A renewed focus on the interplay between viruses and mitochondrial metabolism

Claus, Claudia; Liebert, Uwe G.

doi:10.1007/s00705-013-1841-1

Cited by 40 publications

(39 citation statements)

References 77 publications

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“…25,26 The glycolytic pathway implicated from our enrichment analysis is known to be linked to GSK3B activity and there is increasing appreciation that the glycolytic pathway is critical to the Ebola life cycle. 27 The non-specificity of kenpaullone makes studying its molecular mechanisms and direct targets difficult. However, here we observe that kenpaullone induces the expression of immune response genes and as such it is potentially a general anti-viral candidate.…”

Section: Discussionmentioning

confidence: 99%

L1000CDS2: LINCS L1000 characteristic direction signatures search engine

et al. 2016

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The library of integrated network-based cellular signatures (LINCS) L1000 data set currently comprises of over a million gene expression profiles of chemically perturbed human cell lines. Through unique several intrinsic and extrinsic benchmarking schemes, we demonstrate that processing the L1000 data with the characteristic direction (CD) method significantly improves signal to noise compared with the MODZ method currently used to compute L1000 signatures. The CD processed L1000 signatures are served through a state-of-the-art web-based search engine application called L1000CDS2. The L1000CDS2 search engine provides prioritization of thousands of small-molecule signatures, and their pairwise combinations, predicted to either mimic or reverse an input gene expression signature using two methods. The L1000CDS2 search engine also predicts drug targets for all the small molecules profiled by the L1000 assay that we processed. Targets are predicted by computing the cosine similarity between the L1000 small-molecule signatures and a large collection of signatures extracted from the gene expression omnibus (GEO) for single-gene perturbations in mammalian cells. We applied L1000CDS2 to prioritize small molecules that are predicted to reverse expression in 670 disease signatures also extracted from GEO, and prioritized small molecules that can mimic expression of 22 endogenous ligand signatures profiled by the L1000 assay. As a case study, to further demonstrate the utility of L1000CDS2, we collected expression signatures from human cells infected with Ebola virus at 30, 60 and 120 min. Querying these signatures with L1000CDS2 we identified kenpaullone, a GSK3B/CDK2 inhibitor that we show, in subsequent experiments, has a dose-dependent efficacy in inhibiting Ebola infection in vitro without causing cellular toxicity in human cell lines. In summary, the L1000CDS2 tool can be applied in many biological and biomedical settings, while improving the extraction of knowledge from the LINCS L1000 resource.

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Section: Discussionmentioning

confidence: 99%

L1000CDS2: LINCS L1000 characteristic direction signatures search engine

et al. 2016

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“…Mitochondria play important roles in metabolism, apoptosis, and innate antiviral cell immune defenses (68,69). Viruses frequently perturb those functions to gain a replicative advantage (70,71). There are multiple reports implicating HBV Pol in modulating the host innate immune response, but none of these reports indicate the involvement of the mitochondria in manifesting these effects of Pol.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal

Unchwaniwala

Sherer

Loeb

2016

J Virol

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To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria. The Pol of duck hepatitis B virus (DHBV) also localized to the mitochondria. This result indicates that localization of Pol to mitochondria is likely a feature of all hepadnaviruses. To map the MTS within HBV Pol, we generated a series of Pol-green fluorescent protein (Pol-GFP) fusions and found that a stretch spanning amino acids (aa) 141 to 160 of Pol was sufficient to target GFP to the mitochondria. Surprisingly, deleting aa 141 to 160 in full-length Pol did not fully ablate Pol's mitochondrial localization, suggesting that additional sequences are involved in mitochondrial targeting. Only by deleting the N-terminal 160 amino acids in fulllength Pol was mitochondrial localization ablated. Crucial residues for pgRNA packaging are contained within aa 141 to 160, indicating a multifunctional role of this region of Pol in the viral life cycle. Our studies show an unexpected Pol trafficking behavior that is uncoupled from its role in viral DNA synthesis. IMPORTANCEChronic infection by HBV is a serious health concern. Existing therapies for chronically infected individuals are not curative, underscoring the need for a better understanding of the viral life cycle to develop better antiviral therapies. To date, the most thoroughly studied function of Pol is to package the pgRNA and reverse transcribe it to double-stranded DNA within capsids. This study provides evidence for mitochondrial localization of Pol and defines the MTS. Recent findings have implicated a nonreverse transcription role for Pol in evading host innate immune responses. Mitochondria play an important role in controlling cellular metabolism, apoptosis, and innate immunity. Pol may alter one or more of these host mitochondrial functions to gain a replicative advantage and persist in chronically infected individuals.

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“…In this review article, we discuss the events of virus-regulated mitochondrial dynamics and their implications in viral pathogenesis. The impact of viral infection on mitochondrial functions has been described elsewhere [10] , [11] .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dynamics and viral infections: A close nexus

Khan

Syed

Kim

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

153

143

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Viruses manipulate cellular machinery and functions to subvert intracellular environment conducive for viral proliferation. They strategically alter functions of the multitasking mitochondria to influence energy production, metabolism, survival, and immune signaling. Mitochondria either occur as heterogeneous population of individual organelles or large interconnected tubular network. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections, and is dynamically maintained by mitochondrial fission and fusion. Mitochondrial dynamics in tandem with mitochondria-selective autophagy ‘mitophagy’ coordinates mitochondrial quality control and homeostasis. Mitochondrial dynamics impacts cellular homeostasis, metabolism, and innate-immune signaling, and thus is a major determinant of the outcome of viral infections. Hepatitis B and C viruses exploit mitochondrial dynamics to ensure cell survival and escape from innate immunity, thereby promoting persistent/chronic viral infection. Herein, we review how mitochondrial dynamics is affected during viral infections and how this complex interplay benefits the viral infectious process and associated diseases.

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A renewed focus on the interplay between viruses and mitochondrial metabolism

Cited by 40 publications

References 77 publications

L1000CDS2: LINCS L1000 characteristic direction signatures search engine

L1000CDS2: LINCS L1000 characteristic direction signatures search engine

Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal

Mitochondrial dynamics and viral infections: A close nexus

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