1.
AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1.
Doshi, H, Spengler, K, Godbole, A, Gee, YS, Baell, J, Oakhill, JS, Henke, A, Heller, R
Microbiology spectrum. 2023;(5):e0041723
Abstract
Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells. The current study addresses the question of whether the host cell protein AMP-activated protein kinase (AMPK), an important metabolic sensor, can control HSV-1 replication in endothelial cells. We show that downregulation of the catalytic subunits AMPKα1 and/or AMPKα2 increased HSV-1 replication as monitored by TCID50 titrations, while a potent AMPK agonist, MK-8722, strongly inhibited it. MK-8722 induced a persistent phosphorylation of the AMPK downstream targets acetyl-CoA carboxylase (ACC) and the rapamycin-sensitive adaptor protein of mTOR (Raptor) and, related to this, impairment of ACC1-mediated lipid synthesis and the mechanistic target of the rapamycin complex-1 (mTORC1) pathway. Since blockade of mTOR by Torin-2 as well as downregulation of ACC1 by siRNA also decreased HSV-1 replication, MK-8722 is likely to exert its anti-viral effect via mTORC1 and ACC1 inhibition. Importantly, MK-8722 was able to reduce virus replication even when added after HSV-1. Together, our data highlight the importance of endothelial cells as host cells for HSV-1 replication upon systemic infection and identify AMPK, a metabolic host cell protein, as a potential target for antiviral strategies against HSV-1 infection and its severe consequences. IMPORTANCE Herpes simplex virus type 1 (HSV-1) is a common pathogen that causes blisters or cold sores in humans. It remains latent in infected individuals and can be reactivated multiple times. In adverse conditions, for instance, in immunocompromised patients, HSV-1 can lead to serious complications such as encephalitis, meningitis, or blindness. In these situations, infection of endothelial cells lining the surface of blood vessels may contribute to the manifestation of disease. Here, we describe the role of AMP-activated protein kinase (AMPK), a potent regulator of cellular energy metabolism, in HSV-1 replication in endothelial cells. While downregulation of AMPK potentiates HSV-1 replication, pharmacological AMPK activation inhibits it by limiting the availability of required host cell macromolecules such as proteins or fatty acids. These data highlight the role of metabolic host cell proteins as antiviral targets and reveal activation of endothelial AMPK as a potential strategy to protect from severe consequences of HSV-1 infection.
2.
Personalized phosphoproteomics identifies functional signaling.
Needham, EJ, Hingst, JR, Parker, BL, Morrison, KR, Yang, G, Onslev, J, Kristensen, JM, Højlund, K, Ling, NXY, Oakhill, JS, et al
Nature biotechnology. 2022;(4):576-584
Abstract
Protein phosphorylation dynamically integrates environmental and cellular information to control biological processes. Identifying functional phosphorylation amongst the thousands of phosphosites regulated by a perturbation at a global scale is a major challenge. Here we introduce 'personalized phosphoproteomics', a combination of experimental and computational analyses to link signaling with biological function by utilizing human phenotypic variance. We measure individual subject phosphoproteome responses to interventions with corresponding phenotypes measured in parallel. Applying this approach to investigate how exercise potentiates insulin signaling in human skeletal muscle, we identify both known and previously unidentified phosphosites on proteins involved in glucose metabolism. This includes a cooperative relationship between mTOR and AMPK whereby the former directly phosphorylates the latter on S377, for which we find a role in metabolic regulation. These results establish personalized phosphoproteomics as a general approach for investigating the signal transduction underlying complex biology.
3.
Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders.
Nay, K, Smiles, WJ, Kaiser, J, McAloon, LM, Loh, K, Galic, S, Oakhill, JS, Gundlach, AL, Scott, JW
International journal of molecular sciences. 2021;22(8)
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Exercise as therapy for mental health disorders has become common due to its reported benefits and low cost. There are many biological ways in which exercise may help mood disorders and diseases associated with brain degeneration and this review article aimed to highlight these. The authors first highlighted the research indicating that exercise may be protective in mood disorders with studies showing reduction of symptoms of depression, anxiety, schizophrenia, autism, and bipolar disorder. Exercise may also be of benefit in several brain degenerative disorders with studies indicating a positive impact in individuals with Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Multiple Sclerosis. Studies have also indicated that individuals with brain injuries, such as stroke may also benefit. Several reasons for this were highlighted. When muscle is stimulated during exercise a key brain signalling molecule may be produced, known as brain-derived neurotrophic factor (BDNF). BDNF may have the effect of preventing brain degeneration and promoting regeneration. Exercise may also increase gut microbial diversity and increase beneficial bacteria which may benefit the brain in several ways. It was concluded that exercise may have beneficial effects for individuals with brain disorders. This study could be used by healthcare professionals to understand how exercise may be of benefit to individuals with mood disorders, brain degenerative diseases and brain injuries as part of a holistic treatment plan.
Abstract
As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle-brain, liver-brain and gut-brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise-brain communication and their benefits for physiology and brain function.
4.
Transferrin-mediated iron acquisition by pathogenic Neisseria.
Evans, RW, Oakhill, JS
Biochemical Society transactions. 2002;(4):705-7
Abstract
The pathogenic Neisseria have a siderophore-independent iron-uptake system reliant on a direct interaction between the bacterial cell and transferrin. In the meningococcus this uptake system is dependent on two surface-exposed transferrin-binding proteins. This short account will review our current knowledge of the transferrin-mediated iron-acquisition system of pathogenic Neisseria.