Biochemical Society Transactions

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ISSN / EISSN : 0300-5127 / 1470-8752
Published by: Portland Press Ltd. (10.1042)
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Published: 16 September 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20220333

Abstract:
How does an organism regulate its genes? The involved regulation typically occurs in terms of a signal processing chain: an externally applied stimulus or a maternally supplied transcription factor leads to the expression of some downstream genes, which, in turn, are transcription factors for further genes. Especially during development, these transcription factors are frequently expressed in amounts where noise is still important; yet, the signals that they provide must not be lost in the noise. Thus, the organism needs to extract exactly relevant information in the signal. New experimental approaches involving single-molecule measurements at high temporal precision as well as increased precision in manipulations directly on the genome are allowing us to tackle this question anew. These new experimental advances mean that also from the theoretical side, theoretical advances should be possible. In this review, I will describe, specifically on the example of fly embryo gene regulation, how theoretical approaches, especially from inference and information theory, can help in understanding gene regulation. To do so, I will first review some more traditional theoretical models for gene regulation, followed by a brief discussion of information-theoretical approaches and when they can be applied. I will then introduce early fly development as an exemplary system where such information-theoretical approaches have traditionally been applied and can be applied; I will specifically focus on how one such method, namely the information bottleneck approach, has recently been used to infer structural features of enhancer architecture.
Christian A. Lobos, Jonathan Downing, Lloyd J. D'Orsogna, ,
Published: 16 September 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20220244

Abstract:
Understanding the basis of the immune determinants controlling disease outcome is critical to provide better care to patients and could be exploited for therapeutics and vaccine design. The discovery of the human immunodeficiency virus (HIV) virus as the causing agent of acquired immunodeficiency syndrome (AIDS) decades ago, led to a tremendous amount of research. Among the findings, it was discovered that some rare HIV+ individuals, called HIV controllers (HICs), had the ability to control the virus and keep a low viral load without the need of treatment. This ability allows HICs to delay or avoid progression to AIDS. HIV control is strongly associated with the expression of human leukocyte antigen (HLA) alleles in HICs. From the HIV protective HLAs described, HLA-B57 is the most frequent in HIC patients. HLA-B57 can present a large range of highly conserved Gag-derived HIV peptides to CD8+ T cells and natural killer (NK) cells, both the focus of this review. So far there are limited differences in the immune response strength, magnitude, or receptor repertoire towards HIV epitopes that could explain viral control in HICs. Interestingly, some studies revealed that during early infection the large breadth of the immune response towards HIV mutants in HLA-B57+ HIC patients, might in turn influence the disease outcome.
Rogério Lopes dos Santos,
Published: 16 September 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20220900

Abstract:
Cell shape changes that are fuelled by the dynamics of the actomyosin cytoskeleton control cellular processes such as motility and division. However, the mechanisms of interplay between cell membranes and actomyosin are complicated to decipher in the complex environment of the cytoplasm. Using biomimetic systems offers an alternative approach to studying cell shape changes in assays with controlled biochemical composition. Biomimetic systems allow quantitative experiments that can help to build physical models describing the processes of cell shape changes. This article reviews works in which actin networks are reconstructed inside or outside cell-sized Giant Unilamellar Vesicles (GUVs), which are models of cell membranes. We show how various actin networks affect the shape and mechanics of GUVs and how some cell shape changes can be reproduced in vitro using these minimal systems.
Barbara Tedesco, Veronica Ferrari, Marta Cozzi, Marta Chierichetti, Elena Casarotto, Paola Pramaggiore, Francesco Mina, Margherita Piccolella, Riccardo Cristofani, Valeria Crippa, et al.
Published: 16 September 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20220778

