Transcriptional and Post-Transcriptional Regulation of Viral Gene Expression in the Gamma-Herpesvirus Kaposi’s Sarcoma-Associated Herpesvirus

Butnaru, Matthew; Gaglia, Marta Maria

doi:10.1007/s40588-018-0102-1

Cited by 3 publications

(2 citation statements)

References 111 publications

(189 reference statements)

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“…Because ORF42 is itself expressed with late kinetics, the easiest explanation is that early proteins have already accumulated to some level by the time ORF42 is expressed, and thus the impact of ORF42 activity on their levels is lower. However, we cannot exclude the possibility that late protein translation in general or production of specific KSHV virion proteins requires additional cellular and/or viral factors that are dispensable for early protein expression, as is the case for late gene transcription [59]. It will also be interesting to determine whether ORF42 has any effect on cellular protein production, since we observed an ORF42-dependent change in total protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

The Kaposi’s Sarcoma-Associated Herpesvirus Protein ORF42 Is Required for Efficient Virion Production and Expression of Viral Proteins

Butnaru

Gaglia

2019

Viruses

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Kaposi’s sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi’s sarcoma and other aggressive AIDS-associated malignancies, encodes over 90 genes, most of which are expressed only during the lytic replication cycle. The role of many of the KSHV lytic proteins in the KSHV replication cycle remains unknown, and many proteins are annotated based on known functions of homologs in other herpesviruses. Here we investigate the role of the previously uncharacterized KSHV lytic protein ORF42, a presumed tegument protein. We find that ORF42 is dispensable for reactivation from latency but is required for efficient production of viral particles. Like its alpha- and beta-herpesviral homologs, ORF42 is a late protein that accumulates in the viral particles. However, unlike its homologs, ORF42 appears to be required for efficient expression of at least some viral proteins and may potentiate post-transcriptional stages of gene expression. These results demonstrate that ORF42 has an important role in KSHV replication and may contribute to shaping viral gene expression.

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Section: Discussionmentioning

confidence: 99%

The Kaposi’s Sarcoma-Associated Herpesvirus Protein ORF42 Is Required for Efficient Virion Production and Expression of Viral Proteins

Butnaru

Gaglia

2019

Viruses

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“…KSHV-encoded LANA, vCyclin and vFLIP are expressed from the same polycistronic operon, however, their expression at the transcript or protein remains different (Toth et al, 2010;Kumar Singh et al, 2021). This further indicate role of posttranscriptional and post-translational regulation for the expression of KSHV encoded genes (Campbell and Izumiya, 2012;Butnaru and Gaglia, 2018;Singh et al, 2018). The LANA protein is essential for attaching viral episomal DNA with host chromosome where its binds with its N-terminal region with KSHV episome and with its C-terminal region with host chromosome (Lu et al, 2012;Vazquez Ede et al, 2013).…”

Section: Introductionmentioning

confidence: 95%

Targeting Kaposi’s sarcoma associated herpesvirus encoded protease (ORF17) by a lysophosphatidic acid molecule for treating KSHV associated diseases

Rafeeq¹,

Habib²,

Nahhas

et al. 2023

Front. Cell Dev. Biol.

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Kaposi’s sarcoma associated herpesvirus (KSHV) is causative agent of Kaposi’s sarcoma, Multicentric Castleman Disease and Pleural effusion lymphoma. KSHV-encoded ORF17 encodes a protease which cleaves -Ala-Ala-, -Ala-Ser- or -Ala-Thr-bonds. The protease plays an important role in assembly and maturation of new infective virions. In the present study, we investigated expression pattern of KSHV-encoded protease during physiologically allowed as well as chemically induced reactivation condition. The results showed a direct and proportionate relationship between ORF17 expression with reactivation time. We employed virtual screening on a large database of natural products to identify an inhibitor of ORF17 for its plausible targeting and restricting Kaposi’s sarcoma associated herpesvirus assembly/maturation. A library of 307,814 compounds of biological origin (A total 481,799 structures) has been used as a screen library. 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1′-myo-inositol) was highly effective against ORF17 in in-vitro experiments. The screened compound was tested for the cytotoxic effect and potential for inhibiting Kaposi’s sarcoma associated herpesvirus production upon induced reactivation by hypoxia, TPA and butyric acid. Treatment of reactivated KSHV-positive cells with 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1′-myo-inositol) resulted in significant reduction in the production of Kaposi’s sarcoma associated herpesvirus. The study identified a lysophosphatidic acid molecule for alternate strategy to inhibit KSHV-encoded protease and target Kaposi’s sarcoma associated herpesvirus associated malignancies.

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A screen for gene regulators encoded by Kaposi’s sarcoma-associated herpesvirus uncovers a novel role for the ORF42 protein in regulating the production of cellular and viral proteins

Butnaru

Rivas

Gaglia³

2018

Preprint

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17The tight control of viral and host gene expression is critical to the replication of herpesviruses, 18 including the gamma-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV). While 19 some of the KSHV proteins that contribute to viral and host gene regulation are known, it is clear 20 that there are additional uncharacterized contributing viral factors. Identifying these proteins and 21 their role in gene regulation is important to determine the mechanistic underpinnings of the 22 complex replication cycle of KSHV. Through a reporter-based screen, we have identified several 23 new potential KSHV-encoded gene regulators, including the previously uncharacterized protein 24 ORF42, which we find stimulates global protein production upon overexpression. We have 25 generated an ORF42-null virus, which revealed that ORF42 is required for wild-type levels of 26 virus production. Moreover, global protein synthesis and the accumulation of viral proteins are 27 reduced in infected cells in the absence of ORF42, suggesting that ORF42 regulates protein 28 synthesis during infection. A comparison of the effects of ORF42 on the levels of RNA and 29 protein suggests that ORF42 acts post-transcriptionally to control protein levels. In addition to 30 gene regulation, ORF42 may have other functions in virion formation, as it is found in viral 31 particles, which is consistent with the described roles of the ORF42 homologs in alpha-and beta-32 herpesviruses. 33 3 Importance 34 Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, an AIDS-associated 35 malignancy that remains one of the leading causes of cancer deaths in sub-Saharan Africa. 36 Replication of the virus is important for tumor formation and inhibition of viral replication may 37 be used for treatment. The correct levels and temporal expression of viral and host genes during 38 KSHV replication are key to viral replication, but the mechanisms that control this regulation 39 remain enigmatic. Here we identify several new KSHV proteins involved in viral and cellular 40 gene regulation and characterize the previously unstudied KSHV ORF42 protein in regulation of 41 viral and host protein levels and efficient formation of viral progeny. 42 4 Introduction 43

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Transcriptional and Post-Transcriptional Regulation of Viral Gene Expression in the Gamma-Herpesvirus Kaposi’s Sarcoma-Associated Herpesvirus

Cited by 3 publications

References 111 publications

The Kaposi’s Sarcoma-Associated Herpesvirus Protein ORF42 Is Required for Efficient Virion Production and Expression of Viral Proteins

The Kaposi’s Sarcoma-Associated Herpesvirus Protein ORF42 Is Required for Efficient Virion Production and Expression of Viral Proteins

Targeting Kaposi’s sarcoma associated herpesvirus encoded protease (ORF17) by a lysophosphatidic acid molecule for treating KSHV associated diseases

A screen for gene regulators encoded by Kaposi’s sarcoma-associated herpesvirus uncovers a novel role for the ORF42 protein in regulating the production of cellular and viral proteins

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