VHS, US3 and UL13 viral tegument proteins are required for Herpes Simplex Virus-Induced modification of protein kinase R

Pennisi, Rosamaria; Musarra‐Pizzo, Maria; Lei, Zhixiang; Zhou, Grace Guoying; Sciortino, Maria Teresa

doi:10.1038/s41598-020-62619-2

Cited by 15 publications

(16 citation statements)

References 68 publications

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“…For example, UL12.5 proteins degrade mitochondrial DNA [15], and UL7 and UL16 also target mitochondria [14,26,27]. On the other hand, US3 and UL13 encode protein kinases that participate in the process of protein phosphorylation [28,29]. Our study con rmed that HSV-1 UL43 protein is target to mitochondria and affects the channel transport function of mitochondrial ATP production.…”

Section: Discussionmentioning

confidence: 54%

Herpes simplex type 1 UL43 multiple membrane-spanning protein increases energy metabolism in of host cells through interacting with ARL2

Deng¹,

Zhong²,

Geng³

et al. 2022

Preprint

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Non-essential proteins for viral replication affect host cell metabolism, while the function of the UL43 protein of herpes simplex virus 1 (HSV-1) is not clear. Herein, we performed a comprehensive microarray analysis of HUVEC cells infected with HSV-1 and its UL43-deficient mutant and found significant variation in genes associated with cellular energy metabolic pathways. The localization of UL43 protein in host cells and how it affects cellular energy metabolism pathways were further investigated. Internalization analysis showed that UL43 protein could be endocytosis mediated by YPLF motif (aa144–147) and localized to mitochondria. At the same time, more ATP was produced by coupling with mitochondrial small G protein ARF-like 2 (ARL2) GTPase, which triggered the phosphorylation of ANT1 (SLC25A4) to affect the opening degree of mitochondrial permeability transition pore (mPTP), and significantly promoted the aerobic oxidation and oxidative phosphorylation of glucose. Our study shows that UL43 mediates the improvement of host cell metabolism after HSV-1 infection. Also, UL43 protein could be a valuable ATP stimulating factor for mammalian cells.

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Section: Discussionmentioning

confidence: 54%

Herpes simplex type 1 UL43 multiple membrane-spanning protein increases energy metabolism in of host cells through interacting with ARL2

Deng¹,

Zhong²,

Geng³

et al. 2022

Preprint

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“…Additionally, fluorescence microscope analyses were performed to verify the accumulation of p18-fragment in actively replicating cells. To this purpose, THP-1 cells were infected or not with a recombinant virus expressing the viral capsid VP26 tagged with GFP (HSV-1-VP26GFP) 19 . As shown in Figure 1 f, uninfected cells showed fluorescence corresponding to the basal level of caspase-8.…”

Section: Resultsmentioning

confidence: 99%

“…In this scenario, the apoptosis pathway represents an innate immune response activated in order to restrict viral replication. In this regard, HSV-1 has evolved several immune escape strategies which involve the production of virulence factors 19 . The immune cells such as lymphocytes, monocytes/macrophages and dendritic cells, sustain a low-productive infection characterized by induction of apoptosis as cytopathic effect.…”

Section: Discussionmentioning

confidence: 99%

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Direct cleavage of caspase-8 by herpes simplex virus 1 tegument protein US11

Musarra‐Pizzo

Pennisi

Lombardo

et al. 2022

Sci Rep

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The HSV-1 tegument protein Us11 counteracts the antiviral defense mechanisms by precluding the host protein shutoff. Previous works demonstrated that Us11 prevents heat-and staurosporine-induced apoptosis and inhibits autophagy. Therefore, in the present study, we investigated the hypothesis that HSV-1, through Us11, could recruit caspase-8, a key enzyme regulating programmed cell death. We first show that HSV-1 promotes the accumulation of caspase-8-p18 active fragments in both semi permissive THP-1 cells and fully permissive HEp-2 cells to HSV-1 replication. Using a recombinant virus R3630 (ΔUs11/ΔUs12) and a plasmid encoding Us11-recombinant protein we have proven that Us11 promotes p18 accumulation, which does not trigger the apoptotic signaling. Additional, in an in vitro model, we demonstrated that Us11-recombinant protein induces caspase-8-p18 cleavage by physically interacting with the caspase-8 recombinant protein. Finally, we found that, during HSV-1 replication, activated-caspase-8 cleaves Atg3 protein to potentially block autophagy and support its replication.

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“…U L 13 has been found to be important for the induction of a set of suppression of cytokine signaling (SOCS) genes late during infection, which is important for blocking the interferon response during HSV-1 infection of cells [ 602 , 603 , 604 , 605 ]. Recently, U L 13 was found with the other viral kinase U S 3 to be important for regulating phosphorylation of protein kinase R (a nucleic acid sensor) during infection [ 606 ]. U L 13 was also found to hyperphosphorylate an important host factor for the elongation of peptide chains during mRNA translation, eF-1δ during HSV-1 infection, supporting viral protein synthesis, and also preventing apoptosis [ 607 , 608 , 609 ].…”

Section: Viral Kinasesmentioning

confidence: 99%

“Non-Essential” Proteins of HSV-1 with Essential Roles In Vivo: A Comprehensive Review

Dogrammatzis

Waisner

Kalamvoki

2020

Viruses

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Viruses encode for structural proteins that participate in virion formation and include capsid and envelope proteins. In addition, viruses encode for an array of non-structural accessory proteins important for replication, spread, and immune evasion in the host and are often linked to virus pathogenesis. Most virus accessory proteins are non-essential for growth in cell culture because of the simplicity of the infection barriers or because they have roles only during a state of the infection that does not exist in cell cultures (i.e., tissue-specific functions), or finally because host factors in cell culture can complement their absence. For these reasons, the study of most nonessential viral factors is more complex and requires development of suitable cell culture systems and in vivo models. Approximately half of the proteins encoded by the herpes simplex virus 1 (HSV-1) genome have been classified as non-essential. These proteins have essential roles in vivo in counteracting antiviral responses, facilitating the spread of the virus from the sites of initial infection to the peripheral nervous system, where it establishes lifelong reservoirs, virus pathogenesis, and other regulatory roles during infection. Understanding the functions of the non-essential proteins of herpesviruses is important to understand mechanisms of viral pathogenesis but also to harness properties of these viruses for therapeutic purposes. Here, we have provided a comprehensive summary of the functions of HSV-1 non-essential proteins.

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VHS, US3 and UL13 viral tegument proteins are required for Herpes Simplex Virus-Induced modification of protein kinase R

Cited by 15 publications

References 68 publications

Herpes simplex type 1 UL43 multiple membrane-spanning protein increases energy metabolism in of host cells through interacting with ARL2

Herpes simplex type 1 UL43 multiple membrane-spanning protein increases energy metabolism in of host cells through interacting with ARL2

Direct cleavage of caspase-8 by herpes simplex virus 1 tegument protein US11

“Non-Essential” Proteins of HSV-1 with Essential Roles In Vivo: A Comprehensive Review

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