Rotavirus activates a noncanonical ATM‐Chk2 branch of DNA damage response during infection to positively regulate viroplasm dynamics

Sarkar, Rakesh; Patra, Upayan; Lo, Mahadeb; Mukherjee, Arpita; Biswas, Asim; Chawla‐Sarkar, Mamta

doi:10.1111/cmi.13149

Cited by 17 publications

(16 citation statements)

References 87 publications

(191 reference statements)

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“…As previously reported, DNA viruses and retroviruses such as the herpes simplex virus [ 17 ], human papillomavirus [ 44 ], human immunodeficiency virus [ 18 ], and polyomavirus [ 21 ] usually initiate the DDR pathway. However, prior to the present study, only a limited number of RNA viruses such as hepatitis C virus [ 45 ], coronavirus [ 14 ], La Crosse encephalitis virus [ 15 ], Rift Valley fever virus [ 13 ], Newcastle disease virus [ 46 ], and rotavirus [ 47 ] had been confirmed to activate the DDR pathway and upregulate the expression of γ-H2AX. In viral life cycle, DNA viruses and retroviruses must integrate their DNA by inserting it into the host genome, which leads to a direct DNA break.…”

Section: Discussionmentioning

confidence: 99%

Regulation of host factor γ-H2AX level and location by enterovirus A71 for viral replication

Zhang

Huo

et al. 2022

Virulence

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Numerous viruses manipulate host factors for viral production. We demonstrated that human enterovirus A71 (EVA71), a primary causative agent for hand, foot, and mouth disease (HFMD), increased the level of the DNA damage response (DDR) marker γ-H2AX. DDR is primarily mediated by the ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), or DNA-dependent protein kinase (DNA-PK) pathways. Upregulation of γ-H2AX by EVA71 was dependent on the ATR but not the ATM or DNA-PK pathway. As a nuclear factor, there is no previous evidence of cytoplasmic distribution of γ-H2AX. However, the present findings demonstrated that EVA71 encouraged the localization of γ-H2AX to the cytoplasm. Of note, γ-H2AX formed a complex with structural protein VP3, non-structural protein 3D, and the viral genome. Treatment with an inhibitor or CRISPR/Cas9 technology to decrease or silence the expression of γ-H2AX decreased viral genome replication in host cells; this effect was accompanied by decreased viral protein expression and virions. In animal experiments, caffeine was used to inhibit DDR; the results revealed that caffeine protected neonatal mice from death after infection with EVA71, laying the foundation for new therapeutic applications of caffeine. More importantly, in children with HFMD, γ-H2AX was upregulated in peripheral blood lymphocytes. The consistent in vitro and in vivo data on γ-H2AX from this study suggested that caffeine or other inhibitors of DDR might be novel therapeutic agents for HFMD.

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Section: Discussionmentioning

confidence: 99%

Regulation of host factor γ-H2AX level and location by enterovirus A71 for viral replication

Zhang

Huo

et al. 2022

Virulence

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“…DNA damage response [65], and in particular, the MRN complex, has also been shown to be critically involved in the maintenance of other viruses such as adenovirus [66], papilloma virus [67], rotavirus [68], and New Castle Disease virus [69]. In addition, MRN proteins were proposed to bind at oriP of EBV and support latent episome replication, probably by resolving recombination like structures [70].…”

Section: Discussionmentioning

confidence: 99%

3D culture conditions support Kaposi’s sarcoma herpesvirus (KSHV) maintenance and viral spread in endothelial cells

