misfolding. Our work reveals previously unexplored aspects of Nrf2 and Keap1 regulation and dysregulation by oxidation-induced protein misfolding.

Chaperone-assisted degradation: multiple paths to destruction

2010 ◽  
Vol 391 (5) ◽  
pp. 481-489 ◽  
Author(s):  
Nadja Kettern ◽  
Michael Dreiseidler ◽  
Riga Tawo ◽  
Jörg Höhfeld
Keyword(s):  
Protein Folding ◽  
Molecular Chaperones ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Degradation Pathways ◽  
Lysosomal Compartment ◽  
Pharmacological Modulation ◽  
Native Proteins ◽  
Multiple Paths ◽  
Protein Folding And Assembly

Abstract Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP (chaperone-assisted proteasomal degradation), CASA (chaperone-assisted selective autophagy), and CMA (chaperone-mediated autophagy). Within these pathways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.

scholarly journals IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin

2012 ◽  
Vol 23 (5) ◽  
pp. 758-770 ◽  
Author(s):  
Wei-Chieh Chiang ◽  
Carissa Messah ◽  
Jonathan H. Lin
Keyword(s):  
Cell Death ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Cell Injury ◽  
Degradation Pathway ◽  
Lysosomal Degradation ◽  
Chemical Genetic ◽  
Wild Type Counterpart

Endoplasmic reticulum (ER) is responsible for folding of secreted and membrane proteins in eukaryotic cells. Disruption of ER protein folding leads to ER stress. Chronic ER stress can cause cell death and is proposed to underlie the pathogenesis of many human diseases. Inositol-requiring enzyme 1 (IRE1) directs a key unfolded protein response signaling pathway that controls the fidelity of ER protein folding. IRE1 signaling may be particularly helpful in preventing chronic ER stress and cell injury by alleviating protein misfolding in the ER. To examine this, we used a chemical-genetic approach to selectively activate IRE1 in mammalian cells and tested how artificial IRE1 signaling affected the fate of misfolded P23H rhodopsin linked to photoreceptor cell death. We found that IRE1 signaling robustly promoted the degradation of misfolded P23H rhodopsin without affecting its wild-type counterpart. We also found that IRE1 used both proteasomal and lysosomal degradation pathways to remove P23H rhodopsin. Surprisingly, when one degradation pathway was compromised, IRE1 signaling could still promote misfolded rhodopsin degradation using the remaining pathway. Last, we showed that IRE1 signaling also reduced levels of several other misfolded rhodopsins with lesser effects on misfolded cystic fibrosis transmembrane conductance regulator. Our findings reveal the diversity of proteolytic mechanisms used by IRE1 to eliminate misfolded rhodopsin.

scholarly journals The safety dance: biophysics of membrane protein folding and misfolding in a cellular context

2014 ◽  
Vol 48 (1) ◽  
pp. 1-34 ◽  
Author(s):  
Jonathan P. Schlebach ◽  
Charles R. Sanders
Keyword(s):  
Protein Folding ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Mammalian Cells ◽  
Conformational Stability ◽  
Cellular Protein ◽  
Biomedical Science ◽  
Molecular Events ◽  
Cellular Context ◽  
Cellular Machinery

AbstractMost biological processes require the production and degradation of proteins, a task that weighs heavily on the cell. Mutations that compromise the conformational stability of proteins place both specific and general burdens on cellular protein homeostasis (proteostasis) in ways that contribute to numerous diseases. Efforts to elucidate the chain of molecular events responsible for diseases of protein folding address one of the foremost challenges in biomedical science. However, relatively little is known about the processes by which mutations prompt the misfolding of α-helical membrane proteins, which rely on an intricate network of cellular machinery to acquire and maintain their functional structures within cellular membranes. In this review, we summarize the current understanding of the physical principles that guide membrane protein biogenesis and folding in the context of mammalian cells. Additionally, we explore how pathogenic mutations that influence biogenesis may differ from those that disrupt folding and assembly, as well as how this may relate to disease mechanisms and therapeutic intervention. These perspectives indicate an imperative for the use of information from structural, cellular, and biochemical studies of membrane proteins in the design of novel therapeutics and in personalized medicine.

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