Abstract:
Motor neuron diseases (MNDs) include a broad group of diseases in which neurodegeneration mainly affects upper and/or lower motor neurons (MNs). Although the involvement of specific MNs, symptoms, age of onset, and progression differ in MNDs, the main pathogenic mechanism common to most MNDs is represented by proteostasis alteration and proteotoxicity. This pathomechanism may be directly related to mutations in genes encoding proteins involved in the protein quality control system, particularly the autophagy-lysosomal pathway (ALP). Alternatively, proteostasis alteration can be caused by aberrant proteins that tend to misfold and to aggregate, two related processes that, over time, cannot be properly handled by the ALP. Here, we summarize the main ALP features, focusing on different routes utilized to deliver substrates to the lysosome and how the various ALP pathways intersect with the intracellular trafficking of membranes and vesicles. Next, we provide an overview of the mutated genes that have been found associated with MNDs, how these gene products are involved in different steps of ALP and related processes. Finally, we discuss how autophagy can be considered a valid therapeutic target for MNDs treatment focusing on traditional autophagy modulators and on emerging approaches to overcome their limitations.
Laura E. Shippey, , , David P. Smith
Published: 16 September 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20220204

Abstract:
Parkinson's disease (PD) is a common neurodegenerative condition affecting a significant number of individuals globally, resulting in the presentation of debilitating motor and non-motor symptoms, including bradykinesia, resting tremor, as well as mood and sleep disorders. The pathology of PD has been observed to spread through the central nervous system resulting in progressive brain degeneration and a poor prognosis. Aggregated forms of the protein α-synuclein, particularly intermediary aggregates, referred to as oligomers, or preformed fibrils, have been implicated as the causative agent in the degeneration of neuronal processes, including the dysfunction of axonal transport, mitochondrial activity, and ultimately cellular death. Extracellular vesicles (EVs) have been strongly implicated in the propagation of PD pathology. Current observations suggest that aggregated α-synuclein is transported between neurons via small EVs in a series of exocytosis and endocytosis cellular processes leading to the observed spread of neurotoxicity and cellular death. Despite some understanding of the role of EVs in neurodegeneration, the exact mechanism by which these lipidic particles participate in the progression of Parkinson's pathology is not entirely understood. Here we review the current understanding of the role of EVs in the propagation of PD and explore their potential as a therapeutic target.
Callaghan Cylke, ,
Published: 12 September 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20210894

Abstract:
Characterizing the physiological response of bacterial cells to antibiotic treatment is crucial for the design of antibacterial therapies and for understanding the mechanisms of antibiotic resistance. While the effects of antibiotics are commonly characterized by their minimum inhibitory concentrations or the minimum bactericidal concentrations, the effects of antibiotics on cell morphology and physiology are less well characterized. Recent technological advances in single-cell studies of bacterial physiology have revealed how different antibiotic drugs affect the physiological state of the cell, including growth rate, cell size and shape, and macromolecular composition. Here, we review recent quantitative studies on bacterial physiology that characterize the effects of antibiotics on bacterial cell morphology and physiological parameters. In particular, we present quantitative data on how different antibiotic targets modulate cellular shape metrics including surface area, volume, surface-to-volume ratio, and the aspect ratio. Using recently developed quantitative models, we relate cell shape changes to alterations in the physiological state of the cell, characterized by changes in the rates of cell growth, protein synthesis and proteome composition. Our analysis suggests that antibiotics induce distinct morphological changes depending on their cellular targets, which may have important implications for the regulation of cellular fitness under stress.
Paul T. Morse, Junmei Wan, Jamie Bell, Icksoo Lee, Dennis J. Goebel, Moh H. Malek, Thomas H. Sanderson,
Published: 6 September 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20220446

