Intricate Roles of Mammalian Sirtuins in Defense against Viral Pathogens

Budayeva, Hanna G.; Rowland, Elizabeth A.; Cristea, Ileana M.

doi:10.1128/jvi.03220-14

Cited by 50 publications

(54 citation statements)

References 21 publications

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“…Recent work demonstrated that addition of this compound to cell culture pre- and post- exposure to ZIKV reduced the viral load from 30% to 90%, respectively, showing another promising venue of sirtuins as viral inhibiting agents [ 102 ]. The bacterial sirtuin CobB, a homolog of Escherichia coli sirtuin negatively impacted the growth of both bacteriophages T4 and λ [ 103 , 104 ]. This all points to sirtuins as another area of study yet to be explored in the context of Wolbachia -mediated pathogen blocking.…”

Section: Discussionmentioning

confidence: 99%

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

2020

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Wolbachia is an intracellular bacterial symbiont of arthropods notorious for inducing many reproductive manipulations that foster its dissemination. Wolbachia affects many aspects of host biology, including metabolism, longevity and physiology, being described as a nutrient provisioning or metabolic parasite, depending on the host-microbe association. Sirtuins (SIRTs) are a family of NAD + -dependent post-translational regulatory enzymes known to affect many of the same processes altered by Wolbachia , including aging and metabolism, among others. Despite a clear overlap in control of host-derived pathways and physiology, no work has demonstrated a link between these two regulators. We used genetically tractable Drosophila melanogaster to explore the role of sirtuins in shaping signaling pathways in the context of a host-symbiont model. By using transcriptional profiling and metabolic assays in the context of genetic knockouts/over-expressions, we examined the effect of several Wolbachia strains on host sirtuin expression across distinct tissues and timepoints. We also quantified the downstream effects of the sirtuin x Wolbachia interaction on host glucose metabolism, and in turn, how it impacted Wolbachia titer. Our results indicate that the presence of Wolbachia is associated with (1) reduced sirt-4 expression in a strain-specific manner, and (2) alterations in host glutamate dehydrogenase expression and ATP levels, key components of glucose metabolism. We detected high glucose levels in Wolbachia- infected flies, which further increased when sirt-4 was over-expressed. However, under sirt-4 knockout, flies displayed a hypoglycemic state not rescued to normal levels in the presence of Wolbachia . Finally, whole body sirt-4 over-expression resulted in reduced Wolbachia ovarian titer. Our results expand knowledge of Wolbachia -host associations in the context of a yet unexplored class of host post-translational regulatory enzymes with implications for conserved host signaling pathways and bacterial titer, factors known to impact host biology and the symbiont’s ability to spread through populations.

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Section: Discussionmentioning

confidence: 99%

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

2020

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“…Because neurons rely on intercellular signaling through synaptic vesicle formation and trafficking, it is tempting to speculate that SIRT2 association with these diseases is partly provided by its role in protein secretion and other membranebound trafficking pathways. SIRT2 impact on viral infection (11,90) might also be connected to intracellular trafficking. Viruses commonly use microtubule networks for capsid trafficking, genome delivery, and assembly (91).…”

