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Cells
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Extracellular and Organismal Proteostasis
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Extracellular and Organismal Proteostasis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 13904

Special Issue Editor

Prof. Dr. Mark R. Wilson

E-Mail Website
Guest Editor
Illawarra Health and Medical Research Institute, and Molecular Horizons, School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia
Interests: extracellular proteostasis; chaperones; protein folding; cytotoxicity; flow cytometry; optical microscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Our current understanding of the mechanisms that operate to maintain protein homeostasis (proteostasis) in spaces outside cells in the body is surprisingly limited. A failure or dysfunction in these processes leads to physiologically dangerous levels of misfolded, aggregated and potentially cytotoxic extracellular proteins, resulting in the development of a variety of serious human diseases and which may contribute directly to the ageing process. The identification of a small but growing family of constitutively secreted extracellular chaperones (ECs) is one important step towards a better understanding of extracellular proteostasis. These secreted ECs are found in body fluids at concentrations in the μg/mL to mg/mL range, and are thought to recognise and specifically bind to extracellular misfolded proteins to maintain their solubility, neutralise their toxicity, and mediate their safe disposal. However, it is almost certain that other yet to be discovered processes play important roles in maintaining proteostasis in body fluids and the organism as a whole. Advances that increase our understanding in these areas are essential for the future development of strategies to treat currently incurable diseases.

The goal of this Special Issue is to present current knowledge of the mechanisms operating in extracellular and organismal proteostasis and to identify important knowledge gaps in the field.

Prof. Mark R. Wilson
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • proteostasis
  • body fluids
  • organism
  • protein folding
  • cytotoxicity
  • extracellular chaperones
  • proteases
  • clearance

Published Papers (6 papers)

