The Hsp70 chaperone system: distinct roles in erythrocyte formation and maintenance

Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates. Extensive reorganization and depletion of the erythroblast proteome leading to the deterioration of general cellular protein quality control pathways and rapid hemoglobin biogenesis rates could generate misfolded/aggregated proteins and trigger proteotoxic stresses during erythropoiesis. Such cytotoxic conditions could prevent proper cell differentiation resulting in premature apoptosis of erythroblasts (ineffective erythropoiesis). The heat shock protein 70 (Hsp70) molecular chaperone system supports a plethora of functions that help maintain cellular protein homeostasis (proteostasis) and promote red blood cell differentiation and survival. Recent findings show that abnormalities in the expression, localization and function of the members of this chaperone system are linked to ineffective erythropoiesis in multiple hematological diseases in humans. In this review, we present latest advances in our understanding of the distinct functions of this chaperone system in differentiating erythroblasts and terminally differentiated mature erythrocytes. We present new insights into the protein repair-only function(s) of the Hsp70 system, perhaps to minimize protein degradation in mature erythrocytes to warrant their optimal function and survival in the vasculature under healthy conditions. The work also discusses the modulatory roles of this chaperone system in a wide range of hematological diseases and the therapeutic gain of targeting Hsp70.

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

Circulation Research ◽

10.1161/res.121.suppl_1.85 ◽

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.

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Mycobacterium tuberculosis Rv0991c Is a Redox-Regulated Molecular Chaperone

mBio ◽

10.1128/mbio.01545-20 ◽

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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Translating protein phosphatase research into treatments for neurodegenerative diseases

Biochemical Society Transactions ◽

10.1042/bst20160157 ◽

2017 ◽

Vol 45 (1) ◽

pp. 101-112 ◽

Cited By ~ 4

Author(s):

Jeyapriya R. Sundaram ◽

Irene C.J. Lee ◽

Shirish Shenolikar

Keyword(s):

Drug Targets ◽

Protein Quality ◽

Neuronal Damage ◽

Critical Role ◽

Great Promise ◽

Control Mechanisms ◽

Wide Range ◽

Progression Of Disease ◽

The Unfolded Protein Response ◽

And Function

Many of the major neurodegenerative disorders are characterized by the accumulation of intracellular protein aggregates in neurons and other cells in brain, suggesting that errors in protein quality control mechanisms associated with the aging process play a critical role in the onset and progression of disease. The increased understanding of the unfolded protein response (UPR) signaling network and, more specifically, the structure and function of eIF2α phosphatases has enabled the development or discovery of small molecule inhibitors that show great promise in restoring protein homeostasis and ameliorating neuronal damage and death. While this review focuses attention on one or more eIF2α phosphatases, the wide range of UPR proteins that are currently being explored as potential drug targets bodes well for the successful future development of therapies to preserve neuronal function and treat neurodegenerative disease.

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The Hsp70-Chaperone Machines in Bacteria

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.694012 ◽

2021 ◽

Vol 8 ◽

Author(s):

Matthias P. Mayer

Keyword(s):

Protein Quality ◽

Cellular Protein ◽

Sequence Motifs ◽

Nucleotide Exchange ◽

Surveillance Network ◽

Nucleotide Exchange Factors ◽

Hsp70 Chaperone ◽

Range Of Functions ◽

Client Proteins ◽

Control Circuits

The ATP-dependent Hsp70s are evolutionary conserved molecular chaperones that constitute central hubs of the cellular protein quality surveillance network. None of the other main chaperone families (Tig, GroELS, HtpG, IbpA/B, ClpB) have been assigned with a comparable range of functions. Through a multitude of functions Hsp70s are involved in many cellular control circuits for maintaining protein homeostasis and have been recognized as key factors for cell survival. Three mechanistic properties of Hsp70s are the basis for their high versatility. First, Hsp70s bind to short degenerate sequence motifs within their client proteins. Second, Hsp70 chaperones switch in a nucleotide-controlled manner between a state of low affinity for client proteins and a state of high affinity for clients. Third, Hsp70s are targeted to their clients by a large number of cochaperones of the J-domain protein (JDP) family and the lifetime of the Hsp70-client complex is regulated by nucleotide exchange factors (NEF). In this review I will discuss advances in the understanding of the molecular mechanism of the Hsp70 chaperone machinery focusing mostly on the bacterial Hsp70 DnaK and will compare the two other prokaryotic Hsp70s HscA and HscC with DnaK.

