scholarly journals The extracellular HDAC6 ZnF UBP domain modulates the actin network and post-translational modifications of Tau

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Ankur Balmik ◽  
Shweta Kishor Sonawane ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Protein Misfolding ◽  
Tau Phosphorylation ◽  
Actin Dynamics ◽  
Histone Deacetylase 6 ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization ◽  
Aggresome Formation ◽  
Gsk 3Β ◽  
Misfolding Diseases

Abstract Background Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein. Methods Here, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization. Results HDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3β increases without any change in total GSK-3β level. Conclusions HDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases.

scholarly journals Modulation of Actin network and Tau phosphorylation by HDAC6 ZnF UBP domain

2019 ◽  
Author(s):  
Abhishek Ankur Balmik ◽  
Shweta Kishor Sonawane ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Nuclear Localization ◽  
Tau Phosphorylation ◽  
Actin Network ◽  
Cytoskeletal Organization ◽  
Protein Tau ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization ◽  
Aggresome Formation ◽  
Gsk 3Β

AbstractMicrotubule-associated protein Tau undergoes aggregation in Alzheimer’s disease and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. HDAC6 plays an important role in aggresome formation where it recruits polyubiquitinated aggregates to the motor protein dynein. Here, we have studied the effect of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemistry. Immunocytochemistry reveals that HDAC6 ZnF UBP can modulate Tau phosphorylation and actin cytoskeleton organization when the cells are exposed to the domain. HDAC6 ZnF UBP treatment to cells does not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting its role in actin re-organization. Also, HDAC6 treatment showed increased nuclear localization of ApoE and tubulin localization in microtubule organizing centre. Our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases.

scholarly journals Modulation of Actin Network and Tau Phosphorylation by HDAC6 ZnF UBP  Domain

2020 ◽  
Author(s):  
Balmik Ankur Balmik ◽  
Shweta Kishor Sonawane ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Nuclear Localization ◽  
Tau Phosphorylation ◽  
Actin Network ◽  
Cytoskeletal Organization ◽  
Protein Tau ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization ◽  
Aggresome Formation ◽  
Gsk 3Β

Abstract Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. HDAC6 plays an important role in aggresome formation where it recruits polyubiquitinated aggregates to the motor protein dynein. Here, we have studied the effect of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemistry. Immunocytochemistry reveals that HDAC6 ZnF UBP can modulate Tau phosphorylation and actin cytoskeleton organization when the cells are exposed to the domain. HDAC6 ZnF UBP treatment to cells does not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting its role in actin re-organization. Also, HDAC6 treatment showed increased nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases.

scholarly journals Modulation of Actin network and Tau phosphorylation by HDAC6 ZnF UBP domain

2020 ◽  
Author(s):  
Abhishek Ankur Balmik ◽  
Shweta Kishor Sonawane ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Membrane Integrity ◽  
Neuronal Cell ◽  
Tau Phosphorylation ◽  
Cytoskeleton Organization ◽  
Treatment Conditions ◽  
Actin Cytoskeleton Organization ◽  
Ldh Assay ◽  
Aggresome Formation ◽  
Gsk 3Β

Abstract Background: Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. HDAC6 plays an important role in aggresome formation where it recruits poly-ubiquitinated aggregates to the motor protein dynein. Methods: Here, we have studied the effect of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunofluorescence analysis using fluorescently tagged molecules or antibodies. We have assessed neuronal cell viability and membrane integrity under different treatment conditions by employing MTT and LDH assay respectively. Results: Immunocytochemistry reveals that HDAC6 ZnF UBP can modulate Tau phosphorylation and actin cytoskeleton organization when the cells are exposed to the domain. HDAC6 ZnF UBP treatment to cells does not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting its role in actin re-organization. Also, HDAC6 treatment showed increased nuclear localization of ApoE and tubulin localization in microtubule organizing centre. Conclusions: Altogether, our studies suggest the regulatory role of this domain in different aspects related to neurodegenerative diseases.