Abstract:
Ischemic stroke affects over 77 million people annually around the globe. Due to the blockage of a blood vessel caused by a stroke, brain tissue becomes ischemic. While prompt restoration of blood flow is necessary to save brain tissue, it also causes reperfusion injury. Mitochondria play a crucial role in early ischemia-reperfusion injury due to the generation of reactive oxygen species (ROS). During ischemia, mitochondria sense energy depletion and futilely attempt to up-regulate energy production. When reperfusion occurs, mitochondria become hyperactive and produce large amounts of ROS which damages neuronal tissue. This ROS burst damages mitochondria and the cell, which results in an eventual decrease in mitochondrial activity and pushes the fate of the cell toward death. This review covers the relationship between the mitochondrial membrane potential (ΔΨm) and ROS production. We also discuss physiological mechanisms that couple mitochondrial energy production to cellular energy demand, focusing on serine 47 dephosphorylation of cytochrome c (Cytc) in the brain during ischemia, which contributes to ischemia-reperfusion injury. Finally, we discuss the use of near infrared light (IRL) to treat stroke. IRL can both stimulate or inhibit mitochondrial activity depending on the wavelength. We emphasize that the use of the correct wavelength is crucial for outcome: inhibitory IRL, applied early during reperfusion, can prevent the ROS burst from occurring, thus preserving neurological tissue.
Anastasia Audrey, Lauren de Haan, , H. Rudolf de Boer
Published: 30 August 2022
Biochemical Society Transactions, Volume 50, pp 1105-1118; https://doi.org/10.1042/bst20220049

Abstract:
Failure of cells to process toxic double-strand breaks (DSBs) constitutes a major intrinsic source of genome instability, a hallmark of cancer. In contrast with interphase of the cell cycle, canonical repair pathways in response to DSBs are inactivated in mitosis. Although cell cycle checkpoints prevent transmission of DNA lesions into mitosis under physiological condition, cancer cells frequently display mitotic DNA lesions. In this review, we aim to provide an overview of how mitotic cells process lesions that escape checkpoint surveillance. We outline mechanisms that regulate the mitotic DNA damage response and the different types of lesions that are carried over to mitosis, with a focus on joint DNA molecules arising from under-replication and persistent recombination intermediates, as well as DNA catenanes. Additionally, we discuss the processing pathways that resolve each of these lesions in mitosis. Finally, we address the acute and long-term consequences of unresolved mitotic lesions on cellular fate and genome stability.
Theresa Riebeling, Ulrich Kunzendorf,
Published: 30 August 2022
Biochemical Society Transactions, Volume 50, pp 1197-1205; https://doi.org/10.1042/bst20220535

Abstract:
The RIP homotypic interaction motif (RHIM) is a conserved protein domain that is approximately 18–22 amino acids in length. In humans, four proteins carrying RHIM domains have been identified: receptor-interacting serine/threonine protein kinase (RIPK) 1, RIPK3, Z-DNA-binding protein 1 (ZBP1), and TIR domain-containing adapter-inducing IFN-β (TRIF), which are all major players in necroptosis, a distinct form of regulated cell death. Necroptosis is mostly presumed to be a fail-safe form of cell death, occurring in cells in which apoptosis is compromised. Upon activation, RIPK1, ZBP1, and TRIF each hetero-oligomerize with RIPK3 and induce the assembly of an amyloid-like structure of RIPK3 homo-oligomers. These act as docking stations for the recruitment of the pseudokinase mixed-lineage kinase domain like (MLKL), the pore-forming executioner of necroptosis. As RHIM domain interactions are a vital component of the signaling cascade and can also be involved in apoptosis and pyroptosis activation, it is unsurprising that viral and bacterial pathogens have developed means of disrupting RHIM-mediated signaling to ensure survival. Moreover, as these mechanisms play an essential part of regulated cell death signaling, they have received much attention in recent years. Herein, we present the latest insights into the supramolecular structure of interacting RHIM proteins and their distinct signaling cascades in inflammation and infection. Their uncovering will ultimately contribute to the development of new therapeutic strategies in the regulation of lytic cell death.
, Sean Massey, , Ben Rollo, Alexander R. Harris, Robert M.I. Kapsa,
Published: 23 August 2022
Biochemical Society Transactions; https://doi.org/10.1042/bst20220791

Abstract:
CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.
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