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Transglutaminase Regulation of Cell Function

Physiological Reviews ◽

10.1152/physrev.00019.2013 ◽

2014 ◽

Vol 94 (2) ◽

pp. 383-417 ◽

Cited By ~ 203

Author(s):

Richard L. Eckert ◽

Mari T. Kaartinen ◽

Maria Nurminskaya ◽

Alexey M. Belkin ◽

Gozde Colak ◽

...

Keyword(s):

Signal Transduction ◽

Cell Differentiation ◽

Cell Fate ◽

Mechanism Of Action ◽

Cell Function ◽

Cellular Systems ◽

Cancer Development ◽

Disease States ◽

Wide Range ◽

And Function

Transglutaminases (TGs) are multifunctional proteins having enzymatic and scaffolding functions that participate in regulation of cell fate in a wide range of cellular systems and are implicated to have roles in development of disease. This review highlights the mechanism of action of these proteins with respect to their structure, impact on cell differentiation and survival, role in cancer development and progression, and function in signal transduction. We also discuss the mechanisms whereby TG level is controlled and how TGs control downstream targets. The studies described herein begin to clarify the physiological roles of TGs in both normal biology and disease states.

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The endoplasmic reticulum associated degradation adaptor Sel1L regulates T cell homeostasis and function

10.1101/2021.05.22.445275 ◽

2021 ◽

Author(s):

Alexander Dils ◽

Luis Correa ◽

J. Paige Gronevelt ◽

Lu Liu ◽

Padma Kadiyala ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

T Cell ◽

Protein Quality ◽

Apoptotic Cell ◽

Cd8 T Cell ◽

Cellular Protein ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Endoplasmic Reticulum Associated Degradation ◽

And Function

Suppressor/Enhancer of Lin-12-like (Sel1L) is a critical adaptor for endoplasmic reticulum-associated degradation (ERAD), a process that maintains cellular protein quality control through degradation of misfolded proteins. Here we investigate the role of Sel1L in T cell homeostasis and function. T cell-specific deletion of Sel1L profoundly impairs peripheral T cell survival and promotes apoptotic cell death. Furthermore, Sel1L is required to maintain naive CD8+ T cell homeostasis in a cell-intrinsic manner with loss of quiescence as evidenced by increased proliferation. Sel1L-deficient T cells exhibit enhanced activation of the mammalian target of rapamycin (mTOR) pathway and altered cellular metabolism, including increased cellular reactive oxygen species, mitochondrial mass and mitochondrial membrane potential in the naive CD8+ T cell compartment. Furthermore, loss of Sel1L impaired CD8+ T cell immune responses following bacterial infection. These results demonstrate a novel role for Sel1L/ERAD in T cell homeostasis and function.

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Pediatric Replantation after Traumatic Amputation at the Distal Forearm: Rehabilitation Protocol and Outcomes

Journal of Hand and Microsurgery ◽

10.1055/s-0040-1703096 ◽

2020 ◽

Author(s):

Nicholas C. Oleck ◽

Radhika Malhotra ◽

Haripriya S. Ayyala ◽

Ramazi O. Datiashvili

Keyword(s):

Operating Room ◽

Multidisciplinary Team ◽

Distal Forearm ◽

Left Forearm ◽

Traumatic Amputation ◽

Postoperative Rehabilitation ◽

Rehabilitation Protocol ◽

Microsurgical Technique ◽

Optimal Function ◽

And Function

AbstractMajor limb replantation is a formidable task, especially in the pediatric setting. While meticulous microsurgical technique is required in the operating room, the authors aim to highlight the importance of postoperative rehabilitation therapy for optimal function. We highlight the case of a 12-year-old boy who suffered complete traumatic amputation through the distal left forearm. The limb was successfully replanted with successful restoration of sensation and function with the aid of intensive postoperative occupational therapy. A multidisciplinary team is of paramount importance to maximize function of a replanted upper extremity.

