Submit to Cells Review for Cells Propose a Special Issue

Journal Browser

► Journal Browser

Multitasking Proteins and Their Involvement in Pathogenesis

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

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

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 33845

Share This Special Issue

Special Issue Editor

Dr. Agnieszka Gizak

E-Mail Website
Guest Editor

Department of Molecular Physiology and Neurobiology, University of Wroclaw, ul. Sienkiewicza 21, 50-335 Wroclaw, Poland
Interests: multifunctional proteins; subcellular organization of energy metabolism; cell-to-cell crosstalk
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The paradigm “one protein–one function" that dominated the 20th-century scientific narrative has long been out of date. The discovery that a protein can act outside its established primary role has challenged our perception of proteins as single-function specialists. To date, research has identified a number of multitasking proteins in a wide variety of organisms. A review from 2020 (Espinosa-Cantú et al.) describes four not always mutually exclusive manifestations of this phenomenon: pleiotropy, multiple domains, promiscuity, and moonlighting. Dysfunction of proteins displaying at least one of these features is frequently—and much more so than the dysfunction of other proteins—at the root of human disease and pathology, including neurodegenerative disorders and cancer. Thus, a comprehensive description of non-canonical functions of proteins and their participation in cross-talk among seemingly unrelated cellular processes might be crucial to the identification of novel targets for effective and side-effect-free therapies. The purpose of this Special Issue is to shed light on the latest discoveries in this area of research and how they might shape our understanding of the functioning of the cell in health and disease.

Dr. Agnieszka Gizak
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

multitasking
moonlighting
pleiotropy
protein promiscuity
cancer
neurodegeneration
pathogenesis
therapies

Published Papers (12 papers)

Download All Papers

Editorial

Jump to: Research, Review

4 pages, 211 KiB

Open AccessEditorial

Multitasking Proteins and Their Involvement in Pathogenesis

by Agnieszka Gizak

Cells 2023, 12(11), 1460; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12111460 - 24 May 2023

Viewed by 772

Abstract

The “one protein, one function” paradigm, similar to the “one gene, one enzyme” hypothesis that dominated our thinking for a long time, has proven to be too simplistic [...] Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

Research

Jump to: Editorial, Review

22 pages, 8161 KiB

Open AccessArticle

Francisella tularensis Glyceraldehyde-3-Phosphate Dehydrogenase Is Relocalized during Intracellular Infection and Reveals Effect on Cytokine Gene Expression and Signaling

by Ivona Pavkova, Monika Kopeckova, Marek Link, Erik Vlcak, Vlada Filimonenko, Lenka Lecova, Jitka Zakova, Pavlina Laskova, Valeria Sheshko, Miloslav Machacek and Jiri Stulik

Cells 2023, 12(4), 607; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12040607 - 13 Feb 2023

Cited by 1 | Viewed by 1771

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is known for its multifunctionality in several pathogenic bacteria. Our previously reported data suggest that the GAPDH homologue of Francisella tularensis, GapA, might also be involved in other processes beyond metabolism. In the present study, we explored GapA’s potential implication in pathogenic processes at the host cell level. Using immunoelectron microscopy, we demonstrated the localization of this bacterial protein inside infected macrophages and its peripheral distribution in bacterial cells increasing with infection time. A quantitative proteomic approach based on stable isotope labeling of amino acids in cell culture (SILAC) combined with pull-down assay enabled the identification of several of GapA’s potential interacting partners within the host cell proteome. Two of these partners were further confirmed by alternative methods. We also investigated the impact of gapA deletion on the transcription of selected cytokine genes and the activation of the main signaling pathways. Our results show that ∆gapA-induced transcription of genes encoding several cytokines whose expressions were not affected in cells infected with a fully virulent wild-type strain. That might be caused, at least in part, by the detected differences in ERK/MAPK signaling activation. The experimental observations together demonstrate that the F. tularensis GAPDH homologue is directly implicated in multiple host cellular processes and, thereby, that it participates in several molecular mechanisms of pathogenesis. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

21 pages, 985 KiB

Open AccessArticle

Role of Moonlighting Proteins in Disease: Analyzing the Contribution of Canonical and Moonlighting Functions in Disease Progression

by Mario Huerta, Luis Franco-Serrano, Isaac Amela, Josep Antoni Perez-Pons, Jaume Piñol, Angel Mozo-Villarías, Enrique Querol and Juan Cedano

