scholarly journals Mechanismen und Funktionen von bakteriellen AAA+­Entfaltungsmaschinen

BIOspektrum ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 22-24
Author(s):  
Axel Mogk
Keyword(s):  
Quality Control ◽  
Drug Target ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Stress Conditions ◽  
Misfolded Proteins ◽  
Antibacterial Drug ◽  
Protein Homeostasis ◽  
Antibacterial Drug Target

AbstractBacterial AAA+ proteins play crucial roles in proteostasis networks and ensure protein homeostasis during stress conditions. They function as ATP-dependent components of proteolytic complexes degrading misfolded proteins or as disaggregases reactivating aggregated proteins. AAA+ proteins generate an ATP-fueled threading force driving substrate unfolding and translocation. Their central functions in protein quality control qualify them as antibacterial drug target.

scholarly journals Cdc48 regulates intranuclear quality control sequestration of the Hsh155 splicing factor

2020 ◽  
Author(s):  
Veena Mathew ◽  
Arun Kumar ◽  
Yangyang Kate Jiang ◽  
Kyra West ◽  
Annie S Tam ◽  
...  
Keyword(s):  
Quality Control ◽  
Essential Role ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Genotoxic Stress ◽  
Stress Conditions ◽  
Splicing Factor ◽  
Misfolded Proteins ◽  
Dna Complexes ◽  
Partner Proteins

Cdc48/VCP is a highly conserved ATPase chaperone that plays an essential role in the assembly or disassembly of protein-DNA complexes and in degradation of misfolded proteins. We find that Cdc48 accumulates during cellular stress at intranuclear protein quality control (INQ) sites. Cdc48 function is required to suppress INQ formation under non-stress conditions and to promote recovery following genotoxic stress. Cdc48 physically associates with the INQ substrate and splicing factor Hsh155 and regulates its assembly with partner proteins. Accordingly, cdc48 mutants have defects in splicing and show spontaneous distribution of Hsh155 to INQ aggregates where it is stabilized. Overall, this study shows that Cdc48 regulates deposition of proteins at INQ and suggests a previously unknown role for Cdc48 in the regulation or stability of splicing subcomplexes.

scholarly journals Protein quality control: from mechanism to disease

2019 ◽  
Vol 24 (6) ◽  
pp. 1013-1026
Author(s):  
Harm H. Kampinga ◽  
Matthias P. Mayer ◽  
Axel Mogk
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Acute Stress ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
Stress Conditions ◽  
Protein Homeostasis ◽  
Physiological Conditions ◽  
Age Related ◽  
Medical Translation

Abstract The cellular protein quality control machinery with its central constituents of chaperones and proteases is vital to maintain protein homeostasis under physiological conditions and to protect against acute stress conditions. Imbalances in protein homeostasis also are keys to a plethora of genetic and acquired, often age-related, diseases as well as aging in general. At the EMBO Workshop, speakers covered all major aspects of cellular protein quality control, from basic mechanisms at the molecular, cellular, and organismal level to medical translation. In this report, the highlights of the meeting will be summarized.

Protein Quality Control Degradation in the Nucleus

2018 ◽  
Vol 87 (1) ◽  
pp. 725-749 ◽  
Author(s):  
Charisma Enam ◽  
Yifat Geffen ◽  
Tommer Ravid ◽  
Richard G. Gardner
Keyword(s):  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Current Knowledge ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Cellular Processes ◽  
Human Disorders ◽  
Protein Misfolding And Aggregation

Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins’ toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.

scholarly journals Molecular chaperones and stress-inducible protein-sorting factors coordinate the spatiotemporal distribution of protein aggregates

2012 ◽  
Vol 23 (16) ◽  
pp. 3041-3056 ◽  
Author(s):  
Liliana Malinovska ◽  
Sonja Kroschwald ◽  
Matthias C. Munder ◽  
Doris Richter ◽  
Simon Alberti
Keyword(s):  
Quality Control ◽  
Molecular Chaperones ◽  
Cellular Response ◽  
Protein Quality ◽  
Acute Stress ◽  
Protein Sorting ◽  
Protein Quality Control ◽  
Normal Growth ◽  
Small Heat Shock Protein ◽  
Misfolded Proteins

Acute stress causes a rapid redistribution of protein quality control components and aggregation-prone proteins to diverse subcellular compartments. How these remarkable changes come about is not well understood. Using a phenotypic reporter for a synthetic yeast prion, we identified two protein-sorting factors of the Hook family, termed Btn2 and Cur1, as key regulators of spatial protein quality control in Saccharomyces cerevisiae. Btn2 and Cur1 are undetectable under normal growth conditions but accumulate in stressed cells due to increased gene expression and reduced proteasomal turnover. Newly synthesized Btn2 can associate with the small heat shock protein Hsp42 to promote the sorting of misfolded proteins to a peripheral protein deposition site. Alternatively, Btn2 can bind to the chaperone Sis1 to facilitate the targeting of misfolded proteins to a juxtanuclear compartment. Protein redistribution by Btn2 is accompanied by a gradual depletion of Sis1 from the cytosol, which is mediated by the sorting factor Cur1. On the basis of these findings, we propose a dynamic model that explains the subcellular distribution of misfolded proteins as a function of the cytosolic concentrations of molecular chaperones and protein-sorting factors. Our model suggests that protein aggregation is not a haphazard process but rather an orchestrated cellular response that adjusts the flux of misfolded proteins to the capacities of the protein quality control system.

scholarly journals The nucleolus functions as a phase-separated protein quality control compartment

Science ◽  
2019 ◽  
Vol 365 (6451) ◽  
pp. 342-347 ◽  
Author(s):  
F. Frottin ◽  
F. Schueder ◽  
S. Tiwary ◽  
R. Gupta ◽  
R. Körner ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Misfolded Proteins ◽  
Control Mechanisms ◽  
Culture Cells ◽  
Irreversible Aggregation ◽  
Nuclear Proteome ◽  
Prolonged Stress

The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggregation. Refolding and extraction of proteins from the nucleolus during recovery from stress was Hsp70-dependent. The capacity of the nucleolus to store misfolded proteins was limited, and prolonged stress led to a transition of the nucleolar matrix from liquid-like to solid, with loss of reversibility and dysfunction in quality control. Thus, we suggest that the nucleolus has chaperone-like properties and can promote nuclear protein maintenance under stress.

scholarly journals A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yifei Zhou ◽  
Xueqing Wang ◽  
Mengjiao Song ◽  
Zhidong He ◽  
Guizhong Cui ◽  
...  
Keyword(s):  
Quality Control ◽  
Caenorhabditis Elegans ◽  
Extracellular Vesicles ◽  
Body Wall ◽  
Protein Quality ◽  
Protein Quality Control ◽  
The Body ◽  
Protein Homeostasis ◽  
Age Related ◽  
Different Tissues

Abstract Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83/miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans. Upregulated in the intestine by hsf-1/HSF1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5/MCOLN, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity. These findings thus identify a microRNA-based mechanism to coordinate the decreasing macroautophagy in various tissues with age.

The role of protein quality control in mitochondrial protein homeostasis under oxidative stress

PROTEOMICS ◽  
2010 ◽  
Vol 10 (7) ◽  
pp. 1426-1443 ◽  
Author(s):  
Tom Bender ◽  
Claudia Leidhold ◽  
Thomas Ruppert ◽  
Sebastian Franken ◽  
Wolfgang Voos
Keyword(s):  
Oxidative Stress ◽  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Protein Homeostasis

scholarly journals The Glyoxysomal Protease LON2 Is Involved in Fruiting-Body Development, Ascosporogenesis and Stress Resistance in Sordaria macrospora

2021 ◽  
Vol 7 (2) ◽  
pp. 82
Author(s):  
Antonia Werner ◽  
Kolja Otte ◽  
Gertrud Stahlhut ◽  
Leon M. Hanke ◽  
Stefanie Pöggeler
Keyword(s):  
Quality Control ◽  
Fruiting Body ◽  
Protein Quality ◽  
Model Organism ◽  
Protein Quality Control ◽  
Stress Conditions ◽  
Dual Function ◽  
Sordaria Macrospora ◽  
Body Development ◽  
Fruiting Body Development

Microbodies, including peroxisomes, glyoxysomes and Woronin bodies, are ubiquitous dynamic organelles that play important roles in fungal development. The ATP-dependent chaperone and protease family Lon that maintain protein quality control within the organelle significantly regulate the functionality of microbodies. The filamentous ascomycete Sordaria macrospora is a model organism for studying fruiting-body development. The genome of S. macrospora encodes one Lon protease with the C-terminal peroxisomal targeting signal (PTS1) serine-arginine-leucine (SRL) for import into microbodies. Here, we investigated the function of the protease SmLON2 in sexual development and during growth under stress conditions. Localization studies revealed a predominant localization of SmLON2 in glyoxysomes. This localization depends on PTS1, since a variant without the C-terminal SRL motif was localized in the cytoplasm. A ΔSmlon2 mutant displayed a massive production of aerial hyphae, and produced a reduced number of fruiting bodies and ascospores. In addition, the growth of the ΔSmlon2 mutant was completely blocked under mild oxidative stress conditions. Most of the defects could be complemented with both variants of SmLON2, with and without PTS1, suggesting a dual function of SmLON2, not only in microbody, but also in cytosolic protein quality control.

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