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Chaperonin as the normal controls and pathological anti-stress response in the human reproductive system

HEALTH OF WOMAN ◽

10.15574/hw.2016.111.126 ◽

2016 ◽

pp. 126-129

Author(s):

M. Makarenko ◽

◽

D. Hovsyeyev ◽

L. Sydoryk ◽

◽

...

Keyword(s):

Reproductive System ◽

Stress Proteins ◽

Physiological Stress ◽

Protein Complexes ◽

Reproductive Function ◽

Intercellular Signaling ◽

Toll Like Receptors ◽

Wide Range ◽

Protein Functions ◽

And Function

Different kinds of physiological stress cause mass changes in the cells, including the changes in the structure and function of the protein complexes and in separate molecules. The protein functions is determined by its folding (the spatial conclusion), which depends on the functioning of proteins of thermal shock- molecular chaperons (HSPs) or depends on the stress proteins, that are high-conservative; specialized proteins that are responsible for the correct proteinaceous folding. The family of the molecular chaperones/ chaperonins/ Hsp60 has a special place due to the its unique properties of activating the signaling cascades through the system of Toll-like receptors; it also stimulates the cells to produce anti- inflammatory cytokines, defensins, molecules of cell adhesion and the molecules of MHC; it functions as the intercellular signaling molecule. The pathological role of Hsp60 is established in a wide range of illnesses, from diabetes to atherosclerosis, where Hsp60 takes part in the regulation of both apoptosis and the autoimmune processes. The presence of the HSPs was found in different tissues that are related to the reproductive system. Key words: molecular chaperons (HSPs), Toll-like receptors, reproductive function, natural auto antibody.

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Possession and Repetition

Postscripts The Journal of Sacred Texts and Contemporary Worlds ◽

10.1558/post.v6i1-3.243 ◽

2012 ◽

Vol 6 (1-3) ◽

pp. 243-259 ◽

Cited By ~ 2

Author(s):

Yohan Yoo

Keyword(s):

First Century ◽

Daily Lives ◽

Modern Times ◽

Sacred Texts ◽

New Methods ◽

Wide Range ◽

Lay Buddhists ◽

Iconic Status ◽

And Function ◽

To Receive

This article demonstrates the need for the iconic status and function of Buddhist scripture to receive more attention by illuminating how lay Korean Buddhists try to appropriate the power of sutras. The oral and aural aspects of scripture, explained by Wilfred Cantwell Smith, provide only a limited understanding of the characteristics of scripture. It should be noted that, before modern times, most lay people, not only in Buddhist cultures but also in Christian and other traditions, neither had the chance to recite scriptures nor to listen to their recitations regularly. Several clear examples demonstrate contemporary Korean Buddhists’ acceptance of the iconic status of sutras and their attempt to appropriate the power and status of those sacred texts. In contemporary Korea, lay Buddhists try to claim the power of scriptures in their daily lives by repeating and possessing them. Twenty-first century lay believers who cannot read or recite in a traditional style have found new methods of repetition, such as internet programs for copying sacred texts and for playing recordings of their recitations. In addition, many Korean Buddhists consider the act of having sutras in one’s possession to be an effective way of accessing the sacred status and power of these texts. Hence, various ways of possessing them have been developed in a wide range of products, from fancy gilded sutras to sneakers embroidered with mantras.

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