Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Ubiquitin E3 Ligases Have Stage-Specific Immune Evasion Roles during Lytic Replication

Brulois, Kevin; Tóth, Zsolt; Wong, Li Chin; Feng, Pinghui; Gao, Shou‐Jiang; Ensser, Armin; Jung, Jae U.

doi:10.1128/jvi.00873-14

Cited by 71 publications

(93 citation statements)

References 112 publications

(153 reference statements)

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“…8A and B). A number of E3 ubiquitin ligases have been reported for KSHV, including K5, K7, and ORF50 (RTA) (90)(91)(92). All three of these proteins are early lytic proteins induced within 12 h of lytic induction.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency

Roy

Dutta

Iqbal

et al. 2016

J Virol

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IMPORTANCELike all herpesviruses, latency is an integral part of the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), an etiological agent for many human cancers. Herpesviruses utilize viral and host factors to successfully evade the host immune system to maintain latency. Reactivation is a complex event where the latent episomal viral genome springs back to active transcription of lytic cycle genes. Our studies reveal that KSHV has evolved to utilize the innate immune sensor IFI16 to keep lytic cycle transcription in dormancy. We demonstrate that IFI16 binds to the lytic gene promoter, acts as a transcriptional repressor, and thereby helps to maintain latency. We also discovered that during the late stage of lytic replication, KSHV selectively degrades IFI16, thus relieving transcriptional repression. This is the first report to demonstrate the role of IFI16 in latency maintenance of a herpesvirus, and further understanding will lead to the development of strategies to eliminate latent infection. The human gammaherpesvirus Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also referred to as human herpesvirus 8 (HHV-8), is an oncogenic virus etiologically associated with KS, primary effusion B-cell lymphoma (PEL) or body cavity B-cell lymphoma (BCBL), and plasmablastic multicentric Castleman's disease (pMCD) (1-3). In vivo, KSHV DNA and transcripts have been identified in human B cells, endothelial cells, epithelial cells, macrophages, and keratinocytes (3, 4). Similar to other herpesviruses, KSHV undergoes two distinguishable phases in its life cycle: latent and lytic infection (3, 4). During primary infection, KSHV initially establishes latent infection in specific target cells, during which multiple copies of the viral genome are stably maintained as extrachromosomal episomes (3,5). Only a few viral genes, primarily localized in the major latency locus of the genome, are expressed during this phase. These gene products bestow numerous essential functionalities to the dormant viral genome, such as evading host immune surveillance (6), promoting cellular proliferation (7-9), maintaining the viral episome (10), and tightly suppressing viral lytic gene expression (11). However, both spontaneous reactivation and induced reactivation of the latent genome occur, resulting in the systematic expression of the full repertoire of viral genes, which leads to viral genome replication and virion production (4). Previous studies suggested that lytic reactivation

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Section: Discussionmentioning

confidence: 99%

Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency

Roy

Dutta

Iqbal

et al. 2016

J Virol

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“…KSHV also encodes genes that inhibit these immune responses. KSHV K3/MIR1 and K5/ MIR2 are ubiquitin ligases that inhibit MHC class I display (68,69). K3/MIR 1 downregulates four HLA allotypes (HLA-A, B, C, and E), while K5/MIR2 downregulates HLA-A and HLA-B (70,71).…”

Section: Latent Kshv Infection and Reactivationmentioning

confidence: 99%

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

Dittmer

Damania

2016

Journal of Clinical Investigation

175

152

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“…The targeting of MHC molecules for ubiquitination has been described for other viral immune evasion proteins, but the mechanism of action of BDLF3 is clearly distinct. An example is the K3 and K5 proteins encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), which function as two membrane-bound E3 ubiquitin ligases and have been shown to facilitate the rapid endocytosis and subsequent degradation of MHC class I by inducing ubiquitination (32)(33)(34)(35)(36)(37). Unlike K3 and K5, there is no evidence to show that BDLF3 itself is an E3 ubiquitin ligase; therefore, it is very likely that BDLF3 functions via a different mechanism.…”

Section: Discussionmentioning

confidence: 99%

The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II

Quinn

Williams

White

et al. 2016

J Virol

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The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8؉ cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8 ؉ cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8 ؉ cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4 ؉ cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8؉ and CD4 ؉ T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. IMPORTANCE Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8؉ T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8 ؉ T cells specific for early lytic cycle antigens. The present work identifies an additional immune evasion protein, BDLF3, that is expressed late in the lytic cycle and impairs CD8 ؉ T cell recognition by targeting cell surface MHC class I molecules for ubiquitination and proteasome-dependent downregulation. Interestingly, BDLF3 also targets MHC class II molecules to impair CD4 ؉ T cell recognition. BDLF3 is therefore a rare example of a viral protein that impairs both the MHC class I and class II antigen-presenting pathways. E pstein-Barr virus (EBV) is a gammaherpesvirus found in more than 90% of the human population. Primary infection with EBV is usually followed by establishment of a lifelong latent infection, with occasional reactivation (1). The balance between host immune responses, including CD4 ϩ and CD8 ϩ T cells, and viral immune evasion of these responses is key to the spread and survival of EBV in human populations. Passive evasion through the ability to establish antigenically silent latent infections is an important characteristic of all herpesviruses, ...

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Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Ubiquitin E3 Ligases Have Stage-Specific Immune Evasion Roles during Lytic Replication

Cited by 71 publications

References 112 publications

Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency

Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency

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

The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II

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