Cells 2023, 12(2), 235; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12020235 - 05 Jan 2023

Cited by 3 | Viewed by 1929

Abstract

The term moonlighting proteins refers to those proteins that present alternative functions performed by a single polypeptide chain acquired throughout evolution (called canonical and moonlighting, respectively). Over 78% of moonlighting proteins are involved in human diseases, 48% are targeted by current drugs, and over 25% of them are involved in the virulence of pathogenic microorganisms. These facts encouraged us to study the link between the functions of moonlighting proteins and disease. We found a large number of moonlighting functions activated by pathological conditions that are highly involved in disease development and progression. The factors that activate some moonlighting functions take place only in pathological conditions, such as specific cellular translocations or changes in protein structure. Some moonlighting functions are involved in disease promotion while others are involved in curbing it. The disease-impairing moonlighting functions attempt to restore the homeostasis, or to reduce the damage linked to the imbalance caused by the disease. The disease-promoting moonlighting functions primarily involve the immune system, mesenchyme cross-talk, or excessive tissue proliferation. We often find moonlighting functions linked to the canonical function in a pathological context. Moonlighting functions are especially coordinated in inflammation and cancer. Wound healing and epithelial to mesenchymal transition are very representative. They involve multiple moonlighting proteins with a different role in each phase of the process, contributing to the current-phase phenotype or promoting a phase switch, mitigating the damage or intensifying the remodeling. All of this implies a new level of complexity in the study of pathology genesis, progression, and treatment. The specific protein function involved in a patient’s progress or that is affected by a drug must be elucidated for the correct treatment of diseases. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

21 pages, 8337 KiB

Open AccessArticle

Ubiquitination Occurs in the Mitochondrial Matrix by Eclipsed Targeted Components of the Ubiquitination Machinery

by Yu Zhang, Ofri Karmon, Koyeli Das, Reuven Wiener, Norbert Lehming and Ophry Pines

Cells 2022, 11(24), 4109; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11244109 - 17 Dec 2022

Cited by 6 | Viewed by 3322

Abstract

Ubiquitination is a critical type of post-translational modification in eukaryotic cells. It is involved in regulating nearly all cellular processes in the cytosol and nucleus. Mitochondria, known as the metabolism heart of the cell, are organelles that evolved from bacteria. Using the subcellular compartment-dependent α-complementation, we detect multiple components of ubiquitination machinery as being eclipsed distributed to yeast mitochondria. Ubiquitin conjugates and mono-ubiquitin can be detected in lysates of isolated mitochondria from cells expressing HA-Ub and treated with trypsin. By expressing MTS (mitochondrial targeting sequence) targeted HA-tagged ubiquitin, we demonstrate that certain ubiquitination events specifically occur in yeast mitochondria and are independent of proteasome activity. Importantly, we show that the E2 Rad6 affects the pattern of protein ubiquitination in mitochondria and provides an in vivo assay for its activity in the matrix of the organelle. This study shows that ubiquitination occurs in the mitochondrial matrix by eclipsed targeted components of the ubiquitin machinery, providing a new perspective on mitochondrial and ubiquitination research. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Graphical abstract

17 pages, 4209 KiB

Open AccessArticle

FBP2—A New Player in Regulation of Motility of Mitochondria and Stability of Microtubules in Cardiomyocytes

by Łukasz Pietras, Ewa Stefanik, Dariusz Rakus and Agnieszka Gizak

Cells 2022, 11(10), 1710; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101710 - 21 May 2022

Cited by 3 | Viewed by 2669

Abstract

Recently, we have shown that the physiological roles of a multifunctional protein fructose 1,6-bisphosphatase 2 (FBP2, also called muscle FBP) depend on the oligomeric state of the protein. Here, we present several lines of evidence that in HL-1 cardiomyocytes, a forced, chemically induced reduction in the FBP2 dimer-tetramer ratio that imitates AMP and NAD⁺ action and restricts FBP2-mitochondria interaction, results in an increase in Tau phosphorylation, augmentation of FBP2-Tau and FBP2-MAP1B interactions, disturbance of tubulin network, marked reduction in the speed of mitochondrial trafficking and increase in mitophagy. These results not only highlight the significance of oligomerization for the regulation of FBP2 physiological role in the cell, but they also demonstrate a novel, important cellular function of this multitasking protein—a function that might be crucial for processes that take place during physiological and pathological cardiac remodeling, and during the onset of diseases which are rooted in the destabilization of MT and/or mitochondrial network dynamics. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

