The Hedgehog Signaling Pathway Emerges as a Pathogenic Target

Smelkinson, Margery

doi:10.3390/jdb5040014

Cited by 39 publications

(62 citation statements)

References 128 publications

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“…CYP124 is the only CYP that is able to bind and metabolize 20S-hydroxy-cholesterol (20SOHC , Table 1), a ligand of smoothened receptor (SMO) in the Hedgehog signaling pathway, which is also activated in response to pathogens, including mycobacteria (20,21).…”

Section: Cyp124 Cyp125 Cyp142 and 3βhsd Metabolize Immunoactive Oxymentioning

confidence: 99%

Metabolic fate of human immunoactive sterols in Mycobacterium tuberculosis

Varaksa

Bukhdruker

Grabovec

et al. 2020

Preprint

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AbstractMycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 – the most potent among them – can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.

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Section: Cyp124 Cyp125 Cyp142 and 3βhsd Metabolize Immunoactive Oxymentioning

confidence: 99%

Metabolic fate of human immunoactive sterols in Mycobacterium tuberculosis

Varaksa

Bukhdruker

Grabovec

et al. 2020

Preprint

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“…Additionally, recent studies showed that Mycbp is a positive modulator of the Hedgehog signalling pathway (Lin et al, 2014), which is conserved among metazoans (Ingham et al, 2011). The roles of Hedgehog post-natal signalling have been recently reviewed by Smelkinson (2017), and include tissue homeostasis maintenance and immunity, which can be activated by pathogenic agents, tissue injury and damaging agents. Considering this, the present results showing increased levels of Mycbp in C. angulata exposed to Low pH + As could be linked to Hedgehog signalling activation, as a response mechanism resulting from external stress stimuli for homeostatic maintenance.…”

Section: Protein Changes Under Low Ph + Asmentioning

confidence: 99%

Impacts of the combined exposure to seawater acidification and arsenic on the proteome of Crassostrea angulata and Crassostrea gigas

et al. 2018

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Proteomic analysis was performed to compare the effects of Arsenic (As), seawater acidification (Low pH) and the combination of both stressors (Low pH + As) on Crassostrea angulata and Crassostrea gigas juveniles in the context of global environmental change. This study aimed to elucidate if two closely related Crassostrea species respond similarly to these environmental stressors, considering both single and combined exposures, to infer if the simultaneous exposure to both stressors induced a differentiated response. Identification of the most important differentially expressed proteins between conditions revealed marked differences in the response of each species towards single and combined exposures, evidencing species-related differences towards each experimental condition. Moreover, protein alterations observed in the combined exposure (Low pH + As) were substantially different from those observed in single exposures. Identified proteins and their putative biological functions revealed an array of modes of action in each condition. Among the most important, those involved in cellular structure (Actin, Atlastin, Severin, Gelsolin, Coronin) and extracellular matrix modulation (Ependymin, Tight junction ZO-1, Neprilysin) were strongly regulated, although in different exposure conditions and species. Data also revealed differences regarding metabolic modulation capacity (ATP β, Enolase, Aconitate hydratase) and oxidative stress response (Aldehyde dehydrogenase, Lactoylglutathione, Retinal dehydrogenase) of each species, which also depended on single or combined exposures, illustrating a different response capacity of both oyster species to the presence of multiple stressors. Interestingly, alterations of piRNA abundance in C. angulata suggested genome reconfiguration in response to multiple stressors, likely an important mode of action related to adaptive evolution mechanisms previously unknown to oyster species, which requires further investigation. The present findings provide a deeper insight into the complexity of C. angulata and C. gigas responses to environmental stress at the proteome level, evidencing different capacities to endure abiotic changes, with relevance regarding the ecophysiological fitness of each species and competitive advantages in a changing environment.

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“…2 MTOC reorganization and polarization to the IS is dependent on Hedgehog (Hh) signaling, a pathway that is traditionally associated with primary cilia in nonhematopoietic cells. 3,4 De la Roche et al demonstrated that inhibitors of Hh signaling can disrupt the IS and the ability of CD8 + T cells to become activated and lyse antigenpresenting targets. 3 Overactivation of Hh signaling in the thymus can lead to decreased negative selection and the escape of autoreactive T cell clones.…”

Section: Introductionmentioning

confidence: 99%

<p>PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulation: Applications in Rheumatic Autoimmunity</p>

Haycook¹,

Balsamo²,

Glass³

et al. 2020

IJN

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Background: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity. Methods: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4 + T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm. Results: Our novel delivery system achieved a highly specific association with the majority of CD4 + T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4 + T cell responses mediated by nanoparticle-formulated Egm. Conclusion: This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.

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The Hedgehog Signaling Pathway Emerges as a Pathogenic Target

Cited by 39 publications

References 128 publications

Metabolic fate of human immunoactive sterols in Mycobacterium tuberculosis

Metabolic fate of human immunoactive sterols in Mycobacterium tuberculosis

Impacts of the combined exposure to seawater acidification and arsenic on the proteome of Crassostrea angulata and Crassostrea gigas

<p>PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulation: Applications in Rheumatic Autoimmunity</p>

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