Symmetry breaking meets multisite modification

Multisite modification is a basic way of conferring functionality to proteins, and a key component of post-translational modification networks. Additional interest in multisite modification stems from its capability of acting as complex information processors. In this paper we connect two seemingly disparate themes: symmetry and multisite modification. We examine different classes of random modification networks of substrates involving separate or common enzymes. We demonstrate that under different instances of symmetry of the modification network (invoked explicitly or implicitly and discussed in the literature), the biochemistry of multisite modification can lead to the symmetry being broken. This is shown computationally and consolidated analytically, revealing parameter regions where this can (and in fact does) happen, and characteristics of the symmetry broken state. We discuss the relevance of these results in situations where exact symmetry is not present. Overall, through our study we show how symmetry breaking (i) can confer new capabilities to protein networks, including concentration robustness of different combinations of species (in conjunction with multiple steady states) (ii) could have been the basis for ordering of multisite modification, which is widely observed in cells (iii) can significantly impact information processing in multisite modification and in cell signalling networks/pathways where multisite modification is present (iv) can be a fruitful new angle for engineering in synthetic biology and chemistry. All in all, the emerging conceptual synthesis provides a new vantage point for the elucidation and the engineering of molecular systems at the junction of chemical and biological systems.

Download Full-text

Yet another lesson on the stability conditions in multi-Higgs potentials

Journal of High Energy Physics ◽

10.1007/jhep11(2020)104 ◽

2020 ◽

Vol 2020 (11) ◽

Author(s):

Igor P. Ivanov ◽

Francisco Vazão

Keyword(s):

Symmetry Breaking ◽

Global Symmetries ◽

Symmetry Group ◽

Higgs Doublet ◽

Symmetric Case ◽

Stability Conditions ◽

Exact Symmetry ◽

The Stability ◽

Necessary And Sufficient

Abstract We discuss a rather common but often unnoticed pitfall which arises when deriving the bounded-from-below (BFB) conditions in multi-Higgs models with softly broken global symmetries. Namely, necessary and sufficient BFB conditions derived for the case with an exact symmetry can be ruined by introducing soft symmetry breaking terms. Using S4 and A4-symmetric three-Higgs-doublet models as an example, we argue that all published necessary and sufficient BFB conditions, even those which are correct for the exactly symmetric case, are no longer sufficient if soft symmetry breaking is added. Using the geometric formalism, we derive the exact necessary and sufficient BFB conditions for the 3HDM with the symmetry group S4, either exact or softly broken, and review the situation for the A4-symmetric case.

Download Full-text

Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium

Biochemical Society Transactions ◽

10.1042/bst0331385 ◽

2005 ◽

Vol 33 (6) ◽

pp. 1385-1389 ◽

Cited By ~ 43

Author(s):

J.W. Zmijewski ◽

A. Landar ◽

N. Watanabe ◽

D.A. Dickinson ◽

N. Noguchi ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Lipid Oxidation ◽

Protein Function ◽

Cell Signalling ◽

Reactive Oxygen ◽

Oxidation Products ◽

Oxidized Lipids ◽

Oxygen Species ◽

Post Translational Modification ◽

Lipid Oxidation Products

The controlled formation of ROS (reactive oxygen species) and RNS (reactive nitrogen species) is now known to be critical in cellular redox signalling. As with the more familiar phosphorylation-dependent signal transduction pathways, control of protein function is mediated by the post-translational modification at specific amino acid residues, notably thiols. Two important classes of oxidant-derived signalling molecules are the lipid oxidation products, including those with electrophilic reactive centres, and decomposition products such as lysoPC (lysophosphatidylcholine). The mechanisms can be direct in the case of electrophiles, as they can modify signalling proteins by post-translational modification of thiols. In the case of lysoPC, it appears that secondary generation of ROS/RNS, dependent on intracellular calcium fluxes, can cause the secondary induction of H2O2 in the cell. In either case, the intracellular source of ROS/RNS has not been defined. In this respect, the mitochondrion is particularly interesting since it is now becoming apparent that the formation of superoxide from the respiratory chain can play an important role in cell signalling, and oxidized lipids can stimulate ROS formation from an undefined source. In this short overview, we describe recent experiments that suggest that the cell signalling mediated by lipid oxidation products involves their interaction with mitochondria. The implications of these results for our understanding of adaptation and the response to stress in cardiovascular disease are discussed.