23 pages, 3147 KiB

Open AccessReview

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

by Caitlyn M. Brenner, Muaaz Choudhary, Michael G. McCormick, David Cheung, Gavin P. Landesberg, Ju-Fang Wang, Jianliang Song, Thomas G. Martin, Joseph Y. Cheung, Hui-Qi Qu, Hakon Hakonarson and Arthur M. Feldman

Cells 2023, 12(6), 937; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12060937 - 19 Mar 2023

Cited by 3 | Viewed by 3347

Abstract

BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolded proteins and damaged organelles, inhibits apoptosis, maintains the homeostasis of the mitochondria, and facilitates excitation contraction coupling through the L-type calcium channel and the beta-adrenergic receptor. High levels of BAG3 are associated with insensitivity to chemotherapy in malignant cells whereas both loss of function and gain of function variants are associated with cardiomyopathy. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

25 pages, 2191 KiB

Open AccessReview

UPF1—From mRNA Degradation to Human Disorders

by Jacek Staszewski, Natalia Lazarewicz, Julia Konczak, Iwona Migdal and Ewa Maciaszczyk-Dziubinska

Cells 2023, 12(3), 419; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12030419 - 27 Jan 2023

Cited by 2 | Viewed by 3430

Abstract

Up-frameshift protein 1 (UPF1) plays the role of a vital controller for transcripts, ready to react in the event of an incorrect translation mechanism. It is well known as one of the key elements involved in mRNA decay pathways and participates in transcript and protein quality control in several different aspects. Firstly, UPF1 specifically degrades premature termination codon (PTC)-containing products in a nonsense-mediated mRNA decay (NMD)-coupled manner. Additionally, UPF1 can potentially act as an E3 ligase and degrade target proteins independently from mRNA decay pathways. Thus, UPF1 protects cells against the accumulation of misfolded polypeptides. However, this multitasking protein may still hide many of its functions and abilities. In this article, we summarize important discoveries in the context of UPF1, its involvement in various cellular pathways, as well as its structural importance and mutational changes related to the emergence of various pathologies and disease states. Even though the state of knowledge about this protein has significantly increased over the years, there are still many intriguing aspects that remain unresolved. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Graphical abstract

18 pages, 1722 KiB

Open AccessReview

Calcium/Calmodulin-Stimulated Protein Kinase II (CaMKII): Different Functional Outcomes from Activation, Depending on the Cellular Microenvironment

by John A. P. Rostas and Kathryn A. Skelding

Cells 2023, 12(3), 401; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12030401 - 23 Jan 2023

Cited by 16 | Viewed by 4206

Abstract

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a family of broad substrate specificity serine (Ser)/threonine (Thr) protein kinases widely expressed in many tissues that is capable of mediating diverse functional responses depending on its cellular and molecular microenvironment. This review briefly summarises current knowledge on the structure and regulation of CaMKII and focuses on how the molecular environment, and interaction with binding partner proteins, can produce different populations of CaMKII in different cells, or in different subcellular locations within the same cell, and how these different populations of CaMKII can produce diverse functional responses to activation following an increase in intracellular calcium concentration. This review also explores the possibility that identifying and characterising the molecular interactions responsible for the molecular targeting of CaMKII in different cells in vivo, and identifying the sites on CaMKII and/or the binding proteins through which these interactions occur, could lead to the development of highly selective inhibitors of specific CaMKII-mediated functional responses in specific cells that would not affect CaMKII-mediated responses in other cells. This may result in the development of new pharmacological agents with therapeutic potential for many clinical conditions. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

40 pages, 1243 KiB

Open AccessReview

S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains

by Anna Buszka, Agata Pytyś, Domnic Colvin, Jakub Włodarczyk and Tomasz Wójtowicz

Cells 2023, 12(3), 387; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12030387 - 21 Jan 2023

