scholarly journals The Role of Proteostasis Derailment in Cardiac Diseases

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2317
Author(s):  
Bianca J. J. M. Brundel
Keyword(s):  
Quality Control ◽  
Cardiac Disease ◽  
Protein Quality ◽  
Disease Onset ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
Cardiac Diseases ◽  
Wear And Tear ◽  
Central Factors

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing and changes in lifestyle. Prevailing theories about the mechanisms of cardiac disease onset feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of the protein quality control as central factors. In the heart, loss of protein patency, due to flaws in design (genetically) or environmentally-induced wear and tear, may overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac disease onset.

scholarly journals Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation

2021 ◽  
Vol 8 ◽  
Author(s):  
Diego Ruano
Keyword(s):  
Quality Control ◽  
Control Systems ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Normal Aging ◽  
Cellular Protein ◽  
World Population ◽  
Age Related

Aging is a biological and multifactorial process characterized by a progressive and irreversible deterioration of the physiological functions leading to a progressive increase in morbidity. In the next decades, the world population is expected to reach ten billion, and globally, elderly people over 80 are projected to triple in 2050. Consequently, it is also expected an increase in the incidence of age-related pathologies such as cancer, diabetes, or neurodegenerative disorders. Disturbance of cellular protein homeostasis (proteostasis) is a hallmark of normal aging that increases cell vulnerability and might be involved in the etiology of several age-related diseases. This review will focus on the molecular alterations occurring during normal aging in the most relevant protein quality control systems such as molecular chaperones, the UPS, and the ALS. Also, alterations in their functional cooperation will be analyzed. Finally, the role of inflammation, as a synergistic negative factor of the protein quality control systems during normal aging, will also be addressed. A better comprehension of the age-dependent modifications affecting the cellular proteostasis, as well as the knowledge of the mechanisms underlying these alterations, might be very helpful to identify relevant risk factors that could be responsible for or contribute to cell deterioration, a fundamental question still pending in biomedicine.

Abstract 30: Nub1l Suppresses Neddylation And Enhances Misfolded Protein Clearance In Cardiomyocytes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Huabo Su ◽  
Jie Li ◽  
Wenxia Ma ◽  
Ning Hou ◽  
Faqian Li
Keyword(s):  
Quality Control ◽  
Protein Degradation ◽  
Cardiac Disease ◽  
Protein Modification ◽  
Protein Quality ◽  
Ischemia Reperfusion ◽  
Protein Quality Control ◽  
Misfolded Protein ◽  
Dependent Manner

Protein modification by ubiquitin (Ub) or Ub-like proteins such as NEDD8 (neddylation) constitutes a fundamental regulatory mechanism of protein function. In contrast to well-recognized role of Ub in protein degradation, little is known about the role of NEDD8 in protein quality control. We have previously revealed that CM-restricted inactivation of deneddylation, a process that removes NEDD8 from modified proteins, accumulates neddylated proteins and impairs proteasomal and autophagic proteolysis. Here we report that proteasome inhibitors, simulated ischemia/reperfusion and H2O2 significantly increase NEDD8 conjugates in cardiomyocytes (CMs). Immunoprecipitation analysis reveals mixed modification of these proteins by Ub and NEDD8. Expression of NEDD8 but not the conjugation-deficient mutant increases neddylated proteins and accumulates a proteasome surrogate substrate GFPu in a dose-dependent manner, suggesting that excessive neddylation disrupts proteasomal proteolysis. We further targets to NUB1L, a UBL (Ub-like domain)-UBA (Ub associating domain) family protein that was shown to negatively regulate neddylation. NUB1L expression markedly reduces free NEDD8 by promoting its degradation, and abrogates proteasome inhibition-induced neddylation in CMs. Suppression of neddylation by NUB1L expression enhances GFPu degradation at baseline, and attenuates GFPu accumulation upon sI/R and H2O2 treatment. Furthermore, NUB1L expression promotes, while down-regulation of NUB1L impairs, the clearance of a bona fide misfolded protein in CMs. NUB1L expression also ameliorates proteotoxic stress- and sI/R-induced CM injury. Finally, increased NEDD8 conjugates are evident in the mouse hearts of a number of cardiac disease models as well as in human failing hearts. Together, our findings suggest that excessive neddylation disrupts protein quality control and that antagonizing neddylation by NUB1L promotes misfolded protein degradation. Targeting neddylation/NUB1L could be a novel therapeutic strategy for prevention and treatment of insufficient protein quality control-associated cardiac disease.

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 TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

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.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

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.

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