Common and specific mechanisms of AAA+ proteins involved in protein quality control

2008 ◽  
Vol 36 (1) ◽  
pp. 120-125 ◽  
Author(s):  
Axel Mogk ◽  
Tobias Haslberger ◽  
Peter Tessarz ◽  
Bernd Bukau
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Divergent Evolution ◽  
Aaa Atpase ◽  
Middle Domain ◽  
Hsp70 Chaperone ◽  
Protein Quality Control System ◽  
Aaa Protein

A protein quality control system, consisting of molecular chaperones and proteases, controls the folding status of proteins and mediates the refolding or degradation of misfolded proteins. Ring-forming AAA+ (ATPase associated with various cellular activities) proteins play crucial roles in both processes by co-operating with either peptidases or chaperone systems. Peptidase-associated AAA+ proteins bind substrates and thread them through their axial channel into the attached proteolytic chambers for degradation. In contrast, the AAA+ protein ClpB evolved independently from an interacting peptidase and co-operates with a cognate Hsp70 (heat-shock protein 70) chaperone system to solubilize and refold aggregated proteins. The activity of this bi-chaperone system is crucial for the survival of bacteria, yeast and plants during severe stress conditions. Hsp70 acts at initial stages of the disaggregation process, enabling ClpB to extract single unfolded polypeptides from the aggregate via a threading activity. Although both classes of AAA+ proteins share a common threading activity, it is apparent that their divergent evolution translates into specific mechanisms, reflecting adaptations to their respective functions. The ClpB-specific M-domain (middle domain) represents such an extra feature that verifies ClpB as the central disaggregase in vivo. M-domains act as regulatory devices to control both ClpB ATPase activity and the Hsp70-dependent binding of aggregated proteins to the ClpB pore, thereby coupling the Hsp70 chaperone activity with the ClpB threading motor to ensure efficient protein disaggregation.

scholarly journals Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kenichi Kimura ◽  
Astrid Ooms ◽  
Kathrin Graf-Riesen ◽  
Maithreyan Kuppusamy ◽  
Andreas Unger ◽  
...  
Keyword(s):  
Quality Control ◽  
Control System ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Restrictive Cardiomyopathy ◽  
Quality Control System ◽  
Rna Seq ◽  
Protein Quality Control System ◽  
Acid Exchange

AbstractAn amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.

Abstract 85: The AAA-ATPase p97 is a Critical Regulator of Cardiac Homeostasis

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Matthew J Brody ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Complexes ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Dominant Negative ◽  
Aaa Atpase ◽  
And Function ◽  
Thrombospondin 4

p97 is a AAA-ATPase that plays critical roles in a myriad of cellular protein quality control processes, including the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway that targets misfolded proteins in the ER for degradation in the cytosol by the ubiquitin proteasome system. Mutations in p97 cause a multisystem degenerative proteinopathy disorder called inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) that includes pathologies of the nervous system, skeletal muscle, bone, and heart. Previous studies in the laboratory into the mechanisms whereby thrombospondin 4 has its cardioprotective effects and enhanced ERAD activity identified p97 as a direct interacting partner. This observation suggested that p97 itself could be an important cardioprotective effector by benefiting protein quality control in the heart. To address this hypothesis here we generated cardiac-specific transgenic mice overexpressing wildtype p97 or a p97 K524A mutant with deficient ATPase activity, the latter of which functioned as a dominant negative. Mice overexpressing wildtype p97 exhibit normal cardiac structure and function while mutant p97 overexpressing mice develop cardiomyopathy, upregulate several ERAD complex components, and have elevated levels of ubiquitinated proteins. Proteomics and immunoprecipitation assays identified overwhelming interactions between endogenous p97 and a number of interesting protein complexes that suggest unique functions for this protein in regulating protein quality control in the heart. The results and novel regulatory relationships will be presented, which suggests entirely unique pathways whereby p97 functions in the heart.

scholarly journals A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

2020 ◽  
Vol 12 ◽  
Author(s):  
Riccardo Cristofani ◽  
Valeria Crippa ◽  
Maria Elena Cicardi ◽  
Barbara Tedesco ◽  
Veronica Ferrari ◽  
...  
Keyword(s):  
Quality Control ◽  
Control System ◽  
Motor Neuron ◽  
Crucial Role ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Quality Control System ◽  
Motor Neuron Diseases ◽  
Protein Quality Control System

scholarly journals Mycobacterium tuberculosis Rv0991c Is a Redox-Regulated Molecular Chaperone

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Samuel H. Becker ◽  
Kathrin Ulrich ◽  
Avantika Dhabaria ◽  
Beatrix Ueberheide ◽  
William Beavers ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Quality Control ◽  
Mycobacterium Tuberculosis ◽  
Molecular Chaperone ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
Content Type ◽  
Hsp70 Chaperone

ABSTRACT The bacterial pathogen Mycobacterium tuberculosis is the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterized M. tuberculosis protein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologs in most bacterial lineages and appears to function analogously to the well-characterized Escherichia coli redox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally coregulated with hsp60 and hsp70 chaperone genes in M. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded protein in vitro and promotes its refolding by the M. tuberculosis Hsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and can associate with many other M. tuberculosis proteins. We therefore propose that Rv0991c, which we named “Ruc” (redox-regulated protein with unstructured C terminus), represents a founding member of a new chaperone family that protects M. tuberculosis and other species from proteotoxicity during oxidative stress. IMPORTANCE M. tuberculosis infections are responsible for more than 1 million deaths per year. Developing effective strategies to combat this disease requires a greater understanding of M. tuberculosis biology. As in all cells, protein quality control is essential for the viability of M. tuberculosis, which likely faces proteotoxic stress within a host. Here, we identify an M. tuberculosis protein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial superkingdom. Additionally, we found that oxidized Ruc promotes the protein-folding activity of the essential M. tuberculosis Hsp70 chaperone system. This work contributes to a growing body of evidence that oxidative stress provides a particular strain on cellular protein stability.

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 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.

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