et al. 2021

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Kaposi’s sarcoma–associated herpesvirus (KSHV) is a human tumorigenic virus and the etiological agent of an endothelial tumor (Kaposi’s sarcoma) and two B cell proliferative diseases (primary effusion lymphoma and multicentric Castleman’s disease). While in patients with late stage of Kaposi’s sarcoma the majority of spindle cells are KSHV-infected, viral copies are rapidly lost in vitro, both upon culture of tumor-derived cells or from newly infected endothelial cells. We addressed this discrepancy by investigating a KSHV-infected endothelial cell line in various culture conditions and in tumors of xenografted mice. We show that, in contrast to two-dimensional endothelial cell cultures, KSHV genomes are maintained under 3D cell culture conditions and in vivo. Additionally, an increased rate of newly infected cells was detected in 3D cell culture. Furthermore, we show that the PI3K/Akt/mTOR and ATM/γH2AX pathways are modulated and support an improved KSHV persistence in 3D cell culture. These mechanisms may contribute to the persistence of KSHV in tumor tissue in vivo and provide a novel target for KS specific therapeutic interventions. Key messages In vivo maintenance of episomal KSHV can be mimicked in 3D spheroid cultures 3D maintenance of KSHV is associated with an increased de novo infection frequency PI3K/Akt/mTOR and ATM/ γH2AX pathways contribute to viral maintenance

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“…Sensitivity of the co-IP reactions to RNase A treatment further enabled differentiating the hostviroplasm interactions which are dependent on an intermediate scaffold of RNAs such as the viral RNAs . Interestingly, co-localization events observed under a microscope did not always accompany the occurrence of physical interaction identified by AP-MS or co-IP-immunoblot approach, possibly differentiating between proximity-based association and protein-protein interaction Criglar et al, 2020;Sarkar et al, 2020). Indeed, some viral proteins such as NSP2 exist in two different forms.…”

Section: Methods To Study Host-viroplasm Interactionsmentioning

confidence: 95%

Sneaking into the viral safe-houses: Implications of host components in regulating integrity and dynamics of rotaviral replication factories

Chandra

Banerjee

Saha

et al. 2022

Front. Cell. Infect. Microbiol.

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The biology of the viral life cycle essentially includes two structural and functional entities—the viral genome and protein machinery constituting the viral arsenal and an array of host cellular components which the virus closely associates with—to ensure successful perpetuation. The obligatory requirements of the virus to selectively evade specific host cellular factors while exploiting certain others have been immensely important to provide the platform for designing host-directed antiviral therapeutics. Although the spectrum of host-virus interaction is multifaceted, host factors that particularly influence viral replication have immense therapeutic importance. During lytic proliferation, viruses usually form replication factories which are specialized subcellular structures made up of viral proteins and replicating nucleic acids. These viral niches remain distinct from the rest of the cellular milieu, but they effectively allow spatial proximity to selective host determinants. Here, we will focus on the interaction between the replication compartments of a double stranded RNA virus rotavirus (RV) and the host cellular determinants of infection. RV, a diarrheagenic virus infecting young animals and children, forms replication bodies termed viroplasms within the host cell cytoplasm. Importantly, viroplasms also serve as the site for transcription and early morphogenesis of RVs and are very dynamic in nature. Despite advances in the understanding of RV components that constitute the viroplasmic architecture, knowledge of the contribution of host determinants to viroplasm dynamicity has remained limited. Emerging evidence suggests that selective host determinants are sequestered inside or translocated adjacent to the RV viroplasms. Functional implications of such host cellular reprogramming are also ramifying—disarming the antiviral host determinants and usurping the pro-viral components to facilitate specific stages of the viral life cycle. Here, we will provide a critical update on the wide variety of host cellular pathways that have been reported to regulate the spatial and temporal dynamicity of RV viroplasms. We will also discuss the methods used so far to study the host-viroplasm interactions and emphasize on the potential host factors which can be targeted for therapeutic intervention in the future.

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Rotavirus activates a noncanonical ATM‐Chk2 branch of DNA damage response during infection to positively regulate viroplasm dynamics

Cited by 17 publications

References 87 publications

Regulation of host factor γ-H2AX level and location by enterovirus A71 for viral replication

Regulation of host factor γ-H2AX level and location by enterovirus A71 for viral replication

3D culture conditions support Kaposi’s sarcoma herpesvirus (KSHV) maintenance and viral spread in endothelial cells

Sneaking into the viral safe-houses: Implications of host components in regulating integrity and dynamics of rotaviral replication factories

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