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Research

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12 pages, 1886 KiB  
Article
The Extracellular Molecular Chaperone Clusterin Inhibits Amyloid Fibril Formation and Suppresses Cytotoxicity Associated with Semen-Derived Enhancer of Virus Infection (SEVI)
by Abigail K. Elias, Mark R. Wilson, John A. Carver and Ian F. Musgrave
Cells 2022, 11(20), 3259; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11203259 - 17 Oct 2022
Cited by 2 | Viewed by 1266
Abstract
Clusterin is a glycoprotein present at high concentrations in many extracellular fluids, including semen. Its increased expression accompanies disorders associated with extracellular amyloid fibril accumulation such as Alzheimer’s disease. Clusterin is an extracellular molecular chaperone which prevents the misfolding and amorphous and amyloid [...] Read more.
Clusterin is a glycoprotein present at high concentrations in many extracellular fluids, including semen. Its increased expression accompanies disorders associated with extracellular amyloid fibril accumulation such as Alzheimer’s disease. Clusterin is an extracellular molecular chaperone which prevents the misfolding and amorphous and amyloid fibrillar aggregation of a wide variety of unfolding proteins. In semen, amyloid fibrils formed from a 39-amino acid fragment of prostatic acid phosphatase, termed Semen-derived Enhancer of Virus Infection (SEVI), potentiate HIV infectivity. In this study, clusterin potently inhibited the in vitro formation of SEVI fibrils, along with dissociating them. Furthermore, clusterin reduced the toxicity of SEVI to pheochromocytoma-12 cells. In semen, clusterin may play an important role in preventing SEVI amyloid fibril formation, in dissociating SEVI fibrils and in mitigating their enhancement of HIV infection. Full article
(This article belongs to the Special Issue Extracellular and Organismal Proteostasis)
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16 pages, 2611 KiB  
Article
Proteostasis Response to Protein Misfolding in Controlled Hypertension
by Manuel Teixeira, Dário Trindade, Marisol Gouveia, Roberta Eller-Borges, Sandra Magalhães, Ana Duarte, Miriam Ferreira, Maria I. Simões, Maria Conceição, Alexandra Nunes, Ana Gabriela Henriques, Fernando Ribeiro and Sandra I. Vieira
Cells 2022, 11(10), 1686; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101686 - 19 May 2022
Cited by 4 | Viewed by 2344
Abstract
Hypertension is the most determinant risk factor for cardiovascular diseases. Early intervention and future therapies targeting hypertension mechanisms may improve the quality of life and clinical outcomes. Hypertension has a complex multifactorial aetiology and was recently associated with protein homeostasis (proteostasis). This work [...] Read more.
Hypertension is the most determinant risk factor for cardiovascular diseases. Early intervention and future therapies targeting hypertension mechanisms may improve the quality of life and clinical outcomes. Hypertension has a complex multifactorial aetiology and was recently associated with protein homeostasis (proteostasis). This work aimed to characterize proteostasis in easy-to-access plasma samples from 40 individuals, 20 with controlled hypertension and 20 age- and gender-matched normotensive individuals. Proteostasis was evaluated by quantifying the levels of protein aggregates through different techniques, including fluorescent probes, slot blot immunoassays and Fourier-transform infrared spectroscopy (FTIR). No significant between-group differences were observed in the absolute levels of various protein aggregates (Proteostat or Thioflavin T-stained aggregates; prefibrillar oligomers and fibrils) or total levels of proteostasis-related proteins (Ubiquitin and Clusterin). However, significant positive associations between Endothelin 1 and protein aggregation or proteostasis biomarkers (such as fibrils and ubiquitin) were only observed in the hypertension group. The same is true for the association between the proteins involved in quality control and protein aggregates. These results suggest that proteostasis mechanisms are actively engaged in hypertension as a coping mechanism to counteract its pathological effects in proteome stability, even when individuals are chronically medicated and presenting controlled blood pressure levels. Full article
(This article belongs to the Special Issue Extracellular and Organismal Proteostasis)
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17 pages, 5187 KiB  
Article
ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors
by Jaleh S. Mesgarzadeh, Isabelle C. Romine, Ethan M. Smith-Cohen, Julia M. D. Grandjean, Jeffery W. Kelly, Joseph C. Genereux and R. Luke Wiseman
Cells 2022, 11(10), 1661; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101661 - 17 May 2022
Cited by 4 | Viewed by 2204
Abstract
The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce the toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone proteins secreted from mammalian cells. The [...] Read more.
The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce the toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone proteins secreted from mammalian cells. The stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases the secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass-spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions in destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent mechanism. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction in destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases. Full article
(This article belongs to the Special Issue Extracellular and Organismal Proteostasis)
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15 pages, 4195 KiB  
Article
A Novel Role for Plasminogen Activator Inhibitor Type-2 as a Hypochlorite-Resistant Serine Protease Inhibitor and Holdase Chaperone
by Jordan H. Cater, Noralyn B. Mañucat-Tan, Demi K. Georgiou, Guomao Zhao, Irina A. Buhimschi, Amy R. Wyatt and Marie Ranson
Cells 2022, 11(7), 1152; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11071152 - 29 Mar 2022
Cited by 6 | Viewed by 2082
Abstract
Plasminogen activator inhibitor type-2 (PAI-2), a member of the serpin family, is dramatically upregulated during pregnancy and in response to inflammation. Although PAI-2 exists in glycosylated and non-glycosylated forms in vivo, the majority of in vitro studies of PAI-2 have exclusively involved the [...] Read more.
Plasminogen activator inhibitor type-2 (PAI-2), a member of the serpin family, is dramatically upregulated during pregnancy and in response to inflammation. Although PAI-2 exists in glycosylated and non-glycosylated forms in vivo, the majority of in vitro studies of PAI-2 have exclusively involved the intracellular non-glycosylated form. This study shows that exposure to inflammation-associated hypochlorite induces the oligomerisation of PAI-2 via a mechanism involving dityrosine formation. Compared to plasminogen activator inhibitor type-1 (PAI-1), both forms of PAI-2 are more resistant to hypochlorite-induced inactivation of its protease inhibitory activity. Holdase-type extracellular chaperone activity plays a putative non-canonical role for PAI-2. Our data demonstrate that glycosylated PAI-2 more efficiently inhibits the aggregation of Alzheimer’s disease and preeclampsia-associated amyloid beta peptide (Aβ), compared to non-glycosylated PAI-2 in vitro. However, hypochlorite-induced modification of non-glycosylated PAI-2 dramatically enhances its holdase activity by promoting the formation of very high-molecular-mass chaperone-active PAI-2 oligomers. Both PAI-2 forms protect against Aβ-induced cytotoxicity in the SH-SY5Y neuroblastoma cell line in vitro. In the villous placenta, PAI-2 is localised primarily to syncytiotrophoblast with wide interpersonal variation in women with preeclampsia and in gestational-age-matched controls. Although intracellular PAI-2 and Aβ staining localised to different placental cell types, some PAI-2 co-localised with Aβ in the extracellular plaque-like aggregated deposits abundant in preeclamptic placenta. Thus, PAI-2 potentially contributes to controlling aberrant fibrinolysis and the accumulation of misfolded proteins in states characterised by oxidative and proteostasis stress, such as in Alzheimer’s disease and preeclampsia. Full article
(This article belongs to the Special Issue Extracellular and Organismal Proteostasis)
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Review