Download Full-text

Comprehensive Network Analysis of Cancer Stem Cell Signalling through Systematic Integration of Post-Translational Modification Dynamics

Applications of RNA-Seq and Omics Strategies - From Microorganisms to Human Health ◽

10.5772/intechopen.69647 ◽

2017 ◽

Author(s):

Hiroko Kozuka‐Hata ◽

Masaaki Oyama

Keyword(s):

Stem Cell ◽

Network Analysis ◽

Cancer Stem Cell ◽

Cell Signalling ◽

Post Translational Modification

Download Full-text

Redox signalling: from nitric oxide to oxidized lipids

Biochemical Society Symposium ◽

10.1042/bss0710107 ◽

2004 ◽

Vol 71 ◽

pp. 107-120 ◽

Cited By ~ 31

Author(s):

Sruti Shiva ◽

Doug Moellering ◽

Anup Ramachandran ◽

Anna-Liisa Levonen ◽

Aimee Landar ◽

...

Keyword(s):

Signal Transduction ◽

Conformational Changes ◽

Soluble Guanylate Cyclase ◽

Cell Signalling ◽

Oxidation Reactions ◽

Reaction Products ◽

Adaptive Responses ◽

Post Translational Modification ◽

Redox Signalling ◽

Electrophilic Lipids

Cellular redox signalling is mediated by the post-translational modification of proteins in signal-transduction pathways by ROS/RNS (reactive oxygen species/reactive nitrogen species) or the products derived from their reactions. NO is perhaps the best understood in this regard with two important modifications of proteins known to induce conformational changes leading to modulation of function. The first is the addition of NO to haem groups as shown for soluble guanylate cyclase and the newly discovered NO/cytochrome c oxidase signalling pathway in mitochondria. The second mechanism is through the modification of thiols by NO to form an S-nitrosated species. Other ROS/RNS can also modify signalling proteins although the mechanisms are not as clearly defined. For example, electrophilic lipids, formed as the reaction products of oxidation reactions, orchestrate adaptive responses in the vasculature by reacting with nucleophilic cysteine residues. In modifying signalling proteins ROS/RNS appear to change the overall activity of signalling pathways in a process that we have termed 'redox tone'. In this review, we discuss these different mechanisms of redox cell signalling, and give specific examples of ROS/RNS participation in signal transduction.

Download Full-text

Mechanisms of signal transduction mediated by oxidized lipids: the role of the electrophile-responsive proteome

Biochemical Society Transactions ◽

10.1042/bst0320151 ◽

2004 ◽

Vol 32 (1) ◽

pp. 151-155 ◽

Cited By ~ 61

Author(s):

E.K. Ceaser ◽

D.R. Moellering ◽

S. Shiva ◽

A. Ramachandran ◽

A. Landar ◽

...

Keyword(s):

Transcriptional Activation ◽

Cell Signalling ◽

Antioxidant Response ◽

Oxidized Lipids ◽

Reaction Products ◽

Adaptive Responses ◽

Post Translational Modification ◽

Promoter Regions ◽

Antioxidant Defences ◽

Electrophilic Lipids

Cellular redox signalling is mediated by the post-translational modification of proteins by reactive oxygen/nitrogen species or the products derived from their reactions. In the case of oxidized lipids, several receptor-dependent and -independent mechanisms are now emerging. At low concentrations, adaptation to oxidative stress in the vasculature appears to be mediated by induction of antioxidant defences, including the synthesis of the intracellular antioxidant glutathione. At high concentrations apoptosis occurs through mechanisms that have yet to be defined in detail. Recent studies have revealed a mechanism through which electrophilic lipids, formed as the reaction products of oxidation, orchestrate these adaptive responses in the vasculature. Using a proteomics approach, we have identified a subset of proteins in cells that we term the electrophile-responsive proteome. Electrophilic modification of thiol groups in these proteins can initiate cell signalling events through the transcriptional activation of genes regulated by consensus sequences for the antioxidant response element found in their promoter regions. The insights gained from our understanding of the biology of these mechanisms will be discussed in the context of cardiovascular disease.

Download Full-text

KEAP1–NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity

Biochemical Journal ◽

10.1042/bj20150568 ◽

2015 ◽

Vol 469 (3) ◽

pp. 347-355 ◽

Cited By ~ 101

Author(s):

Matthew Dodson ◽

Matthew Redmann ◽

Namakkal S. Rajasekaran ◽

Victor Darley-Usmar ◽

Jianhua Zhang

Keyword(s):