scholarly journals Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

2020 ◽  
Vol 21 (23) ◽  
pp. 9186
Author(s):  
Rubén Hervás ◽  
Javier Oroz
Keyword(s):  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Protective Role ◽  
Soluble Proteins ◽  
Protein Deposits ◽  
Client Proteins ◽  
Recognition Motifs ◽  
Misfolding Diseases

Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

scholarly journals Physiological role of ROCKs in the cardiovascular system

2006 ◽  
Vol 290 (3) ◽  
pp. C661-C668 ◽  
Author(s):  
Kensuke Noma ◽  
Naotsugu Oyama ◽  
James K. Liao
Keyword(s):  
Protein Kinase ◽  
Cardiovascular System ◽  
Vascular Inflammation ◽  
Physiological Role ◽  
Smooth Muscle Contraction ◽  
Kinase Substrate ◽  
Cytoskeleton Organization ◽  
Beneficial Effects ◽  
Actin Cytoskeleton Organization

Rho-associated kinases (ROCKs), the immediate downstream targets of RhoA, are ubiquitously expressed serine-threonine protein kinases that are involved in diverse cellular functions, including smooth muscle contraction, actin cytoskeleton organization, cell adhesion and motility, and gene expression. Recent studies have shown that ROCKs may play a pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke, and heart failure. Indeed, inhibition of ROCKs by statins or other selective inhibitors leads to the upregulation and activation of endothelial nitric oxide synthase (eNOS) and reduction of vascular inflammation and atherosclerosis. Thus inhibition of ROCKs may contribute to some of the cholesterol-independent beneficial effects of statin therapy. Currently, two ROCK isoforms have been identified, ROCK1 and ROCK2. Because ROCK inhibitors are nonselective with respect to ROCK1 and ROCK2 and also, in some cases, may be nonspecific with respect to other ROCK-related kinases such as myristolated alanine-rich C kinase substrate (MARCKS), protein kinase A, and protein kinase C, the precise role of ROCKs in cardiovascular disease remains unknown. However, with the recent development of ROCK1- and ROCK2-knockout mice, further dissection of ROCK signaling pathways is now possible. Herein we review what is known about the physiological role of ROCKs in the cardiovascular system and speculate about how inhibition of ROCKs could provide cardiovascular benefits.

scholarly journals Nanoimaging for Protein Misfolding Diseases. Critical Role of Misfolded Dimers in the Amyloid Self-Assembly

2011 ◽  
Vol 17 (S2) ◽  
pp. 170-171
Author(s):  
A Krasnoslobodtsev ◽  
B-H Kim ◽  
Y Lyubchenko
Keyword(s):  
Self Assembly ◽  
Protein Misfolding ◽  
Critical Role ◽  
Misfolding Diseases

Extended abstract of a paper presented at Microscopy and Microanalysis 2011 in Nashville, Tennessee, USA, August 7–August 11, 2011.

scholarly journals Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes

2011 ◽  
Vol 22 (18) ◽  
pp. 3277-3288 ◽  
Author(s):  
Xingqian Zhang ◽  
Shu-Bing Qian
Keyword(s):  
Protein Folding ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Hierarchical Control ◽  
Dominant Negative ◽  
Misfolded Proteins ◽  
Interacting Protein ◽  
Aggresome Formation

Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Despite the well-established role of chaperones in both protein folding and degradation, how chaperones regulate the aggregation process remains controversial. Here we investigate the molecular mechanisms underlying aggresome formation in mammalian cells. Analysis of the chaperone requirements for the fate of misfolded proteins reveals an unexpected role of heat shock protein 70 (Hsp70) in promoting aggresome formation. This proaggregation function of Hsp70 relies on the interaction with the cochaperone ubiquitin ligase carboxyl terminal of Hsp70/Hsp90 interacting protein (CHIP). Disrupting Hsp70–CHIP interaction prevents the aggresome formation, whereas a dominant-negative CHIP mutant sensitizes the aggregation of misfolded protein. This accelerated aggresome formation also relies on the stress-induced cochaperone Bcl2-associated athanogene 3. Our results indicate that a hierarchy of cochaperone interaction controls different aspects of the intracellular protein triage decision, extending the function of Hsp70 from folding and degradation to aggregation.

