Inhibition of RIG-I-Mediated Signaling by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Deubiquitinase ORF64

Inn, Kyung‐Soo; Lee, Sun-Hwa; Rathbun, Jessica Y.; Wong, Li Chin; Tóth, Zsolt; Machida, Keigo; Ou, Jing-hsiung James; Jung, Jae U.

doi:10.1128/jvi.00690-11

Cited by 141 publications

(156 citation statements)

References 41 publications

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“…ORF64 is another conserved herpesviral tegument protein that encodes potent deubiquitinating activity (57). ORF64 can reduce TRIM25-dependent ubiquitination and activation of RIG-I, thereby inhibiting this sensing pathway in KSHV-infected cells (40).…”

Section: Latent Kshv Infection and Reactivationmentioning

confidence: 99%

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Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

171

152

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Section: Latent Kshv Infection and Reactivationmentioning

confidence: 99%

“…Infant, aging-, chemical-, or HIV-induced immune deficiency is an essential cofactor for the development of KS. production and suppresses viral gene expression following de novo infection with KSHV as well as during viral reactivation (39,40).…”

Section: Introductionmentioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

171

152

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“…This necessarily implicates the prior addition of ubiquitin as a factor in disease progression, either as part of the virus neuroinvasive program or as a cellular defense mechanism that is overcome by the DUB. Although several substrates of the DUB have been identified, how this enzyme promotes the potent neuroinvasive property of these viruses is unknown (23)(24)(25)(26)(27)(28)(29)(30). To elucidate the role of the DUB, we set out to examine the role of ubiquitination during neuroinvasive herpesvirus infection.…”

mentioning

confidence: 99%

Dynamic ubiquitination drives herpesvirus neuroinvasion

Huffmaster

Sollars

Richards

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Neuroinvasive herpesviruses display a remarkable propensity to enter the nervous system of healthy individuals in the absence of obvious trauma at the site of inoculation. We document a repurposing of cellular ubiquitin during infection to switch the virus between two invasive states. The states act sequentially to defeat consecutive host barriers of the peripheral nervous system and together promote the potent neuroinvasive phenotype. The first state directs virus access to nerve endings in peripheral tissue, whereas the second delivers virus particles within nerve fibers to the neural ganglia. Mutant viruses locked in either state remain competent to overcome the corresponding barrier but fail to invade the nervous system. The herpesvirus “ubiquitin switch” may explain the unusual ability of these viruses to routinely enter the nervous system and, as a consequence, their prevalence in human and veterinary hosts.

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“…Although the USP activity in MHV-68 does not seem to be involved in the establishment of latency or reactivation, loss of the USP function by a site mutation compromises in vitro virus replication and persistent infection in vivo (26). In addition, ORF64 has been reported to inhibit type I interferon production, suggesting that it may play a role in allowing the virus to evade host immunity (27).…”

mentioning

confidence: 99%

ZAP Inhibits Murine Gammaherpesvirus 68 ORF64 Expression and Is Antagonized by RTA

Xuan

Gong

et al. 2013

J Virol

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bZinc finger antiviral protein (ZAP) is an interferon-inducible host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1 and Ebola virus. ZAP functions as a dimer formed through intermolecular interactions of its N-terminal tails. ZAP binds directly to specific viral mRNAs and inhibits their expression by repressing translation and/or promoting degradation of the target mRNA. ZAP is not a universal antiviral factor, since some viruses grow normally in ZAP-expressing cells. It is not fully understood what determines whether a virus is susceptible to ZAP. We explored the interaction between ZAP and murine gammaherpesvirus 68 (MHV-68), whose life cycle has latent and lytic phases. We previously reported that ZAP inhibits the expression of M2, which is expressed mainly in the latent phase, and regulates MHV-68 latency in cultured cells. Here, we report that ZAP inhibits the expression of ORF64, a tegument protein that is expressed in the lytic phase and is essential for lytic replication. MHV-68 infection induced ZAP expression. However, ZAP did not inhibit lytic replication of MHV-68. We provide evidence showing that the antiviral activity of ZAP is antagonized by MHV-68 RTA, a critical viral transactivator expressed in the lytic phase. We further show that RTA inhibits the antiviral activity of ZAP by disrupting the N-terminal intermolecular interaction of ZAP. Our results provide an example of how a virus can escape ZAP-mediated immunity.

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Inhibition of RIG-I-Mediated Signaling by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Deubiquitinase ORF64

Abstract: Virus infection triggers interferon (IFN)-

Cited by 141 publications

References 41 publications

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dynamic ubiquitination drives herpesvirus neuroinvasion

ZAP Inhibits Murine Gammaherpesvirus 68 ORF64 Expression and Is Antagonized by RTA

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