Peroxisome-localized hepatitis Bx protein increases the invasion property of hepatocellular carcinoma cells

Han, Jing; Kang, Jung‐Ah; Han, Minhee; Chung, Kyung-Hun; Lee, Cho-Rong; Song, Wookeun; Jun, Youngsoo; Park, Sung‐Gyoo

doi:10.1007/s00705-014-2105-4

Cited by 21 publications

(14 citation statements)

References 24 publications

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“…Since our findings show that the TP domain contains the MTS, it still remains to be seen if localization of Pol to the mitochondria plays a role in the reported interaction between Pol and STING (73). HBx, a regulatory protein specific to mammalian hepadnaviruses, has also been detected at mitochondria in some studies (75)(76)(77)(78). HBx has been linked to both pro-and antiapoptotic roles, mitochondrial membrane potential modulation, generation of oxidative stress, and downregulation of innate immune responses (79).…”

Section: Discussionmentioning

confidence: 69%

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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Section: Discussionmentioning

confidence: 69%

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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“…In addition, it has been shown that (i) several RNA viruses that are of great importance for global public health (e.g., rotavirus, HIV, and influenza) exploit these organelles in their replication cycle [176,177,178]; (ii) pathogenic flaviviruses such as West Nile and dengue impair peroxisome biogenesis in infected cells, thereby suppressing the induction of type III IFNs [179]; and (iii) hepatitis B virus X protein, a multifunctional viral protein that binds to MAVS and promotes the development and progression of hepatocellular carcinoma, triggers the production of ROS and activation of NF-κB upon association with mitochondria [180] or peroxisomes [181]. In summary, these observations highlight the critical and cooperative role of peroxisomes and mitochondria in antiviral defense.…”

Section: Peroxisome-mitochondria Communication: Physiological Impomentioning

confidence: 99%

The Peroxisome-Mitochondria Connection: How and Why?

Fransen

Lismont

Walton

2017

IJMS

263

249

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Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks. To exert these activities, peroxisomes must interact both functionally and physically with other cell organelles. This review provides a comprehensive look of what is currently known about the interconnectivity between peroxisomes and mitochondria within mammalian cells. We first outline how peroxisomal and mitochondrial abundance are controlled by common sets of cis- and trans-acting factors. Next, we discuss how peroxisomes and mitochondria may communicate with each other at the molecular level. In addition, we reflect on how these organelles cooperate in various metabolic and signaling pathways. Finally, we address why peroxisomes and mitochondria have to maintain a healthy relationship and why defects in one organelle may cause dysfunction in the other. Gaining a better insight into these issues is pivotal to understanding how these organelles function in their environment, both in health and disease.

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“…However, a limited but growing number of studies lend strong support to the idea that these organelles do actively contribute to transcompartmental ROS signaling in mammalian cells (Figure 2 ). For example, alterations in peroxisomal H 2 O 2 metabolism have been shown to influence the cellular protein disulfide content (Yang et al, 2007 ; Ivashchenko et al, 2011 ), NF-kB activation (Li et al, 2000 ; Han et al, 2014 ), E-cadherin expression (Han et al, 2014 ), the secretion of matrix metalloproteinases (Koepke et al, 2008 ; Han et al, 2014 ), mTORC1 activity and autophagy (Zhang et al, 2013 ), neuronal activity (Diano et al, 2011 ), and cell fate decisions in response to different stressors (Carter et al, 2004 ; Chen et al, 2004 ; Elsner et al, 2011 ). Unfortunately, the precise molecular mechanisms underlying most of these observations remain poorly understood and sometimes even controversial.…”

Section: Peroxisomes As Redox Signaling Nodesmentioning

confidence: 99%

Redox interplay between mitochondria and peroxisomes

Lismont

Nordgren

Veldhoven

et al. 2015

Front. Cell Dev. Biol.

160

139

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Reduction-oxidation or “redox” reactions are an integral part of a broad range of cellular processes such as gene expression, energy metabolism, protein import and folding, and autophagy. As many of these processes are intimately linked with cell fate decisions, transient or chronic changes in cellular redox equilibrium are likely to contribute to the initiation and progression of a plethora of human diseases. Since a long time, it is known that mitochondria are major players in redox regulation and signaling. More recently, it has become clear that also peroxisomes have the capacity to impact redox-linked physiological processes. To serve this function, peroxisomes cooperate with other organelles, including mitochondria. This review provides a comprehensive picture of what is currently known about the redox interplay between mitochondria and peroxisomes in mammals. We first outline the pro- and antioxidant systems of both organelles and how they may function as redox signaling nodes. Next, we critically review and discuss emerging evidence that peroxisomes and mitochondria share an intricate redox-sensitive relationship and cooperate in cell fate decisions. Key issues include possible physiological roles, messengers, and mechanisms. We also provide examples of how data mining of publicly-available datasets from “omics” technologies can be a powerful means to gain additional insights into potential redox signaling pathways between peroxisomes and mitochondria. Finally, we highlight the need for more studies that seek to clarify the mechanisms of how mitochondria may act as dynamic receivers, integrators, and transmitters of peroxisome-derived mediators of oxidative stress. The outcome of such studies may open up exciting new avenues for the community of researchers working on cellular responses to organelle-derived oxidative stress, a research field in which the role of peroxisomes is currently highly underestimated and an issue of discussion.

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Peroxisome-localized hepatitis Bx protein increases the invasion property of hepatocellular carcinoma cells

Cited by 21 publications

References 24 publications

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

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

The Peroxisome-Mitochondria Connection: How and Why?

Redox interplay between mitochondria and peroxisomes

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