Pseudorabies virus kinase UL13 phosphorylates H2AX to foster viral replication

Xin, Ming; Bo, Zongyi; Miao, Yurun; Chen, Huan; Sun, Lingzhi; Rui, Xiaoting; Zhong, Qiuping; Zhao, Pu; Jung, Yong‐Sam; Qian, Yingjuan

doi:10.1096/fj.202101360rr

Cited by 9 publications

(6 citation statements)

References 49 publications

(112 reference statements)

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“…Inhibition of DDR attenuated PRV proliferation, suggesting that PRV-induced DDR was beneficial for viral proliferation. The PRV kinase UL13 phosphorylates H2AX to foster viral replication, and DDR promotes HSV-1 protein expression in a neuroblastoma cell line, 40,41 further supporting our findings. However, it has been reported that H2AX phosphorylation and DNA damage kinase activity are dispensable for HSV-1 replication.…”

Section: Discussionsupporting

confidence: 86%

Alphaherpesvirus upregulates NDRG1 expression to facilitate the nuclear import of viral UL31 and UL34 proteins

Zhang

Ming

Zeng

et al. 2023

Journal of Medical Virology

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Proteins UL31 and UL34 encoded by alphaherpesvirus are critical for viral primary envelopment and nuclear egress. We report here that pseudorabies virus (PRV), a useful model for research on herpesvirus pathogenesis, uses N‐myc downstream regulated 1 (NDRG1) to assist the nuclear import of UL31 and UL34. PRV promoted NDRG1 expression through DNA damage‐induced P53 activation, which was beneficial to viral proliferation. PRV induced the nuclear translocation of NDRG1, and its deficiency resulted in the cytosolic retention of UL31 and UL34. Therefore, NDRG1 assisted the nuclear import of UL31 and UL34. Furthermore, in the absence of the nuclear localization signal (NLS), UL31 could still translocate to the nucleus, and NDRG1 lacked an NLS, thus suggesting the existence of other mediators for the nuclear import of UL31 and UL34. We demonstrated that heat shock cognate protein 70 (HSC70) was the key factor in this process. UL31 and UL34 interacted with the N‐terminal domain of NDRG1 and the C‐terminal domain of NDRG1 bound to HSC70. Replenishment of HSC70ΔNLS in HSC70‐knockdown cells, or interference in importin α expression, abolished the nuclear translocation of UL31, UL34, and NDRG1. These results indicated that NDRG1 employs HSC70 to facilitate viral proliferation in the nuclear import of PRV UL31 and UL34.

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Section: Discussionsupporting

confidence: 86%

Alphaherpesvirus upregulates NDRG1 expression to facilitate the nuclear import of viral UL31 and UL34 proteins

Zhang

Ming

Zeng

et al. 2023

Journal of Medical Virology

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“…Some studies have shown that DDR is commonly encountered during several DNA and a few RNA viral infections and is important for the viral life cycle, like the herpes simplex virus 1 (HSV-1), Zika virus, and Marek’s disease virus ( 32 ). This has been particularly evidenced in herpesvirus infections, for which ATM and ATR DNA damage pathway proteins play beneficial roles for viral replication ( 32 ). Alphaherpesviruses HSV-1 and HSV-2 can cause ATM-dependent DDR ( 33 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

HDAC6 Triggers the ATM-Dependent DNA Damage Response To Promote PRV Replication

Yan

Zhou

et al. 2023

Microbiol Spectr

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“…Previously, we have found that IRF3, an important transcription factor that participates in the production of interferon, is phosphorylated by PRV UL13 protein kinase, resulting in the inhibition of IFN-β ( 17 ). Additionally, we also found that γH2AX, the marker of DNA damage response, can also be upregulated by PRV UL13 protein kinase to promote viral proliferation ( 18 ). What is more, it was also reported PRV US3 protein kinase could promote retrograde transport in axons via activation of PI3K/Akt-mTORC1 pathway ( 19 ).…”

Section: Introductionmentioning

confidence: 93%

Phosphoproteomic landscape of pseudorabies virus infection reveals multiple potential antiviral targets

Bo,

Li,

Zhang

et al. 2024

Microbiol Spectr

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Phosphorylation, a significant posttranslational modification, is implicated in nearly two-thirds of all proteins. The involvement of phosphorylation in various cellular responses is known to play a crucial role in the replication of pseudorabies virus (PRV). However, the phosphoproteomic landscape during PRV infection remains unknown. To address this, a tandem mass tag-based liquid chromatography-tandem mass spectrometry was performed. It was found that a total of 7,342 phosphosites were detected; among these, 1,197 phosphosites were significantly upregulated, and 1,120 phosphosites were significantly downregulated when the threshold was set at 1.5. Gene ontology analysis of these significantly changed proteins showed that they mainly participated in mRNA processing, RNA splicing, stress granule assembly, and other pathways. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that these proteins were associated with cell cycle, spliceosome, tight junction, mRNA surveillance, and other pathways. Additionally, an immunoblotting assay confirmed the phosphoproteomic results by detecting the protein level of several upregulated phosphorylated proteins, which included pBRAF, pRPS6KA1, and pSTMN1. Further experiments using siRNA showed that knockdown of BRAF, RPS6KA1, and STMN1 significantly inhibited the replication of PRV. In summary, this study provides insight into the phosphoproteomic landscape during PRV infection and contributes to a better understanding of the mechanisms underlying PRV replication. IMPORTANCE Pseudorabies virus (PRV) is a kind of alpha herpesvirus that infects a wide range of animals and even human beings. Therefore, it is important to explore the mechanisms behind PRV replication and pathogenesis. By conducting a tandem mass tag-based phosphoproteome, this study revealed the phosphorylated proteins and cellular response pathways involved in PRV infection. Findings from this study shed light on the relationship between the phosphorylated cellular proteins and PRV infection, as well as guiding the discovery of targets for the development of antiviral compounds against PRV.

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Pseudorabies virus kinase UL13 phosphorylates H2AX to foster viral replication

Cited by 9 publications

References 49 publications

Alphaherpesvirus upregulates NDRG1 expression to facilitate the nuclear import of viral UL31 and UL34 proteins

Alphaherpesvirus upregulates NDRG1 expression to facilitate the nuclear import of viral UL31 and UL34 proteins

HDAC6 Triggers the ATM-Dependent DNA Damage Response To Promote PRV Replication

Phosphoproteomic landscape of pseudorabies virus infection reveals multiple potential antiviral targets

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