Extracellular vesicles activate ATM‐Chk2 signaling pathway through the intercellular transfer of mitochondrial DNA in HBV‐infected human hepatocytes

Dansako, Hiromichi; Ueda, Youki; Satoh, Shinya; Kato, Naoya

doi:10.1096/fj.202002678r

Cited by 6 publications

(5 citation statements)

References 35 publications

(84 reference statements)

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“…MDVs carry not only the damaged mitochondrial components but also the healthy mitochondrial compartments that can be transferred and released to the unhealthy mitochondria for maintaining cellular functions and survival. Previous studies have demonstrated that MDVs can transport functional mtDNA, mitochondrial matrix, IMM, OMM and fragmented mitochondria to other malfunctioned mitochondria inside the same cell or outside (adjacent cells) [ 41 , 174 – 179 ]. Recently, the in vitro synthesis of MDVs has been developed and applied for reduction of cell apoptosis [ 2 , 40 , 73 ].…”

Section: Potential Roles Of Mdvs In Ksdmentioning

confidence: 99%

Mitochondria-derived vesicles and their potential roles in kidney stone disease

Chaiyarit

Thongboonkerd

2023

J Transl Med

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Recent evidence has shown significant roles of mitochondria-derived vesicles (MDVs) in mitochondrial quality control (MQC) system. Under mild stress condition, MDVs are formed to carry the malfunctioned mitochondrial components, such as mitochondrial DNA (mtDNA), peptides, proteins and lipids, to be eliminated to restore normal mitochondrial structure and functions. Under severe oxidative stress condition, mitochondrial dynamics (fission/fusion) and mitophagy are predominantly activated to rescue mitochondrial structure and functions. Additionally, MDVs generation can be also triggered as the major MQC machinery to cope with unhealthy mitochondria when mitophagy is unsuccessful for eliminating the damaged mitochondria or mitochondrial fission/fusion fail to recover the mitochondrial structure and functions. This review summarizes the current knowledge on MDVs and discuss their roles in physiologic and pathophysiologic conditions. In addition, the potential clinical relevance of MDVs in therapeutics and diagnostics of kidney stone disease (KSD) are emphasized.

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Section: Potential Roles Of Mdvs In Ksdmentioning

confidence: 99%

Mitochondria-derived vesicles and their potential roles in kidney stone disease

Chaiyarit

Thongboonkerd

2023

J Transl Med

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“…The importance of the ATM signaling pathway in HBV infection and HBV-associated carcinogenesis was also recently supported by the study of Dansako et al [72], who demonstrated that HBV infection led to the activation of the ATM-Chk2 signaling pathway in infected cells. Moreover, they proposed the model in which the extracellular vesicles (EVs) derived from HBV-infected cells activated the ATM-Chk2 signaling in naïve cell through intercellular transfer of mitochondrial DNA (mtDNA) from HBV-infected cells to neighboring cells.…”

Section: Interaction Between Hbv and Host Atm-regulated Pathwaymentioning

confidence: 76%

ATM-Dependent Phosphorylation of Hepatitis B Core Protein in Response to Genotoxic Stress