Section: Fig 6 Sirt2 Impact On Protein Levels Of Membrane Traffickimentioning

confidence: 99%

Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking

Budayeva

Cristea

2016

Molecular & Cellular Proteomics

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Human sirtuin 2 (SIRT2) is an NAD-dependent deacetylase that primarily functions in the cytoplasm, where it can regulate α-tubulin acetylation levels. SIRT2 is linked to cancer progression, neurodegeneration, and infection with bacteria or viruses. However, the current knowledge about its interactions and the means through which it exerts its functions has remained limited. Here, we aimed to gain a better understanding of its cellular functions by characterizing SIRT2 subcellular localization, the identity and relative stability of its protein interactions, and its impact on the proteome of primary human fibroblasts. To assess the relative stability of SIRT2 interactions, we used immunoaffinity purification in conjunction with both label-free and metabolic labeling quantitative mass spectrometry. In addition to the expected associations with cytoskeleton proteins, including its known substrate TUBA1A, our results reveal that SIRT2 specifically interacts with proteins functioning in membrane trafficking, secretory processes, and transcriptional regulation. By quantifying their relative stability, we found most interactions to be transient, indicating a dynamic SIRT2 environment. We discover that SIRT2 localizes to the ER-Golgi intermediate compartment (ERGIC), and that this recruitment requires an intact ER-Golgi trafficking pathway. Further expanding these findings, we used microscopy and interaction assays to establish the interaction and coregulation of SIRT2 with liprin-β1 scaffolding protein (PPFiBP1), a protein with roles in focal adhesions disassembly. As SIRT2 functions may be accomplished via interactions, enzymatic activity, and transcriptional regulation, we next assessed the impact of SIRT2 levels on the cellular proteome. SIRT2 knockdown led to changes in the levels of proteins functioning in membrane trafficking, including some of its interaction partners. Altogether, our study expands the knowledge of SIRT2 cytoplasmic functions to define a previously unrecognized involvement in intracellular trafficking pathways, which may contribute to its roles in cellular homeostasis and human diseases.

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“…Viruses have been known to appropriate Sirt regulatory pathways through the manipulation of host epigenetic and transcriptional changes (Budaveva et al, 2016). For example, Influenza A evolved to encode NS1 to mimic histone H3 and suppress antiviral genes; thus, Sirt inhibition increased Influenza A titers (Budaveva et al, 2016). Although, to our knowledge, there is no literature on how phages, would affect Sirt3, our findings suggest that phages may induce similar effects as that of a viral infection.…”

Section: Decreases Neuroprotectionmentioning

confidence: 71%

“…Sirt3 is a mitochondrial de-acetylate that influences almost every pathway in the mitochondria and plays a primary role in stress resistance, metabolism, neurodegenerative disease and aging (McDonnell et al, 2015;Ansari et al, 2017;Anamika, Khanna, Acharjee, Acharjee, & Trigun, 2017;Budaveva, Rowland & Cristea, 2016). Mitochondrial dysfunction is linked to aging due to being both a source and target of ROS (Kincaid & Bossy-Wetzel, 2013), Sirt3 can eliminate ROS and prevent apoptosis; hence, it is generally thought to be neuroprotective (McDonnell et al, 2015).…”

Section: Decreases Neuroprotectionmentioning

confidence: 99%

“…The lowest levels of Sirt3 were evident in old mice that also received the phage treatment. Viruses have been known to appropriate Sirt regulatory pathways through the manipulation of host epigenetic and transcriptional changes (Budaveva et al, 2016). For example, Influenza A evolved to encode NS1 to mimic histone H3 and suppress antiviral genes; thus, Sirt inhibition increased Influenza A titers (Budaveva et al, 2016).…”

Section: Decreases Neuroprotectionmentioning

confidence: 99%

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The Impact of Bacteriophage on the Aging Brain and Inflammatory Response: Relevance to Parkinson’s Disease

Beauchamp¹

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Parkinson's disease (PD) is associated with age and inflammation. New studies have found a link between gut dysbiosis and the prevalence of PD. Phage 936, which is found in dairy products, has been associated with disruptions in the gut microbiome and leaky gut causalities. The present thesis sought to assess the impact of phage 936 in young or old mice and whether the virus augments or diminishes the impact of an inflammatory (LPS) stimulus. To this end, an initial study was conducted to first determine if bacteriophage alone could actually produce some degree of measurable changes (e.g. neutrophil mobilization or change in cytokine or other circulating

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Intricate Roles of Mammalian Sirtuins in Defense against Viral Pathogens

Cited by 50 publications

References 21 publications

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking

The Impact of Bacteriophage on the Aging Brain and Inflammatory Response: Relevance to Parkinson’s Disease

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