Cited by 10 | Viewed by 3031

Abstract

Protein lipidation is a common post-translational modification of proteins that plays an important role in human physiology and pathology. One form of protein lipidation, S-palmitoylation, involves the addition of a 16-carbon fatty acid (palmitate) onto proteins. This reversible modification may affect the regulation of protein trafficking and stability in membranes. From multiple recent experimental studies, a picture emerges whereby protein S-palmitoylation is a ubiquitous yet discrete molecular switch enabling the expansion of protein functions and subcellular localization in minutes to hours. Neural tissue is particularly rich in proteins that are regulated by S-palmitoylation. A surge of novel methods of detection of protein lipidation at high resolution allowed us to get better insights into the roles of protein palmitoylation in brain physiology and pathophysiology. In this review, we specifically discuss experimental work devoted to understanding the impact of protein palmitoylation on functional changes in the excitatory and inhibitory synapses associated with neuronal activity and neuronal plasticity. The accumulated evidence also implies a crucial role of S-palmitoylation in learning and memory, and brain disorders associated with impaired cognitive functions. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Graphical abstract

18 pages, 1643 KiB

Open AccessFeature PaperReview

Plant Plasma Membrane Proton Pump: One Protein with Multiple Functions

by Adrianna Michalak, Anna Wdowikowska and Małgorzata Janicka

Cells 2022, 11(24), 4052; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11244052 - 14 Dec 2022

Cited by 8 | Viewed by 2421

Abstract

In plants, the plasma membrane proton pump (PM H⁺-ATPase) regulates numerous transport-dependent processes such as growth, development, basic physiology, and adaptation to environmental conditions. This review explores the multifunctionality of this enzyme in plant cells. The abundance of several PM H⁺-ATPase isogenes and their pivotal role in energizing transport in plants have been connected to the phenomena of pleiotropy. The multifunctionality of PM H⁺-ATPase is a focal point of numerous studies unraveling the molecular mechanisms of plant adaptation to adverse environmental conditions. Furthermore, PM H⁺-ATPase is a key element in plant defense mechanisms against pathogen attack; however, it also functions as a target for pathogens that enable plant tissue invasion. Here, we provide an extensive review of the PM H⁺-ATPase as a multitasking protein in plants. We focus on the results of recent studies concerning PM H⁺-ATPase and its role in plant growth, physiology, and pathogenesis. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

20 pages, 1229 KiB

Open AccessReview

Interplay of Developmental Hippo–Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer

by Ioanna Mourkioti, Andriani Angelopoulou, Konstantinos Belogiannis, Nefeli Lagopati, Spyridon Potamianos, Efthymios Kyrodimos, Vassilis Gorgoulis and Angelos Papaspyropoulos

Cells 2022, 11(15), 2449; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152449 - 07 Aug 2022

Cited by 9 | Viewed by 2480

Abstract

Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related ‘hubs’ such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR–Hippo–Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

25 pages, 2228 KiB

Open AccessReview

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

by Alberto M. Martelli, Francesca Paganelli, Camilla Evangelisti, Francesca Chiarini and James A. McCubrey

Cells 2022, 11(11), 1812; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11111812 - 31 May 2022

Cited by 6 | Viewed by 3153

Abstract

Glycogen synthase kinase-3 (GSK-3) is an evolutionarily conserved, ubiquitously expressed, multifunctional serine/threonine protein kinase involved in the regulation of a variety of physiological processes. GSK-3 comprises two isoforms (α and β) which were originally discovered in 1980 as enzymes involved in glucose metabolism via inhibitory phosphorylation of glycogen synthase. Differently from other proteins kinases, GSK-3 isoforms are constitutively active in resting cells, and their modulation mainly involves inhibition through upstream regulatory networks. In the early 1990s, GSK-3 isoforms were implicated as key players in cancer cell pathobiology. Active GSK-3 facilitates the destruction of multiple oncogenic proteins which include β-catenin and Master regulator of cell cycle entry and proliferative metabolism (c-Myc). Therefore, GSK-3 was initially considered to be a tumor suppressor. Consistently, GSK-3 is often inactivated in cancer cells through dysregulated upstream signaling pathways. However, over the past 10–15 years, a growing number of studies highlighted that in some cancer settings GSK-3 isoforms inhibit tumor suppressing pathways and therefore act as tumor promoters. In this article, we will discuss the multiple and often enigmatic roles played by GSK-3 isoforms in some chronic hematological malignancies (chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin’s lymphomas) which are among the most common blood cancer cell types. We will also summarize possible novel strategies targeting GSK-3 for innovative therapies of these disorders. Full article

(This article belongs to the Special Issue Multitasking Proteins and Their Involvement in Pathogenesis)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Multitasking Proteins and Their Involvement in Pathogenesis

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (12 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI