Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Inhibits Major Histocompatibility Complex Class II Expression by Disrupting Enhanceosome Assembly through Binding with the Regulatory Factor X Complex

Thakker, Suhani; Purushothaman, Pravinkumar; Gupta, Namrata; Challa, Shanthan; Cai, Qiliang; Verma, Subhash C.

doi:10.1128/jvi.03713-14

Cited by 28 publications

(31 citation statements)

References 79 publications

(109 reference statements)

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“…6B, lower right). This difference may be due to the fact that HLA-DR␣ is regulated not only by RTA but also by the KSHV antigen LANA, a latency-associated protein which can transcriptionally inhibit MHC-II molecules, including HLA-DR␣ (42,45). Similar to previous studies, in this study we showed that exogenously expressed LANA can inhibit the MHC-II molecules, including HLA-DR␣ in BJAB cells (Fig.…”

Section: Resultssupporting

confidence: 77%

“…Regulation of MHC-II molecules during the KSHV latent cycle by LANA has been well reported (42,45). However, how KSHV regulates MHC-II molecules during KSHV de novo infection remains largely unknown.…”

Section: Resultsmentioning

confidence: 99%

“…K3 and K5 encoded by KSHV induce the internalization and degradation of MHC-I molecules (11,13,25). LANA, the major latency antigen, inhibits the expression of MHC-II through binding to the RFX and IRF4 (42,45). Recently, studies showed that primary effusion lymphoma (PEL) cells lost the capability to be recognized by specific CD4 T cell clones.…”

Section: Discussionmentioning

confidence: 99%

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Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8

Sun

Jha

Pei

2016

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) maintains two modes of life cycle, the latent and lytic phases. To evade the attack of the cell host's immune system, KSHV switches from the lytic to the latent phase, a phase in which only a few of viral proteins are expressed. The mechanism by which KSHV evades the attack of the immune system and establishes latency has not been fully understood. Major histocompatibility complex class II (MHC-II) molecules are key components of the immune system defense mechanism against viral infections. Here we report that HLA-DR␣, a member of the MHC-II molecules, was downregulated by the replication and transcription activator (RTA) protein encoded by KSHV ORF50, an important regulator of the viral life cycle. RTA not only downregulated HLA-DR␣ at the protein level through direct binding and degradation through the proteasome pathway but also indirectly downregulated the protein level of HLA-DR␣ by enhancing the expression of MARCH8, a member of the membrane-associated RING-CH (MARCH) proteins. Our findings indicate that KSHV RTA facilitates evasion of the virus from the immune system through manipulation of HLA-DR␣. IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) has a causal role in a number of human cancers, and its persistence in infected cells is controlled by the host's immune system. The mechanism by which KSHV evades an attack by the immune system has not been well understood. This work represents studies which identify a novel mechanism by which the virus can facilitate evasion of an immune system. We now show that RTA, the replication and transcription activator encoded by KSHV (ORF50), can function as an E3 ligase to degrade HLA-DR␣. It can directly bind and induce degradation of HLA-DR␣ through the ubiquitin-proteasome degradation pathway. In addition to the direct regulation of HLA-DR␣, RTA can also indirectly downregulate the level of HLA-DR␣ protein by upregulating transcription of MARCH8. Increased MARCH8 results in the downregulation of HLA-DR␣. Furthermore, we also demonstrate that expression of HLA-DR␣ was impaired in KSHV de novo infection. K aposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is a Rhadinovirus belonging to the Gammaherpesvirinae subfamily. It was discovered in Kaposi's sarcoma (KS) lesions and is also associated with primary effusion lymphoma (PEL) and multicentric Castleman's disease (1-3). Almost 20% of all human malignancies are caused by viruses (4). The majority of infected individuals do not develop tumors, although immunosuppressive conditions like AIDS and organ transplantation can dramatically increase the risk of developing a malignancy. This suggests an active role for the host immune system in controlling KSHV infections (5, 6). During its coevolution with the host, KSHV hijacks and manipulates many of the host machineries to override the host immune surveillance (7,8). The host ubiquitin system has fundamental roles in regulating cellular events, like protein degradation and...

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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8

Sun

Jha

Pei

2016

J Virol

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“…The processed forms of LANA resulting from caspase cleavage blunt apoptosis and caspase 1-mediated inflammasome in KSHV-infected cells exposed to oxidative stress (24). LANA is also involved in the modulation of adaptive immunity by inhibiting antigen presentation of both major histocompatibility complex class I (MHC I) and class II (MHC II) (25)(26)(27)(28). Meanwhile, host restriction factors inhibit KSHV infection by activating immune responses.…”

mentioning

confidence: 99%

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Zhang

Chan

Samarina

et al. 2016

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

130

140

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The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGASmediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.KSHV | cytoplasmic LANA | cyclic GMP-AMP synthase

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“…Approximately 2 × 10 6 293T cells were grown overnight per well in a 6 well plate. The target cells were transiently transfected with specific plasmids using Metafectene (Biontex Laboratories) as described previously [99]. Twenty-four hours post-transfection, the medium was changed and incubated with fresh medium.…”

Section: Luciferase Reporter Assaymentioning

confidence: 99%

Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators

Sarkar

Verma

2017

Oncotarget

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Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Inhibits Major Histocompatibility Complex Class II Expression by Disrupting Enhanceosome Assembly through Binding with the Regulatory Factor X Complex

Cited by 28 publications

References 79 publications

Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8

Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators

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