Cell Signalling ◽

Redox Status ◽

Cellular Damage ◽

Post Translational Modification ◽

Redox Stress ◽

Post Translational Modifications ◽

Protein Thiols ◽

Normal Metabolism ◽

Thiol Redox ◽

Cellular Pathogenesis

Maintaining cellular redox status to allow cell signalling to occur requires modulation of both the controlled production of oxidants and the thiol-reducing networks to allow specific regulatory post-translational modification of protein thiols. The oxidative stress hypothesis captured the concept that overproduction of oxidants can be proteotoxic, but failed to predict the recent finding that hyperactivation of the KEAP1–NRF2 system also leads to proteotoxicity. Furthermore, sustained activation of thiol redox networks by KEAP1–NRF2 induces a reductive stress, by decreasing the lifetime of necessary oxidative post-translational modifications required for normal metabolism or cell signalling. In this context, it is now becoming clear why antioxidants or hyperactivation of antioxidant pathways with electrophilic therapeutics can be deleterious. Furthermore, it suggests that the autophagy–lysosomal pathway is particularly important in protecting the cell against redox-stress-induced proteotoxicity, since it can degrade redox-damaged proteins without causing aberrant changes to the redox network needed for metabolism or signalling. In this context, it is important to understand: (i) how NRF2-mediated redox signalling, or (ii) the autophagy-mediated antioxidant/reductant pathways sense cellular damage in the context of cellular pathogenesis. Recent studies indicate that the modification of protein thiols plays an important role in the regulation of both the KEAP1–NRF2 and autophagy pathways. In the present review, we discuss evidence demonstrating that the KEAP1–NRF2 pathway and autophagy act in concert to combat the deleterious effects of proteotoxicity. These findings are discussed with a special emphasis on their impact on cardiovascular disease and neurodegeneration.

Download Full-text

Single-Cell Signalling Analysis of Heterocellular Organoids

10.1101/659896 ◽

2019 ◽

Cited By ~ 2

Author(s):

Xiao Qin ◽

Jahangir Sufi ◽

Petra Vlckova ◽

Pelagia Kyriakidou ◽

Sophie E. Acton ◽

...

Keyword(s):

Single Cell ◽

High Throughput ◽

Single Cell Analysis ◽

Cell Signalling ◽

Tumour Microenvironment ◽

Cell Type ◽

Mass Cytometry ◽

Post Translational Modification ◽

Stromal Fibroblasts ◽

Cell Type Specific

Organoids are powerful biomimetic tissue models. Despite their widespread adoption, methods to analyse cell-type specific post-translational modification (PTM) signalling networks in organoids are absent. Here we report multivariate single-cell analysis of cell-type specific signalling networks in organoids and organoid co-cultures. Simultaneous measurement of 28 PTMs in >1 million single small intestinal organoid cells by mass cytometry reveals cell-type and cell-state specific signalling networks in stem, Paneth, enteroendocrine, tuft, goblet cells, and enterocytes. Integrating single-cell PTM analysis with Thiol-reactive Organoid Barcoding in situ (TOBis) enables high-throughput comparison of signalling networks between organoid cultures. Multivariate cell-type specific PTM analysis of colorectal cancer tumour microenvironment organoids reveals that shApc, KrasG12D, and Trp53R172H cell-autonomously mimic signalling states normally induced by stromal fibroblasts and macrophages. These results demonstrate how standard mass cytometry workflows can be modified to perform high-throughput multivariate cell-type specific signalling analysis of healthy and cancerous organoids.

Download Full-text

Protein Lipoxidation: Basic Concepts and Emerging Roles

Antioxidants ◽

10.3390/antiox10020295 ◽

2021 ◽

Vol 10 (2) ◽

pp. 295

Author(s):

Álvaro Viedma-Poyatos ◽

Patricia González-Jiménez ◽

Ophélie Langlois ◽

Idoia Company-Marín ◽

Corinne M. Spickett ◽

...

Keyword(s):

Cell Signalling ◽

Stress Protein ◽

Cytoskeletal Proteins ◽

Detailed Knowledge ◽

Post Translational Modification ◽

Complex Interplay ◽

Protein Targets ◽

Post Translational Modifications ◽

Lipid Species ◽

Functionally Diverse

Protein lipoxidation is a non-enzymatic post-translational modification that consists of the covalent addition of reactive lipid species to proteins. This occurs under basal conditions but increases in situations associated with oxidative stress. Protein targets for lipoxidation include metabolic and signalling enzymes, cytoskeletal proteins, and transcription factors, among others. There is strong evidence for the involvement of protein lipoxidation in disease, including atherosclerosis, neurodegeneration, and cancer. Nevertheless, the involvement of lipoxidation in cellular regulatory mechanisms is less understood. Here we review basic aspects of protein lipoxidation and discuss several features that could support its role in cell signalling, including its selectivity, reversibility, and possibilities for regulation at the levels of the generation and/or detoxification of reactive lipids. Moreover, given the great structural variety of electrophilic lipid species, protein lipoxidation can contribute to the generation of multiple structurally and functionally diverse protein species. Finally, the nature of the lipoxidised proteins and residues provides a frameshift for a complex interplay with other post-translational modifications, including redox and redox-regulated modifications, such as oxidative modifications and phosphorylation, thus strengthening the importance of detailed knowledge of this process.

Download Full-text