scholarly journals CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control

2008 ◽  
Vol 28 (12) ◽  
pp. 4018-4025 ◽  
Author(s):  
Jin-Na Min ◽  
Ryan A. Whaley ◽  
Norman E. Sharpless ◽  
Pamela Lockyer ◽  
Andrea L. Portbury ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Degradation ◽  
Cellular Senescence ◽  
Protein Quality ◽  
Functional Decline ◽  
Protein Quality Control ◽  
Biological Aging ◽  
Control Mechanisms ◽  
Age Related

ABSTRACT During the course of biological aging, there is a gradual accumulation of damaged proteins and a concomitant functional decline in the protein degradation system. Protein quality control is normally ensured by the coordinated actions of molecular chaperones and the protein degradation system that collectively help to maintain protein homeostasis. The carboxyl terminus of Hsp70-interacting protein (CHIP), a ubiquitin ligase/cochaperone, participates in protein quality control by targeting a broad range of chaperone substrates for proteasome degradation via the ubiquitin-proteasome system, demonstrating a broad involvement of CHIP in maintaining cytoplasmic protein quality control. In the present study, we have investigated the influence that protein quality control exerts on the aging process by using CHIP−/− mice. CHIP deficiency in mice leads to a markedly reduced life span, along with accelerated age-related pathophysiological phenotypes. These features were accompanied by indications of accelerated cellular senescence and increased indices of oxidative stress. In addition, CHIP−/− mice exhibit a deregulation of protein quality control, as indicated by elevated levels of toxic oligomer proteins and a decline in proteasome activity. Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo.

scholarly journals Novel proteostasis reporter mouse reveals different effects of cytoplasmic and nuclear aggregates on protein quality control in neurons

2020 ◽  
Author(s):  
Sonja Blumenstock ◽  
Elena Katharina Schulz-Trieglaff ◽  
Anna-Lena Bolender ◽  
Kerstin Voelkl ◽  
Paul Lapios ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
Aging Brain ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
Age Related ◽  
Reporter Mice

AbstractThe cellular protein quality control machinery is important for preventing protein misfolding and aggregation, and decline in protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how proteostasis capacity of neurons changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc), a conformationally unstable protein that requires chaperones for proper folding and sensitively reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked impairment in proteostasis in tauopathy mice, but not in Huntington’s disease mice. Mechanistic investigations in primary neuronal cultures demonstrate that cytoplasmic, but not nuclear, aggregates cause defects of cellular protein quality control. Thus, the Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

2021 ◽  
pp. 153537022199981
Author(s):  
Chamithi Karunanayake ◽  
Richard C Page
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Structural Features ◽  
Cellular Protein ◽  
Mechanisms Of Action ◽  
Control Mechanisms ◽  
Nucleotide Exchange ◽  
Domain Organization ◽  
Nucleotide Exchange Factors

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

scholarly journals Targeting Protein Quality Control Mechanisms by Natural Products to Promote Healthy Ageing

Molecules ◽  
2018 ◽  
Vol 23 (5) ◽  
pp. 1219 ◽  
Author(s):  
Sophia Wedel ◽  
Maria Manola ◽  
Maria Cavinato ◽  
Ioannis Trougakos ◽  
Pidder Jansen-Dürr
Keyword(s):  
Quality Control ◽  
Natural Products ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Healthy Ageing ◽  
Control Mechanisms

scholarly journals Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms

2020 ◽  
Vol 11 ◽  
Author(s):  
Sumita Mishra ◽  
Brittany L. Dunkerly-Eyring ◽  
Gizem Keceli ◽  
Mark J. Ranek
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Control Mechanisms

scholarly journals CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mark J. Ranek ◽  
Christian Oeing ◽  
Rebekah Sanchez-Hodge ◽  
Kristen M. Kokkonen-Simon ◽  
Danielle Dillard ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Kinase ◽  
Protein Quality ◽  
Therapeutic Potential ◽  
Protein Quality Control ◽  
Ischemic Injury ◽  
Protein Kinase G ◽  
Interacting Protein ◽  
Important Regulator

Abstract Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.

In vivo analysis of protein quality control in response to aging using transgenic mice

2013 ◽  
Vol 91 ◽  
pp. 0-0
Author(s):  
C MARQUES ◽  
P MATAFOME ◽  
A SANTOS ◽  
C LOBO ◽  
F SHANG ◽  
...  
Keyword(s):  
Quality Control ◽  
Transgenic Mice ◽  
Protein Quality ◽  
Protein Quality Control ◽  
In Vivo Analysis

scholarly journals Spatial protein quality control and the evolution of lineage-specific ageing

2011 ◽  
Vol 366 (1561) ◽  
pp. 71-75 ◽  
Author(s):  
Thomas Nyström
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Division Of Labour ◽  
Cell Renewal ◽  
Periodic Cell ◽  
Age Related ◽  
Selective Forces ◽  
Rate Of Ageing ◽  
Protein Folding Disorders

Propagation of a species requires periodic cell renewal to avoid clonal extinction. Sexual reproduction and the separation of germ cells from the soma provide a mechanism for such renewal, but are accompanied by an apparently mandatory ageing of the soma. Data obtained during the last decade suggest that a division of labour exists also between cells of vegetatively reproducing unicellular organisms, leading to the establishment of a soma-like and germ-like lineage with distinct fitness and longevity characteristics. This division of labour in both bacteria and yeast entails segregation of damaged and aggregated proteins such that the germ-like lineage is kept free of damage to the detriment of the soma-like lineage. In yeast, this spatial protein quality control (SQC) encompasses a CCT-chaperonin-dependent translocation and merging of cytotoxic protein aggregates. This process is regulated by Sir2, a protein deacetylase that modulates the rate of ageing in organisms ranging from yeast to worms and flies. Recent data also demonstrate that SQC is intimately integrated with the machinery establishing proper cell polarity and that this machinery is required for generating a soma-like and germ-like lineage in yeast. Deciphering the details of the SQC network may increase our understanding of the development of age-related protein folding disorders and shed light on the selective forces that paved the way for polarity and lineage-specific ageing to evolve.

Protein quality control at the mitochondrion

2016 ◽  
Vol 60 (2) ◽  
pp. 213-225 ◽  
Author(s):  
Wolfgang Voos ◽  
Witold Jaworek ◽  
Anne Wilkening ◽  
Michael Bruderek
Keyword(s):  
Quality Control ◽  
Structural Integrity ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Eukaryotic Cell ◽  
Control Mechanisms ◽  
Biochemical Processes ◽  
Unfolded Protein ◽  
Protein Response

Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. As mitochondria lack a large part of the required genetic information, most proteins are synthesized in the cytosol and imported into the organelle. After reaching their destination, polypeptides must fold and assemble into active proteins. Under pathological conditions, mitochondrial proteins become misfolded or damaged and need to be repaired with the help of molecular chaperones or eventually removed by specific proteases. Failure of these protein quality control mechanisms results in loss of mitochondrial function and structural integrity. Recently, novel mechanisms have been identified that support mitochondrial quality on the organellar level. A mitochondrial unfolded protein response allows the adaptation of chaperone and protease activities. Terminally damaged mitochondria may be removed by a variation of autophagy, termed mitophagy. An understanding of the role of protein quality control in mitochondria is highly relevant for many human pathologies, in particular neurodegenerative diseases.

scholarly journals Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5265-5275 ◽  
Author(s):  
Eugene Khandros ◽  
Christopher S. Thom ◽  
Janine D'Souza ◽  
Mitchell J. Weiss
Keyword(s):  
Quality Control ◽  
Stress Response ◽  
Protein Quality ◽  
Transcriptional Profiling ◽  
Globin Gene ◽  
Gene Mutations ◽  
Protein Quality Control ◽  
Proteasome Inhibition ◽  
Protective Mechanisms

Cells remove unstable polypeptides through protein quality-control (PQC) pathways such as ubiquitin-mediated proteolysis and autophagy. In the present study, we investigated how these pathways are used in β-thalassemia, a common hemoglobinopathy in which β-globin gene mutations cause the accumulation and precipitation of cytotoxic α-globin subunits. In β-thalassemic erythrocyte precursors, free α-globin was polyubiquitinated and degraded by the proteasome. These cells exhibited enhanced proteasome activity, and transcriptional profiling revealed coordinated induction of most proteasome subunits that was mediated by the stress-response transcription factor Nrf1. In isolated thalassemic cells, short-term proteasome inhibition blocked the degradation of free α-globin. In contrast, prolonged in vivo treatment of β-thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free α-globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, including autophagy, which cooperated with ubiquitin-mediated proteolysis to degrade free α-globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess α-globin. Therefore, β-thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cell-protective mechanisms.

Sign in / Sign up

Export Citation Format

Share Document