scholarly journals Disulfide Bonding in Neurodegenerative Misfolding Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Francesca Mossuto
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Disulfide Bonds ◽  
Protein Misfolding ◽  
Bond Formation ◽  
Specific Protein ◽  
Disulfide Bonding ◽  
Misfolding Diseases ◽  
Protein Misfolding And Aggregation

In recent years an increasing number of neurodegenerative diseases has been linked to the misfolding of a specific protein and its subsequent accumulation into aggregated species, often toxic to the cell. Of all the factors that affect the behavior of these proteins, disulfide bonds are likely to be important, being very conserved in protein sequences and being the enzymes devoted to their formation among the most conserved machineries in mammals. Their crucial role in the folding and in the function of a big fraction of the human proteome is well established. The role of disulfide bonding in preventing and managing protein misfolding and aggregation is currently under investigation. New insights into their involvement in neurodegenerative diseases, their effect on the process of protein misfolding and aggregation, and into the role of the cellular machineries devoted to disulfide bond formation in neurodegenerative diseases are emerging. These studies mark a step forward in the comprehension of the biological base of neurodegenerative disorders and highlight the numerous questions that still remain open.

scholarly journals Role of Protein Misfolding and Proteostasis Deficiency in Protein Misfolding Diseases and Aging

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Karina Cuanalo-Contreras ◽  
Abhisek Mukherjee ◽  
Claudio Soto
Keyword(s):  
Protein Misfolding ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Unfolded Protein ◽  
Natural Defense ◽  
Dependent Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself.

scholarly journals Requisite Role for Nck Adaptors in Cardiovascular Development, Endothelial-to-Mesenchymal Transition, and Directed Cell Migration

2015 ◽  
Vol 35 (9) ◽  
pp. 1573-1587 ◽  
Author(s):  
Derek L. Clouthier ◽  
Cameron N. Harris ◽  
Richard A. Harris ◽  
Claire E. Martin ◽  
Mira C. Puri ◽  
...  
Keyword(s):  
Cell Types ◽  
Actin Dynamics ◽  
Cardiovascular Development ◽  
Vascular Networks ◽  
Mesenchymal Transition ◽  
Perivascular Cell ◽  
Cytoskeleton Organization ◽  
Directed Cell Migration ◽  
Actin Cytoskeleton Organization ◽  
Endothelial To Mesenchymal Transition

Development of the cardiovascular system is critically dependent on the ability of endothelial cells (ECs) to reorganize their intracellular actin architecture to facilitate migration, adhesion, and morphogenesis. Nck family cytoskeletal adaptors function as key mediators of actin dynamics in numerous cell types, though their role in EC biology remains largely unexplored. Here, we demonstrate an essential requirement for Nck within ECs. Mouse embryos lacking endothelial Nck1/2 expression develop extensive angiogenic defects that result in lethality at about embryonic day 10. Mutant embryos show immature vascular networks, with decreased vessel branching, aberrant perivascular cell recruitment, and reduced cardiac trabeculation. Strikingly, embryos deficient in endothelial Nck also fail to undergo the endothelial-to-mesenchymal transition (EnMT) required for cardiac valve morphogenesis, with loss of Nck disrupting expression of major EnMT markers, as well as suppressing mesenchymal outgrowth. Furthermore, we show that Nck-null ECs are unable to migrate downstream of vascular endothelial growth factor and angiopoietin-1, and they exhibit profound perturbations in cytoskeletal patterning, with disorganized cellular projections, impaired focal adhesion turnover, and disrupted actin-based signaling. Our collective findings thereby reveal a crucial role for Nck as a master regulator within the endothelium to control actin cytoskeleton organization, vascular network remodeling, and EnMT during cardiovascular development.

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