Lubyová

Tikalová

Krulova

et al. 2021

Viruses

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Chronic hepatitis caused by infection with the Hepatitis B virus is a life-threatening condition. In fact, 1 million people die annually due to liver cirrhosis or hepatocellular carcinoma. Recently, several studies demonstrated a molecular connection between the host DNA damage response (DDR) pathway and HBV replication and reactivation. Here, we investigated the role of Ataxia-telangiectasia-mutated (ATM) and Ataxia telangiectasia and Rad3-related (ATR) PI3-kinases in phosphorylation of the HBV core protein (HBc). We determined that treatment of HBc-expressing hepatocytes with genotoxic agents, e.g., etoposide or hydrogen peroxide, activated the host ATM-Chk2 pathway, as determined by increased phosphorylation of ATM at Ser1981 and Chk2 at Thr68. The activation of ATM led, in turn, to increased phosphorylation of cytoplasmic HBc at serine-glutamine (SQ) motifs located in its C-terminal domain. Conversely, down-regulation of ATM using ATM-specific siRNAs or inhibitor effectively reduced etoposide-induced HBc phosphorylation. Detailed mutation analysis of S-to-A HBc mutants revealed that S170 (S168 in a 183-aa HBc variant) is the primary site targeted by ATM-regulated phosphorylation. Interestingly, mutation of two major phosphorylation sites involving serines at positions 157 and 164 (S155 and S162 in a 183-aa HBc variant) resulted in decreased etoposide-induced phosphorylation, suggesting that the priming phosphorylation at these serine-proline (SP) sites is vital for efficient phosphorylation of SQ motifs. Notably, the mutation of S172 (S170 in a 183-aa HBc variant) had the opposite effect and resulted in massively up-regulated phosphorylation of HBc, particularly at S170. Etoposide treatment of HBV infected HepG2-NTCP cells led to increased levels of secreted HBe antigen and intracellular HBc protein. Together, our studies identified HBc as a substrate for ATM-mediated phosphorylation and mapped the phosphorylation sites. The increased expression of HBc and HBe antigens in response to genotoxic stress supports the idea that the ATM pathway may provide growth advantage to the replicating virus.

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“…SiRNA duplexes targeting the coding regions of MDA5 (M‐013041‐00), IRF‐3 (M‐006875‐01), TRAF3 (M‐005252‐00), TRAF6 (M‐004712‐00) and luciferase GL2 (D‐001100‐01) as a control were purchased from Horizon Discovery (Cambridge, UK). Cells were transfected with the indicated siRNA duplex using DharmaFECT transfection reagent (Horizon Discovery) [36]. The extraction of total cellular RNA and real‐time LightCycler PCR of IFN‐β were performed as described previously [37].…”

Section: Methodsmentioning

confidence: 99%

Hepatitis C virus NS5B triggers an MDA5‐mediated innate immune response by producing dsRNA without the replication of viral genomes

Dansako,

Ikeda,

Ariumi

et al. 2023

The FEBS Journal

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During the replication of viral genomes, RNA viruses produce double‐stranded RNA (dsRNA), through the activity of their RNA‐dependent RNA polymerases (RdRps) as viral replication intermediates. Recognition of viral dsRNA by host pattern recognition receptors – such as retinoic acid‐induced gene‐I (RIG‐I)‐like receptors and Toll‐like receptor 3 (TLR3) – triggers the production of interferon (IFN)‐β via the activation of IFN regulatory factor (IRF)‐3. It has been proposed that, during the replication of viral genomes, each of RIG‐I and melanoma differentiation‐associated gene 5 (MDA5) form homodimers for the efficient activation of a downstream signaling pathway in host cells. We previously reported that, in the non‐neoplastic human hepatocyte line PH5CH8, the RNA‐dependent RNA polymerase NS5B derived from hepatitis C virus (HCV) could induce IFN‐β expression by its RdRp activity without the actual replication of viral genomes. However, the exact mechanism by which HCV NS5B produced IFN‐β remained unknown. In the present study, we first showed that NS5B derived from another Flaviviridae family member, GB virus B (GBV‐B), also possessed the ability to induce IFN‐β in PH5CH8 cells. Similarly, HCV NS5B, but not its G317V mutant, which lacks RdRp activity, induced the dimerization of MDA5 and subsequently the activation of IRF‐3. Interestingly, immunofluorescence analysis showed that HCV NS5B produced dsRNA. Like HCV NS5B, GBV‐B NS5B also triggered the production of dsRNA and subsequently the dimerization of MDA5. Taken together, our results show that HCV NS5B triggers an MDA5‐mediated innate immune response by producing dsRNA without the replication of viral genomes in human hepatocytes.

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Extracellular vesicles activate ATM‐Chk2 signaling pathway through the intercellular transfer of mitochondrial DNA in HBV‐infected human hepatocytes

Cited by 6 publications

References 35 publications

Mitochondria-derived vesicles and their potential roles in kidney stone disease

Mitochondria-derived vesicles and their potential roles in kidney stone disease

ATM-Dependent Phosphorylation of Hepatitis B Core Protein in Response to Genotoxic Stress

Hepatitis C virus NS5B triggers an MDA5‐mediated innate immune response by producing dsRNA without the replication of viral genomes

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