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19 pages, 1865 KiB  
Review
The Emerging Roles of Extracellular Chaperones in Complement Regulation
by Nicholas J. Geraghty, Sandeep Satapathy and Mark R. Wilson
Cells 2022, 11(23), 3907; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11233907 - 02 Dec 2022
Viewed by 1891
Abstract
The immune system is essential to protect organisms from internal and external threats. The rapidly acting, non-specific innate immune system includes complement, which initiates an inflammatory cascade and can form pores in the membranes of target cells to induce cell lysis. Regulation of [...] Read more.
The immune system is essential to protect organisms from internal and external threats. The rapidly acting, non-specific innate immune system includes complement, which initiates an inflammatory cascade and can form pores in the membranes of target cells to induce cell lysis. Regulation of protein homeostasis (proteostasis) is essential for normal cellular and organismal function, and has been implicated in processes controlling immunity and infection. Chaperones are key players in maintaining proteostasis in both the intra- and extracellular environments. Whilst intracellular proteostasis is well-characterised, the role of constitutively secreted extracellular chaperones (ECs) is less well understood. ECs may interact with invading pathogens, and elements of the subsequent immune response, including the complement pathway. Both ECs and complement can influence the progression of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, as well as other diseases including kidney diseases and diabetes. This review will examine known and recently discovered ECs, and their roles in immunity, with a specific focus on the complement pathway. Full article
(This article belongs to the Special Issue Extracellular and Organismal Proteostasis)
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20 pages, 2218 KiB  
Review
Hsp90: From Cellular to Organismal Proteostasis
by Milán Somogyvári, Saba Khatatneh and Csaba Sőti
Cells 2022, 11(16), 2479; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11162479 - 10 Aug 2022
Cited by 10 | Viewed by 3093
Abstract
Assuring a healthy proteome is indispensable for survival and organismal health. Proteome disbalance and the loss of the proteostasis buffer are hallmarks of various diseases. The essential molecular chaperone Hsp90 is a regulator of the heat shock response via HSF1 and a stabilizer [...] Read more.
Assuring a healthy proteome is indispensable for survival and organismal health. Proteome disbalance and the loss of the proteostasis buffer are hallmarks of various diseases. The essential molecular chaperone Hsp90 is a regulator of the heat shock response via HSF1 and a stabilizer of a plethora of signaling proteins. In this review, we summarize the role of Hsp90 in the cellular and organismal regulation of proteome maintenance. Full article
(This article belongs to the Special Issue Extracellular and Organismal Proteostasis)
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